hypertension and htpr (high on treatment platelet reactivity measured by aggregometry)
TRANSCRIPT
Mr sci med Dragana Šarenac
ICVD DEDINJE- Beograd
IS THERE A CONNECTION BETWEEN HYPERTENSION AND
HTPR (HIGH ndash ON TREATMENT PLATELET REACTIVITY MEASURED BY
AGREGOMETRY))
3 MAIN FACTORS OF THROMBOGENESIS Virchow Triada (1856)
HYPERTENSION
HYPERTENSION ndash SILENT KILLER
1993
bull Platelet indexes in relation to target organ damage in high-risk hypertensive patients A
substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)FREE Sunil K
Nadar MRCP Andrew D Blann PhD Sridhar Kamath MRCP DGareth Beevers MD
FRCP Gregory YH Lip MD
bull J Am Coll Cardiol 200444(2)415-422 doi101016jjacc200403067
IN pts with HYPERTENSION there are EVIDENCE of physiological changes in Platelets
They are BIGGER MORE VOLUMEN and DEFORMATION
USE of Aspirin deacreased selectin level on the surface
Those changes influence the pathophysiology of CV-events in pts with HTA
bull STRUCTURAL
HYPERTENSION AND MICROCELULAR PLATELET CHANGES
bull FUNCTIONAL
THERE ARE NOT ENOUGH STUDIES CONSIDERING CONNECTION OF HTA AND HTPR
( RESIDUAL PLATELET REACTIVITY
Clinical Science (2004) 107 (391ndash397) (Printed in Great Britain)
Diminished L-arginine bioavailability in hypertension
Monique B MOSS Tatiana M C BRUNINI et alLaboratoacuterio de Transporte de Membrana Departamento
de Farmacologia e Psicobiologia Universidade do Estado do Rio de Janeiro
HTA is connected with L Arginin
transport inhibition thus decreased
availability NO in Plt
PROOF
bull Oral supplementation with a combination of L-citrulline and L-arginine rapidly
increases plasma L-arginine concentration and enhances NO bioavailability Masahiko
Moritaa Toshio Hayash Biochem Biophys Res Commun 2014 Nov 7 Volume 454 Issue 1
bull J Cardiovasc Pharmacol Ther 2011 Mar16(1)53-62 Protective effect of L-
arginine in experimentally induced myocardial ischemia comparison with aspirin
Saleh AI1 Abdel Maksoud SM
L-arginine supplementation represents a potentially novel nutritional strategy for preventing and
treating coronary artery diseases especially in cases of aspirin resistance andor hypersensitivity
( but In EXPERimental animals
L- ARGININ ndash PRECURSO NOHAS A POTENTIAL BUT
HTA NO ADHERENCE amp AGREGATION OF PLT
ESSENTIAL HYPERTENSION amp ATHEROTHROMBOSIS
-PLAQUE RUPTURE amp PLATELET ACTIVATION ndash
STIMULACIJA RECEPTORA P2Y12 SEKRECIJOM ADP
Klopidogrel specifično i ireverzibilno inhibiše P2Y12 subjedinicu ADP receptora To je važno
u aktivaciji trombocita i njihovoj agregaciji preko fibrinske mreže
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
3 MAIN FACTORS OF THROMBOGENESIS Virchow Triada (1856)
HYPERTENSION
HYPERTENSION ndash SILENT KILLER
1993
bull Platelet indexes in relation to target organ damage in high-risk hypertensive patients A
substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)FREE Sunil K
Nadar MRCP Andrew D Blann PhD Sridhar Kamath MRCP DGareth Beevers MD
FRCP Gregory YH Lip MD
bull J Am Coll Cardiol 200444(2)415-422 doi101016jjacc200403067
IN pts with HYPERTENSION there are EVIDENCE of physiological changes in Platelets
They are BIGGER MORE VOLUMEN and DEFORMATION
USE of Aspirin deacreased selectin level on the surface
Those changes influence the pathophysiology of CV-events in pts with HTA
bull STRUCTURAL
HYPERTENSION AND MICROCELULAR PLATELET CHANGES
bull FUNCTIONAL
THERE ARE NOT ENOUGH STUDIES CONSIDERING CONNECTION OF HTA AND HTPR
( RESIDUAL PLATELET REACTIVITY
Clinical Science (2004) 107 (391ndash397) (Printed in Great Britain)
Diminished L-arginine bioavailability in hypertension
Monique B MOSS Tatiana M C BRUNINI et alLaboratoacuterio de Transporte de Membrana Departamento
de Farmacologia e Psicobiologia Universidade do Estado do Rio de Janeiro
HTA is connected with L Arginin
transport inhibition thus decreased
availability NO in Plt
PROOF
bull Oral supplementation with a combination of L-citrulline and L-arginine rapidly
increases plasma L-arginine concentration and enhances NO bioavailability Masahiko
Moritaa Toshio Hayash Biochem Biophys Res Commun 2014 Nov 7 Volume 454 Issue 1
bull J Cardiovasc Pharmacol Ther 2011 Mar16(1)53-62 Protective effect of L-
arginine in experimentally induced myocardial ischemia comparison with aspirin
Saleh AI1 Abdel Maksoud SM
L-arginine supplementation represents a potentially novel nutritional strategy for preventing and
treating coronary artery diseases especially in cases of aspirin resistance andor hypersensitivity
( but In EXPERimental animals
L- ARGININ ndash PRECURSO NOHAS A POTENTIAL BUT
HTA NO ADHERENCE amp AGREGATION OF PLT
ESSENTIAL HYPERTENSION amp ATHEROTHROMBOSIS
-PLAQUE RUPTURE amp PLATELET ACTIVATION ndash
STIMULACIJA RECEPTORA P2Y12 SEKRECIJOM ADP
Klopidogrel specifično i ireverzibilno inhibiše P2Y12 subjedinicu ADP receptora To je važno
u aktivaciji trombocita i njihovoj agregaciji preko fibrinske mreže
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
HYPERTENSION ndash SILENT KILLER
1993
bull Platelet indexes in relation to target organ damage in high-risk hypertensive patients A
substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)FREE Sunil K
Nadar MRCP Andrew D Blann PhD Sridhar Kamath MRCP DGareth Beevers MD
FRCP Gregory YH Lip MD
bull J Am Coll Cardiol 200444(2)415-422 doi101016jjacc200403067
IN pts with HYPERTENSION there are EVIDENCE of physiological changes in Platelets
They are BIGGER MORE VOLUMEN and DEFORMATION
USE of Aspirin deacreased selectin level on the surface
Those changes influence the pathophysiology of CV-events in pts with HTA
bull STRUCTURAL
HYPERTENSION AND MICROCELULAR PLATELET CHANGES
bull FUNCTIONAL
THERE ARE NOT ENOUGH STUDIES CONSIDERING CONNECTION OF HTA AND HTPR
( RESIDUAL PLATELET REACTIVITY
Clinical Science (2004) 107 (391ndash397) (Printed in Great Britain)
Diminished L-arginine bioavailability in hypertension
Monique B MOSS Tatiana M C BRUNINI et alLaboratoacuterio de Transporte de Membrana Departamento
de Farmacologia e Psicobiologia Universidade do Estado do Rio de Janeiro
HTA is connected with L Arginin
transport inhibition thus decreased
availability NO in Plt
PROOF
bull Oral supplementation with a combination of L-citrulline and L-arginine rapidly
increases plasma L-arginine concentration and enhances NO bioavailability Masahiko
Moritaa Toshio Hayash Biochem Biophys Res Commun 2014 Nov 7 Volume 454 Issue 1
bull J Cardiovasc Pharmacol Ther 2011 Mar16(1)53-62 Protective effect of L-
arginine in experimentally induced myocardial ischemia comparison with aspirin
Saleh AI1 Abdel Maksoud SM
L-arginine supplementation represents a potentially novel nutritional strategy for preventing and
treating coronary artery diseases especially in cases of aspirin resistance andor hypersensitivity
( but In EXPERimental animals
L- ARGININ ndash PRECURSO NOHAS A POTENTIAL BUT
HTA NO ADHERENCE amp AGREGATION OF PLT
ESSENTIAL HYPERTENSION amp ATHEROTHROMBOSIS
-PLAQUE RUPTURE amp PLATELET ACTIVATION ndash
STIMULACIJA RECEPTORA P2Y12 SEKRECIJOM ADP
Klopidogrel specifično i ireverzibilno inhibiše P2Y12 subjedinicu ADP receptora To je važno
u aktivaciji trombocita i njihovoj agregaciji preko fibrinske mreže
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
1993
bull Platelet indexes in relation to target organ damage in high-risk hypertensive patients A
substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)FREE Sunil K
Nadar MRCP Andrew D Blann PhD Sridhar Kamath MRCP DGareth Beevers MD
FRCP Gregory YH Lip MD
bull J Am Coll Cardiol 200444(2)415-422 doi101016jjacc200403067
IN pts with HYPERTENSION there are EVIDENCE of physiological changes in Platelets
They are BIGGER MORE VOLUMEN and DEFORMATION
USE of Aspirin deacreased selectin level on the surface
Those changes influence the pathophysiology of CV-events in pts with HTA
bull STRUCTURAL
HYPERTENSION AND MICROCELULAR PLATELET CHANGES
bull FUNCTIONAL
THERE ARE NOT ENOUGH STUDIES CONSIDERING CONNECTION OF HTA AND HTPR
( RESIDUAL PLATELET REACTIVITY
Clinical Science (2004) 107 (391ndash397) (Printed in Great Britain)
Diminished L-arginine bioavailability in hypertension
Monique B MOSS Tatiana M C BRUNINI et alLaboratoacuterio de Transporte de Membrana Departamento
de Farmacologia e Psicobiologia Universidade do Estado do Rio de Janeiro
HTA is connected with L Arginin
transport inhibition thus decreased
availability NO in Plt
PROOF
bull Oral supplementation with a combination of L-citrulline and L-arginine rapidly
increases plasma L-arginine concentration and enhances NO bioavailability Masahiko
Moritaa Toshio Hayash Biochem Biophys Res Commun 2014 Nov 7 Volume 454 Issue 1
bull J Cardiovasc Pharmacol Ther 2011 Mar16(1)53-62 Protective effect of L-
arginine in experimentally induced myocardial ischemia comparison with aspirin
Saleh AI1 Abdel Maksoud SM
L-arginine supplementation represents a potentially novel nutritional strategy for preventing and
treating coronary artery diseases especially in cases of aspirin resistance andor hypersensitivity
( but In EXPERimental animals
L- ARGININ ndash PRECURSO NOHAS A POTENTIAL BUT
HTA NO ADHERENCE amp AGREGATION OF PLT
ESSENTIAL HYPERTENSION amp ATHEROTHROMBOSIS
-PLAQUE RUPTURE amp PLATELET ACTIVATION ndash
STIMULACIJA RECEPTORA P2Y12 SEKRECIJOM ADP
Klopidogrel specifično i ireverzibilno inhibiše P2Y12 subjedinicu ADP receptora To je važno
u aktivaciji trombocita i njihovoj agregaciji preko fibrinske mreže
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull Platelet indexes in relation to target organ damage in high-risk hypertensive patients A
substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)FREE Sunil K
Nadar MRCP Andrew D Blann PhD Sridhar Kamath MRCP DGareth Beevers MD
FRCP Gregory YH Lip MD
bull J Am Coll Cardiol 200444(2)415-422 doi101016jjacc200403067
IN pts with HYPERTENSION there are EVIDENCE of physiological changes in Platelets
They are BIGGER MORE VOLUMEN and DEFORMATION
USE of Aspirin deacreased selectin level on the surface
Those changes influence the pathophysiology of CV-events in pts with HTA
bull STRUCTURAL
HYPERTENSION AND MICROCELULAR PLATELET CHANGES
bull FUNCTIONAL
THERE ARE NOT ENOUGH STUDIES CONSIDERING CONNECTION OF HTA AND HTPR
( RESIDUAL PLATELET REACTIVITY
Clinical Science (2004) 107 (391ndash397) (Printed in Great Britain)
Diminished L-arginine bioavailability in hypertension
Monique B MOSS Tatiana M C BRUNINI et alLaboratoacuterio de Transporte de Membrana Departamento
de Farmacologia e Psicobiologia Universidade do Estado do Rio de Janeiro
HTA is connected with L Arginin
transport inhibition thus decreased
availability NO in Plt
PROOF
bull Oral supplementation with a combination of L-citrulline and L-arginine rapidly
increases plasma L-arginine concentration and enhances NO bioavailability Masahiko
Moritaa Toshio Hayash Biochem Biophys Res Commun 2014 Nov 7 Volume 454 Issue 1
bull J Cardiovasc Pharmacol Ther 2011 Mar16(1)53-62 Protective effect of L-
arginine in experimentally induced myocardial ischemia comparison with aspirin
Saleh AI1 Abdel Maksoud SM
L-arginine supplementation represents a potentially novel nutritional strategy for preventing and
treating coronary artery diseases especially in cases of aspirin resistance andor hypersensitivity
( but In EXPERimental animals
L- ARGININ ndash PRECURSO NOHAS A POTENTIAL BUT
HTA NO ADHERENCE amp AGREGATION OF PLT
ESSENTIAL HYPERTENSION amp ATHEROTHROMBOSIS
-PLAQUE RUPTURE amp PLATELET ACTIVATION ndash
STIMULACIJA RECEPTORA P2Y12 SEKRECIJOM ADP
Klopidogrel specifično i ireverzibilno inhibiše P2Y12 subjedinicu ADP receptora To je važno
u aktivaciji trombocita i njihovoj agregaciji preko fibrinske mreže
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull STRUCTURAL
HYPERTENSION AND MICROCELULAR PLATELET CHANGES
bull FUNCTIONAL
THERE ARE NOT ENOUGH STUDIES CONSIDERING CONNECTION OF HTA AND HTPR
( RESIDUAL PLATELET REACTIVITY
Clinical Science (2004) 107 (391ndash397) (Printed in Great Britain)
Diminished L-arginine bioavailability in hypertension
Monique B MOSS Tatiana M C BRUNINI et alLaboratoacuterio de Transporte de Membrana Departamento
de Farmacologia e Psicobiologia Universidade do Estado do Rio de Janeiro
HTA is connected with L Arginin
transport inhibition thus decreased
availability NO in Plt
PROOF
bull Oral supplementation with a combination of L-citrulline and L-arginine rapidly
increases plasma L-arginine concentration and enhances NO bioavailability Masahiko
Moritaa Toshio Hayash Biochem Biophys Res Commun 2014 Nov 7 Volume 454 Issue 1
bull J Cardiovasc Pharmacol Ther 2011 Mar16(1)53-62 Protective effect of L-
arginine in experimentally induced myocardial ischemia comparison with aspirin
Saleh AI1 Abdel Maksoud SM
L-arginine supplementation represents a potentially novel nutritional strategy for preventing and
treating coronary artery diseases especially in cases of aspirin resistance andor hypersensitivity
( but In EXPERimental animals
L- ARGININ ndash PRECURSO NOHAS A POTENTIAL BUT
HTA NO ADHERENCE amp AGREGATION OF PLT
ESSENTIAL HYPERTENSION amp ATHEROTHROMBOSIS
-PLAQUE RUPTURE amp PLATELET ACTIVATION ndash
STIMULACIJA RECEPTORA P2Y12 SEKRECIJOM ADP
Klopidogrel specifično i ireverzibilno inhibiše P2Y12 subjedinicu ADP receptora To je važno
u aktivaciji trombocita i njihovoj agregaciji preko fibrinske mreže
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
THERE ARE NOT ENOUGH STUDIES CONSIDERING CONNECTION OF HTA AND HTPR
( RESIDUAL PLATELET REACTIVITY
Clinical Science (2004) 107 (391ndash397) (Printed in Great Britain)
Diminished L-arginine bioavailability in hypertension
Monique B MOSS Tatiana M C BRUNINI et alLaboratoacuterio de Transporte de Membrana Departamento
de Farmacologia e Psicobiologia Universidade do Estado do Rio de Janeiro
HTA is connected with L Arginin
transport inhibition thus decreased
availability NO in Plt
PROOF
bull Oral supplementation with a combination of L-citrulline and L-arginine rapidly
increases plasma L-arginine concentration and enhances NO bioavailability Masahiko
Moritaa Toshio Hayash Biochem Biophys Res Commun 2014 Nov 7 Volume 454 Issue 1
bull J Cardiovasc Pharmacol Ther 2011 Mar16(1)53-62 Protective effect of L-
arginine in experimentally induced myocardial ischemia comparison with aspirin
Saleh AI1 Abdel Maksoud SM
L-arginine supplementation represents a potentially novel nutritional strategy for preventing and
treating coronary artery diseases especially in cases of aspirin resistance andor hypersensitivity
( but In EXPERimental animals
L- ARGININ ndash PRECURSO NOHAS A POTENTIAL BUT
HTA NO ADHERENCE amp AGREGATION OF PLT
ESSENTIAL HYPERTENSION amp ATHEROTHROMBOSIS
-PLAQUE RUPTURE amp PLATELET ACTIVATION ndash
STIMULACIJA RECEPTORA P2Y12 SEKRECIJOM ADP
Klopidogrel specifično i ireverzibilno inhibiše P2Y12 subjedinicu ADP receptora To je važno
u aktivaciji trombocita i njihovoj agregaciji preko fibrinske mreže
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull Oral supplementation with a combination of L-citrulline and L-arginine rapidly
increases plasma L-arginine concentration and enhances NO bioavailability Masahiko
Moritaa Toshio Hayash Biochem Biophys Res Commun 2014 Nov 7 Volume 454 Issue 1
bull J Cardiovasc Pharmacol Ther 2011 Mar16(1)53-62 Protective effect of L-
arginine in experimentally induced myocardial ischemia comparison with aspirin
Saleh AI1 Abdel Maksoud SM
L-arginine supplementation represents a potentially novel nutritional strategy for preventing and
treating coronary artery diseases especially in cases of aspirin resistance andor hypersensitivity
( but In EXPERimental animals
L- ARGININ ndash PRECURSO NOHAS A POTENTIAL BUT
HTA NO ADHERENCE amp AGREGATION OF PLT
ESSENTIAL HYPERTENSION amp ATHEROTHROMBOSIS
-PLAQUE RUPTURE amp PLATELET ACTIVATION ndash
STIMULACIJA RECEPTORA P2Y12 SEKRECIJOM ADP
Klopidogrel specifično i ireverzibilno inhibiše P2Y12 subjedinicu ADP receptora To je važno
u aktivaciji trombocita i njihovoj agregaciji preko fibrinske mreže
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
HTA NO ADHERENCE amp AGREGATION OF PLT
ESSENTIAL HYPERTENSION amp ATHEROTHROMBOSIS
-PLAQUE RUPTURE amp PLATELET ACTIVATION ndash
STIMULACIJA RECEPTORA P2Y12 SEKRECIJOM ADP
Klopidogrel specifično i ireverzibilno inhibiše P2Y12 subjedinicu ADP receptora To je važno
u aktivaciji trombocita i njihovoj agregaciji preko fibrinske mreže
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
ESSENTIAL HYPERTENSION amp ATHEROTHROMBOSIS
-PLAQUE RUPTURE amp PLATELET ACTIVATION ndash
STIMULACIJA RECEPTORA P2Y12 SEKRECIJOM ADP
Klopidogrel specifično i ireverzibilno inhibiše P2Y12 subjedinicu ADP receptora To je važno
u aktivaciji trombocita i njihovoj agregaciji preko fibrinske mreže
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
STIMULACIJA RECEPTORA P2Y12 SEKRECIJOM ADP
Klopidogrel specifično i ireverzibilno inhibiše P2Y12 subjedinicu ADP receptora To je važno
u aktivaciji trombocita i njihovoj agregaciji preko fibrinske mreže
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull CHANGES AT THE LEVEL OF CARDIVASCULAR SYSTEM
HYPERTENSION amp PLATELET CHANGES IN THE WHOLE BODY
bull SYMPATICAL NERVOUS SYSTEM
bull VESSEL CHANGES
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
Possible routes leading to and from platelet activation in hypertension
Blann A D et al Hypertension 2003421-7
Copyright copy American Heart Association
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
PLATELETS CHANGES AT THE LEVEL OF INJURED VESSEL WALL ndashIN VITRO MEASSURED BY AGREGGOMETRY
Lab Tests for
measurement
of platelet
function
Hypertension
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
IN VIVO VS IN VITRO ndash CLINICAL IMPLICATIOPNS
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
LABORATORY MEASSUREMENT OF PLATELET FUNCTION
Neubauer and Meves suggest that multiple-electrode aggregometry
would be a better test for the adjustment of antiplatelet therapy than
the VerifyNow assay
DR ČALIJA
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
PRU (platelet
reactivity units)
ndashcutt off - 235-270
- 203
LABORATORY MEASSURES OF PLATELET FUNCTION
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull VerifyNow P2Y12 test - cut off 230-270 PRU (platelet reactivity units)
bull 12 to 24 h r after PCI ( ge12 after loading dose 600 mg clopidogrel just before or after PCI)
bull Percutaneous intervention BY ITSELF CAN ACTIVATE PLATELETS resulting in higher PRU
bull For more REAL meassurement of residual platelet reactivity better to do 3-5 days after AMI
bull PRU measured 1 month after PCI CAN better PREDICT future CV events than to do it just after
discharge
PROSPECTIVE EVALUATION OF ON-CLOPIDOGREL PLATELET REACTIVITY OVER TIME IN PATIENTS TREATED WITH PERCUTAN EOUS CORONARY INTERVENTION RELATIONSHIP WITH GENE POLYMORPHISMS AND C LINICAL OUTCOME CAMPO G PARRINELLO G FERRARESI P J AM COLL CARDIOL 57 20112474-2483
LABORATORY MEASSUREMENT OF PLATELET FUNCTION ndash WHEN TO DO
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
GENETIC VARIABILITY
CITOHROM
P 450
subjedinica
2C192
Clopidogrel- pro-drug
Active
metabolite
Konverting in active
metabolits can be
modified by
bull Genetic variability -
CYP2C19 2
bull Drug Interaction
Pts can be stratified to
ekstensive
intermediare
poor metabolizeres CYP2C19
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
Markers of poor response to clopidogrel
1 Genetics x3 2 Diabetes x2
Hochholzer et al J Am Coll Cardiol 2010
Phase aigue (600mg LD) n=760
Diabetes age and biomarkers of inflammation are
independently associated with platelet aggregation
Platelet reactivity and comorbidities in acute coronary syndrome
Fredrik Bjoumlrklund 2012
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
DACC SCORE PREDICTS HTPR IT DOES NOT PREDICT MACE
DM
ACS
CYP2C192
CYP 2C1917
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull Our study suggests a pathway which might explain indirect and direct impact of variables on clinical
outcome ACS diabetes mellitus CYP2C192 and CYP2C1917 genetic variants independently
predicted HTPR In turn age ge75 years and HTPR were the strongest predictors of MACE
416 pts
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull Plateler response to antiagregatin drugs CAN have direct clinical implications
but MECHANISMS that are responsible for it are NOT QUITE KNOWN
bull Response variability
Genetic polimorphysm of Citohrome
P450
Clinical characteristics of pts
Demographic variables
12 variability of ADP
dependent platelet agregability
of clopidogrel
PUB MED 2012
RESPONSE VARIABILITY
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull J Am Coll Cardiol 2013 Feb 2661(8)872-9 Frelinger AL 3rd1 Bhatt DL Lee RD
bull Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or
control of polymorphisms (CYP2C19 ABCB1 PON1) noncompliance diet smoking co-
medications (including proton pump inhibitors) and pre-existent variability in platelet
function
Thus as yet unidentified factors contribute to high on-treatment platelet
reactivity with its known increased risk of major adverse cardiovascular events
RESPONSE VARIABILITY
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull HTPR- high on treatemnet platelet reactivity maybe is a
RISK FACTOR
and NOT a THERAPEUTIC TARGET
ACC 2014
RESPONSE VARIABILITY
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
DIFFERENT PROGNOSTIC SIGNIFICANCE OF HIGH ON-TREATMENT PLATELET REACTIVITY AS ASSESSED BY THE VERIFYNOW P2Y12 ASSAY AFTER CORONARY STENTING IN PATIENTS WITH AND WITHOUT ACUTE MYOCARDIAL INFARCTION SUNG GYUN AHN MD SEUNG-HWAN LEE (J AM COLL CARDIOL INTV 20125259ndash67)
APS+ ACS withwithout HTPR
APS withwithout HTPR
ACS withwithout HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
In pts after ACS the platelet agregation is increased during
first days no matter if we use DAPT
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull The impact of gene polymorphism and high on-treatment platelet reactivity on clinical follow-up outcomes in patients with acute coronary syndrome after drug-eluting stent implantation Zhen-Yang Liang EuroIntervention 2013 9316-327
bull In patients with ACS the CYP2C19 LOF allele was associated with post-procedure HTPR and a subsequently increased risk of adverse clinical events at one-year follow-up following DES implantation and clopidogrel administration
bull Link to HYPERTENSION ndash p=024
GENETIC VARIABILITY
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull Expert Opin Pharmacother 2015 Feb 71-9 Jiang M1 You JH
bull Review of pharmacoeconomic evaluation of genotype-guided antiplatelet
therapy
Cost-effectiveness of genotype-guided use of antiplatelets
was demonstrated in high-risk ACS patients
GENETIC VARIABILITY
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull JACC Cardiovasc Interv 2013 Nov6(11)1166-75 Viviani Anselmi C1 Briguori C
Routine assessment of on-clopidogrel platelet reactivity and gene polymorphisms in
predicting clinical outcome following drug-eluting stent implantation in patients with
stable coronary artery disease
APS + PCI cum DES ndash 1453 pts
CYP2C19 metabolizer status is an independent predictor of MACE after DES
implantation and can be used for prognostication in all stable CAD patients
HTPR (VerifyNow P2Y12 test) independent predictor of MACE only for high-risk
subsets (patients with diabetes or chronic kidney disease)
bull De Caterina et al TRUST
bull Montalescot MD PhD
Eric Vicaut MD PhD DONT TRUST
Jean-Philippe Collet MD PhD
GENETIC VARIABILITY
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
ARCTIC
ANTARCTIC
Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a
Monitoring-guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption
versus Continuation One Year after Stenting (2445 pts)
Did not show
significant
improvement of clinical events by using
monitoring of platelet
function comparing to
those with standard TH
without measuremetn of
PLt function in stented pts
Assessment of a Normal versus Tailored Dose of Prasugrel after Stenting in Patients Aged gt75
Years to Reduce the Composite of Bleeding Stent Thrombosis and Ischemic Complications
N Engl J Med 2013
Feb 28368(9)871
End date Sept 2015
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
Individual approach
Integrated clinical characteristics and other risk factors --- personalized approach to
antiaggregation TH
Expert Opin Pharmacother 2015 Mar16(4)449-52 Reny JL1 Fontana P
Antiplatelet drugs and platelet reactivity is it time to halt clinical research on tailored strategies
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
bull Platelet Activation in Essential Hypertension During Exercise Pre- and Post-
Treatment Changes With an Angiotensin II Receptor BlockerAm J Hypertens first
published online August 23 2013
bull Hypertension as a Risk Factor for Aspirin and Clopidogrel Resistance in Patients With
Stable Coronary Artery Disease CLIN APPL THROMB HEMOST first published on
March 14 2013 ( higher incidence of antiplatelet resistance in patients with HT (145 pts)
bull Am J Cardiol 2014 Jun 1113(11)1807-14
bull Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention Taglieri N1 Bacchi Reggiani ML2 (14 studies including 11959 patients were eligible )
INTERACTION HTA ndash HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
INTERACTION STATIN ndash CLOPIDOGREL= deacreased mortality
Potential role of ndash PCSK9
Pharmacodynamic effects of adjunctive
high dose atorvastatin on double dose
clopidogrel in patients with high on-
treatment platelet reactivity depending
on diabetes mellitus status
J Thromb Thrombolysis Jul 2013
Mario Leoncini et al
High-dose atorvastatin significantly
improved the PD effects of double-
dose clopidogrel in DM patients with
HTPR undergoing elective PCI
CYP2C19
CYP3A45
atorvastatin
clopidogrel effects
Cardiovasc Ther 2013 Dec31(6)344-51
J Atheroscler Thromb 201421(2)140-50
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
Bez kliničkog značajaAt the moment measuremetn of platelet function considering clopidogrel
CAN NOT be recommended in rutine praxis for elective pts
HAS its ROLE in ACS amp complicated high risk pts
Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients Marie Lordkipanidzeacute
Chantal Pharand European Heart Journal Volume 29 Issue 23Pp 2877-2885
INSTEAD OF CONCLUSION
HYPERTENSION
HTPR
HYPERTENSION
HTPR