zofia oko-sarnowska department of clinical pharmacology

Recommendations for the Recommendations for the pharmacological treatment pharmacological treatment

of atherosclerotic of atherosclerotic cardiovascular disease cardiovascular disease based on clinical trialsbased on clinical trials

Zofia Oko-SarnowskaZofia Oko-Sarnowska

Department of Clinical PharmacologyDepartment of Clinical Pharmacology

Differences between chronic Differences between chronic and acute atherosclerotic and acute atherosclerotic

plaquesplaquesChronic(stable)plaq

ue

Little lipide core Thick fibrous cap A low inflammatory

cells migration A low MMP content

Acute(unstable)plaque

Big lipide core Thin fibrous cap A high inflammatory

cells migration A high MMP content

Pharmacological methods of Pharmacological methods of stabilization of atherosclerotic stabilization of atherosclerotic

plaqueplaque

VPI

TNFαA

MMPI

STATIN

BB

ARBs

ACE-I

APA

AP

Proven effect

Potencial effect

Stabilisation of Stabilisation of atherosclerotic plaqueatherosclerotic plaque

Influence on outside risk factor of transition from Influence on outside risk factor of transition from chronic to acute atherosclerosischronic to acute atherosclerosis -reduction of sudden change of blood -reduction of sudden change of blood pressure pressure -reduction of vasospastic reaction -reduction of vasospastic reaction -reduction of inflammatory process -reduction of inflammatory process

Direct influence on atherosclerotic plaqueDirect influence on atherosclerotic plaque

- decrease volume of lipid core- decrease volume of lipid core - reduction of inflammatory process in situ - reduction of inflammatory process in situ - reduction of MMP concentration - reduction of MMP concentration

Classes of Classes of recommendationsrecommendations

Class I Evidence and/or general agreement that a given diagnostic procedure/treatment is beneficial, useful, and effective

Class II

Class IIa

Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the treatment or procedureWeight of evidence/opinion is in favour of usefullness/efficacy

Class IIb

Usefullness/efficacy is less well established by evidence/opinion

Class III Evidence or general agreement that the treatment or procedure is not useful/effective and in some cases may be harmful

Levels of evidenceLevels of evidence

Level of evidence ALevel of evidence A Data derived from Data derived from multiple randomized multiple randomized clinical trials or meta-clinical trials or meta-analysesanalyses

Level of evidence BLevel of evidence B Data derived from a Data derived from a single randomized single randomized clinical trial or large clinical trial or large non-randomized non-randomized studiesstudies

Level of evidence CLevel of evidence C Consensus of opinion Consensus of opinion of the experts and/or of the experts and/or small studies, small studies, retrospective studies, retrospective studies, registriesregistries


plaqueplaque

VPI

TNFαA

MMPI

STATIN

BB

ARBs

ACE-I

APA

AP

Proven effect

Angiotensin converting Angiotensin converting enzyme inhibitors in enzyme inhibitors in

cardiovacular diseasecardiovacular disease Heart failure (HF)Heart failure (HF) Asymptomatic left ventricular systolic Asymptomatic left ventricular systolic

dysfunction (LVSD)dysfunction (LVSD) Diatolic failureDiatolic failure Acute myocardial infarction (AMI)Acute myocardial infarction (AMI) Hypertension (HT)Hypertension (HT) Secondary prevention and high-risk of Secondary prevention and high-risk of

cardiovascular diseasecardiovascular disease

Indication for ACE-IIndication for ACE-I

Heart failure:Heart failure:CONSENSUS, SAVE, VheFT-IICONSENSUS, SAVE, VheFT-IISOLVD Prevention, SOLVD TreatmentSOLVD Prevention, SOLVD Treatment

LVSD after MI (EF<LVSD after MI (EF<4040%)%)

Trial ACE-I n NNTMortality reduction (RRR)

SAVE kaptopril 2231 42 19%

AIRE ramipril 2006 57 27%

TRACE trandolapril 2606 76 22%

AIREX ramipril 603 114 36%

Use of ACE-I in heart Use of ACE-I in heart failurefailure

Setting/indicationSetting/indication ClassClass LevelLevel

All patients with symptomatic HF All patients with symptomatic HF and reduced LVEF, NYHA II-IVand reduced LVEF, NYHA II-IV

II AA

LVSD with/without symptoms after LVSD with/without symptoms after MIMI

II AA

LVSD (EF < LVSD (EF < 40-4540-45%) without %) without symptoms,symptoms, no previous MI no previous MI

II AA

Diastolic HFDiastolic HF IIaIIa CC

Use of ACE-I in myocardial Use of ACE-I in myocardial infarctioninfarction

Setting/indication Class Level

AMI, first 24h ISIS 4, GISSI-3, CCS-1,CONSENSUS-2, SMILE

High risk (HF, LVD, no reperfusion, large MI

I A

All patients IIa A

Evolving AMI (>24h), Post MI SAVE, AIRE, TRACE,

Clinical HF, asymptomatic LVD (EF<45%)

I A

Diabetes or other high risk patients

I A

Use of ACE-I in hypertensionUse of ACE-I in hypertension

Setting/indicationSetting/indication ClassClass LevelLevel TrialTrial

To control blood To control blood pressurepressure

II AASTOP-2, STOP-2, UKPDS,UKPDS,PROGRESSPROGRESS

Patients with HF, LVSD, Patients with HF, LVSD, diabetics, previous MI diabetics, previous MI or stroke, high coronary or stroke, high coronary disease riskdisease risk

II AA CAPPP, CAPPP, ABCD, ABCD, PROGRESSPROGRESS

Use of ACE-I in secondary Use of ACE-I in secondary prevention and high-risk of prevention and high-risk of

cardiovacular diseasecardiovacular disease

Setting/indicationSetting/indication ClassClass LevelLevel TrialTrial

High-risk patients High-risk patients (evidence of (evidence of cardiovascular cardiovascular disease or diabetes disease or diabetes and one other risk and one other risk factorfactor

II AA

QUIET, QUIET, PEACE, PEACE, HOPE, HOPE, EUROPAEUROPA

ONTAGETONTAGET

Hope studyHope study Enrolled 9297 men and women

age > 55 years old Indications:

1. confirmed arterial disease (CHD, peripheral arterial disease, stroke2. Diabetes and one other risk factor (hypertension, cigarette smoking, micoalbuminuria or dyslipidaemia)

Randomisation to ACE-I (ramipril 2,5-10mg) or placebo

Follow-up: 5 years

Hope studyHope study

Results:Results: RamipriRamiprill

PlaceboPlacebo NNTNNT RRRRRR

Primary end-point: death Primary end-point: death from cardiovascular from cardiovascular causes, MI or strokecauses, MI or stroke

14%14% 17,8%17,8% 26,326,3 22%22%

Secondary end-pointsSecondary end-points

SCDSCD 26%26%

StrokeStroke 32%32%

Need for revascularisationNeed for revascularisation 20%20%

Dabetic complicationsDabetic complications 16%16%

Onset of new diabetesOnset of new diabetes 34%34%

Trials in low risk patientsTrials in low risk patients

EUROPAEUROPAn=13655n=13655AP without HFAP without HF

Perindopril Perindopril 8mg/d8mg/d

Reduction of: Reduction of: cardiovascular cardiovascular mortality, MI, mortality, MI, SCDSCDRRR= RRR= 2020%%NNT = NNT = 50/4,250/4,2yearsyears

PEACEPEACEn=n=82908290CAD + EF>CAD + EF> 40 40%%

TrandolaprilTrandolapril2-42-4mg/dmg/d

Reduction of Reduction of cardiovascular cardiovascular mortality, non mortality, non fatal MI, need fatal MI, need for for revascularisationrevascularisation(NS)(NS)

Use of ACE-I to prevent sudden Use of ACE-I to prevent sudden deathdeath

In patients with asymptomatic LV In patients with asymptomatic LV dysfunction, moderate and advanced HF dysfunction, moderate and advanced HF treatement with ACE-I resulted in a treatement with ACE-I resulted in a reduction in mortality from sudden reduction in mortality from sudden cardiac death (SCD)cardiac death (SCD)

This reduction varied from This reduction varied from 20-54%20-54% and was and was statistically significant in some heart statistically significant in some heart failure studies, although SCD was not the failure studies, although SCD was not the primary end-point in this trials.primary end-point in this trials.

Priori et al. For the Task Force on Sudden Cardiac Death of the ESC.Eur Heart J 2001; 22: 1374-450Update on the guidelines for SCD of the ESC. .Eur Heart J 2003; 24: 13-15

Use of ACE-I to prevent sudden Use of ACE-I to prevent sudden deathdeath


Patients with HFPatients with HF II AA

Patients with Patients with previous MIprevious MI

II AA

Patients with dilated Patients with dilated cardiomyopathycardiomyopathy

II BB


plaqueplaque

VPI

TNFαA

MMPI

STATIN

BB

ARBs

ACE-I

APA

AP

Proven effect

Usefulness of beta-Usefulness of beta-adrenoceptor antagonists in adrenoceptor antagonists in

cardiovascular diseasecardiovascular disease

CAD

H HF

DM A

CAD – coranry artery disease, HF-heart failure, H - hypertensionDM - diabetes, A - arrythmia

Use of beta-adrenoceptor Use of beta-adrenoceptor antagonists in coronary heart antagonists in coronary heart

diseasedisease Acute myocardial infarction (AMI)Acute myocardial infarction (AMI) Post MI – secondary preventionPost MI – secondary prevention Acute coronary syndromes NSTEMIAcute coronary syndromes NSTEMI Chronic, stable ischaemic heart diseaseChronic, stable ischaemic heart disease Heart failure (HF)Heart failure (HF) ArrythmiasArrythmias Prevention of sudden cardiac death (SCD)Prevention of sudden cardiac death (SCD)

Use of beta-blockers in AMIUse of beta-blockers in AMI


I.v.administration

For relief of ischaemic pain II BB

To control hypertension, sinus tachycardia

II BB

Primary prevention of SCD II BB

Sustained ventricular tachycardia II CC

Supraventricular tachyarrythmias II CC

To limit infarct size IIaIIa AA

All patients without All patients without contraindicationscontraindications

IIbIIb AA

Oral administrationOral administration

All patients without All patients without contraindicationscontraindications

II AA

Use of beta-blockers in secondary Use of beta-blockers in secondary prevention after MIprevention after MI


All patients without All patients without contraindication, indefinitelycontraindication, indefinitely

II AA

To improve survivalTo improve survival II AA

To prevent reinfarctionTo prevent reinfarction II AA

Primary prevention of SCDPrimary prevention of SCD II AA

To prevent/treat late ventricular To prevent/treat late ventricular arrythmiasarrythmias

IIaIIa BB

Use of beta-blockers in non-ST-Use of beta-blockers in non-ST-segment elevation ACS (NSTEMI segment elevation ACS (NSTEMI

ACS)ACS)Setting/indicationSetting/indication ClassClass LevelLevel

Early benefit, reduction of Early benefit, reduction of ischaemiaischaemia

II BB

Early benefit, prevention MIEarly benefit, prevention MI II BB

Long-term secondary preventionLong-term secondary prevention II BB

Use of beta-blockers in chronic, Use of beta-blockers in chronic, stable ischaemic heart diseasestable ischaemic heart disease


Previous infarction

To improve survival II AA

To reduce reinfarction II AA

To prevent/control ischaemia II AA

No previous infarctionNo previous infarction

To improve survivalTo improve survival II CC

To reduce reinfarctionTo reduce reinfarction II BB

To prevent/control ischaemiaTo prevent/control ischaemia II AA

Usefulness of beta-blockers in Usefulness of beta-blockers in CAD based on clinical trials CAD based on clinical trials

Olson’s meta-analysis 1992 (5 trials with Olson’s meta-analysis 1992 (5 trials with metoprolol)metoprolol)

Yusuf’s meta-analysis 1998Yusuf’s meta-analysis 1998(25 randomized studies)(25 randomized studies)

Freemantle’s meta-analysis 1999 (82 Freemantle’s meta-analysis 1999 (82 trials post MI)trials post MI) 23% reduction of overall mortality 23% reduction of overall mortality despite ACE-I and ASA treatment despite ACE-I and ASA treatment

Use of beta-blockers in chronic Use of beta-blockers in chronic heart failureheart failure


All stable patients, with symptomatic heart All stable patients, with symptomatic heart failure and reduced LVEF, functional class failure and reduced LVEF, functional class II-IV (to prolong survival)II-IV (to prolong survival)

II AA

LVSD without symptoms after AMILVSD without symptoms after AMI II AA

LVSD without symptoms, no previous MILVSD without symptoms, no previous MI II B B

Chronic HF with preserved systolic Chronic HF with preserved systolic function (to reduce heart rate)function (to reduce heart rate)

IIaIIa CC

Acute, compensated heart failure after Acute, compensated heart failure after AMIAMI

IIaIIa BB

Patient stable after acutely Patient stable after acutely decompensated chronic heart failuredecompensated chronic heart failure

II AA

Use of beta-adrenoceptor Use of beta-adrenoceptor antagonists in heart failureantagonists in heart failure

Waagstein et al. – team from GWaagstein et al. – team from Gőőteborg: the pioneers work on teborg: the pioneers work on application of beta-blockers (application of beta-blockers (metoprololmetoprolol) in the treatment of ) in the treatment of HF (HF (19701970y)y)

CIBIS ICIBIS I 1994 1994 ((bisoprololbisoprolol).).

USCPUSCP ( (USUS Carvedilol ProgrammeCarvedilol Programme) ) 1996 1996 ((carvedilolcarvedilol))

Australian/New Zealand Heart Failure StudyAustralian/New Zealand Heart Failure Study 1997 1997 ((carvedilolcarvedilol))

CIBIS IICIBIS II ( (Cardiac Insufficiency Bisoprolol StudyCardiac Insufficiency Bisoprolol Study II)II) 19991999 MERIT-HF MERIT-HF 19991999 ( (metoprolol CRmetoprolol CR))

COPERNICUSCOPERNICUS ((Carvedilol Prospective Randomised Carvedilol Prospective Randomised Cumulative Survival Study)Cumulative Survival Study) 20012001 ( (carvedilolcarvedilol))

CAPRICORNCAPRICORN ( (Carvedilol Post-Infarct Survival Control in Left Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) Ventricular Dysfunction) 2001 2001 ((carvedilolcarvedilol))

Most importent trials in the Most importent trials in the treatment of HF with beta-treatment of HF with beta-

blockersblockers

TrialTrial AgentAgent NN

All-cause All-cause mortalitymortality RRR (%) RRR (%)

CV CV morbidity morbidity

RRR%RRR%

USCPUSCP CarvedilolCarvedilol 451451 6565 2727

CIBIS IICIBIS II BisoprololBisoprolol 26472647 3535 1515

MERIT-HFMERIT-HF Metoprolol Metoprolol CRCR

39913991 3434 1313

COPERNICUCOPERNICUSS

CarvedilolCarvedilol 22892289 3535 2727


Beta-blockers should be considered Beta-blockers should be considered for the treatment for the treatment of all patients (NYHA II-IV)of all patients (NYHA II-IV) with stable, mild, with stable, mild, moderate, and severe heart failure from ischaemic or moderate, and severe heart failure from ischaemic or non-ischaemic cardiomyopathies and reduced LVEF non-ischaemic cardiomyopathies and reduced LVEF on standard treatment, including diuretics, and ACE-I, on standard treatment, including diuretics, and ACE-I, unless there is a contraindication (unless there is a contraindication (Class I, level AClass I, level A))

Beta-blocking therapy reduces hospitalisations (all, Beta-blocking therapy reduces hospitalisations (all, cardiovascular, and HF), improves the functional class cardiovascular, and HF), improves the functional class and leads to less worsening of HF. This beneficial and leads to less worsening of HF. This beneficial effect has been consistently observed in subgroups of effect has been consistently observed in subgroups of different age, gender, functional class, LVEF, and different age, gender, functional class, LVEF, and ischaemic or non-ischaemic aetiology (ischaemic or non-ischaemic aetiology (Class I, level AClass I, level A))


In patients with LV systolic dysfunction, with In patients with LV systolic dysfunction, with or without symptomatic HF, following an or without symptomatic HF, following an AMI long-term beta-blockade is AMI long-term beta-blockade is recommended in addition to ACE inhibition recommended in addition to ACE inhibition to reduce mortalityto reduce mortality ( (Class I,Class I, level B level B))

Differences in clinical effects may be present Differences in clinical effects may be present between different beta-blockers in patients between different beta-blockers in patients with HF. Accordingly, only with HF. Accordingly, only bisoprolol, bisoprolol, carvedilol, metoprolol succinate and carvedilol, metoprolol succinate and nebivololnebivolol can be recommended ( can be recommended (Class I, level Class I, level AA))

Use of beta-adrenoceptor Use of beta-adrenoceptor antagonists in diabetesantagonists in diabetes

Beta-blockers are particularly effective in Beta-blockers are particularly effective in decreasing post-infarction mortality and decreasing post-infarction mortality and new infarctsnew infarcts in patients with a history of in patients with a history of DM.DM.

Thus, oral BBs are, in the absence of Thus, oral BBs are, in the absence of contraindications, recommended contraindications, recommended for all for all diabeticdiabetic patients with ACS patients with ACS(Class IIa, level B)(Class IIa, level B)

Furthermore, such patients are more prone Furthermore, such patients are more prone to develop heart failure and recent trials to develop heart failure and recent trials have documented the have documented the beneficial effects of beneficial effects of beta-blockade in HF patients.beta-blockade in HF patients.

Use of beta-blockers in Use of beta-blockers in diabetesdiabetes

Selective beta-1-antagonistSelective beta-1-antagonist may be may be preferred in case of insulin preferred in case of insulin treatmenttreatment

Alpha-1-beta-adrenergic antagonists Alpha-1-beta-adrenergic antagonists such as such as carvedilol carvedilol may offer may offer additional benefits for patients with additional benefits for patients with peripheral artery disease or peripheral artery disease or substantial insulin resistance.substantial insulin resistance.


plaqueplaque

VPI

TNFαA

MMPI

STATIN

BB

ARBs

ACE-I

APA

AP

Proven effect

Angiotensin II receptor blockers Angiotensin II receptor blockers (ARBs) – (ARBs) – angioprotective action? action? LIFELIFE (losartan vs atenolol): (losartan vs atenolol): 2002 N=9100; age>55lat 2002 N=9100; age>55lat

Hypertension with LVH Results: Risk reduction of CV death, MI and stroke Risk reduction of fatal nad non-fatal stroke Decrease onset of new diabetes

SCOPE – beneficial effect of ARBs in primary prevention of stroke

MOSES – beneficial effect of ARBs in secondary prevention of stroke

DETAIL (telmisartan vs enalapryl): similar nephroprotecive effects in diabetes

VALUE – decrease onset of new diabetes

Use of angiotensin II receptor Use of angiotensin II receptor blockers (ARBs) in heart blockers (ARBs) in heart

failure failure ARBs can be used as ARBs can be used as an alternativean alternative to ACE-I to ACE-I

in symptomatic patients intolerant to ACE-I in symptomatic patients intolerant to ACE-I to improve morbidity and mortality (Class I, to improve morbidity and mortality (Class I, level B) (level B) (ELITE II, OPTIMAALELITE II, OPTIMAAL))

ARBs and ACE-I seem to have ARBs and ACE-I seem to have similar similar efficiacyefficiacy in CHF on mortality and morbidity in CHF on mortality and morbidity (Class IIa, level B). In AMI with signs of HF (Class IIa, level B). In AMI with signs of HF or LVD ARBs and ACE-I have similar or or LVD ARBs and ACE-I have similar or equivalent effects on mortality (Class I, equivalent effects on mortality (Class I, level B) (level B) (CHARM-Added)CHARM-Added)

CHARM Added

CHARMPreserved

CHARM ProgrammeCHARM Programme3 component trials comparing candesartan to

placebo in patients with symptomatic heart failure

CHARMAlternative

n=2028

LVEF 40%ACE inhibitor

intolerant

n=2548

LVEF 40%ACE inhibitor

treated

n=3025

LVEF >40%ACE inhibitor treated/not

treated

Primary outcome for Overall Programme: All-cause death

Primary outcome for each trial: CV death or CHF hospitalisation

Pfeffer et al, Lancet 2003

0 1 2 3 years0

10

20

30

40

50

Placebo

Candesartan

%

HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001

Number at risk

Candesartan 1013 929 831 434 122

Placebo 1015 887 798 427 126

3.5

406 (40%)

334 (33%)

CHARM-AlternativeCHARM-AlternativePrimary outcome, CV Primary outcome, CV deathdeath or or

CHF hospitalisationCHF hospitalisation

Granger et al, Lancet 2003

CHARM-AlternativeCHARM-AlternativeConclusionsConclusions

Despite prior intolerance to another Despite prior intolerance to another inhibitor of the renin-angiotensin-inhibitor of the renin-angiotensin-aldosterone system, candesartan aldosterone system, candesartan waswaswell toleratedwell tolerated

In patients with symptomatic CHF In patients with symptomatic CHF and ACE inhibitor intolerance, and ACE inhibitor intolerance, candesartan reduces cardiovascular candesartan reduces cardiovascular mortality and morbidity mortality and morbidity

Granger et al, Lancet 2003

0 1 2 3 years0

10

20

30

40

50

Placebo

Candesartan

%

Number at risk

Candesartan 1276 1176 1063 948 457

Placebo 1272 1136 1013 906 422

3.5

HR 0.85 (95% CI 0.75-0.96), p=0.011Adjusted HR 0.85, p=0.010

483 (37.9%)538 (42.3%)

McMurray et al, Lancet 2003

CHARM-AddedCHARM-AddedPrimary outcome, Primary outcome, CV CV deathdeath or or


Beta- Yes 223/702 274/711blocker No 260/574 264/561

Recom. Yes 232/643 275/648dose of No 251/633 263/624ACE inhib

All patients 483/1276 538/1272

p-value fortreatment interaction

0.14

0.26


0.6 0.8 1.0 1.2 1.4

CHARM-AddedCHARM-AddedPrespecified subgroups, CV death or Prespecified subgroups, CV death or


Candesartan better

Hazard ratio

Placebo better

Candesartanevent/n

Placeboevent/n

Addition of candesartan to an ACE inhibitor Addition of candesartan to an ACE inhibitor (and beta-blocker) leads to a further and (and beta-blocker) leads to a further and clinically important reduction in CV mortality clinically important reduction in CV mortality and morbidity in patients with CHFand morbidity in patients with CHF

The benefit of candesartan corresponds to a The benefit of candesartan corresponds to a NNT of NNT of 2323 (for a mean of (for a mean of 3.03.0 years) to prevent years) to prevent one CV death or a first CHF hospitalisationone CV death or a first CHF hospitalisation

This benefit is obtained with relatively few This benefit is obtained with relatively few adverse effects, although there is an adverse effects, although there is an increased risk of hypotension, hyperkalaemia increased risk of hypotension, hyperkalaemia and renal dysfunctionand renal dysfunction

CHARM-AddedCHARM-AddedConclusionsConclusions


Mean age (years) 65 65

Women (%) 26 26

NYHA class (%)II 35 34III 62 62IV 3 4

Mean LVEF (%) 29 29

Medical history (%) myocardial infarction 59 58 diabetes 29 29 hypertension 48 50 atrial fibrillation 26 26

Candesartan Placebon=2289 n=2287

CHARM - Low EF trialsCHARM - Low EF trials: b: baseline aseline

characteristics characteristics

Young et al, Circulation 2004

CHARM - Low EF trials CHARM - Low EF trials CV death or CHF hospitalisations

Placebo944 (41.3%)

Candesartan817 (35.7%)

yrs3.50 1 2 30

10

20

30

CV death or CHF hosp (%)

40

Hazard ratio 0.82 (95% CI 0.74 – 0.90), p<0.001

50

One year HR 0.70p<0.001

Two year HR 0.77p<0.001

Number at riskCandesartan 2289 2105 1894 1382 580Placebo 2287 2023 1811 1333 548


CHARM-Low EFCHARM-Low EFImplications

Candesartan significantly reduces Candesartan significantly reduces cardiovascular death, hospital admission for cardiovascular death, hospital admission for heart failure, and all-cause mortality in patients heart failure, and all-cause mortality in patients with CHF and LVEF with CHF and LVEF 40% when added to 40% when added to standard therapies including ACE inhibitors, standard therapies including ACE inhibitors, beta-blockers, and an aldosterone antagonistbeta-blockers, and an aldosterone antagonist

This approach offers the clinician an opportunity This approach offers the clinician an opportunity to make additional improvements in the poor to make additional improvements in the poor prognosis of CHF patients when left ventricular prognosis of CHF patients when left ventricular systolic dysfunction is presentsystolic dysfunction is present


0 1 2 3 years0

10

20

30

40

50%

Placebo

Candesartan

HR 0.84 (95% CI 0.77-0.91), p<0.0001Adjusted HR 0.82, p<0.0001

3.5Number at risk

Candesartan 3803 3563 3271 2215 761

Placebo 3796 3464 3170 2157 743

1310 (34.5%)1150 (30.2%)


CHARM-OverallCHARM-OverallCV death or CHF hospitalisationCV death or CHF hospitalisation

CHARM-Overall CHARM-Overall ConclusionsConclusions

9% reduction in all cause deaths 9% reduction in all cause deaths (p=0.055, covariate adj. p=0.032)(p=0.055, covariate adj. p=0.032)

12% reduction in CV mortality (p=0.012) 12% reduction in CV mortality (p=0.012) 21% reduction in CHF hosp. (p<0.0001)21% reduction in CHF hosp. (p<0.0001) 16% reduction in CV deaths or CHF 16% reduction in CV deaths or CHF

hosp. (p<0.0001)hosp. (p<0.0001)

Treatment of a broad spectrum of patients with symptomatic CHF with candesartan resulted in a:


Use of angiotensin II receptor Use of angiotensin II receptor blockers (ARBs) in heart blockers (ARBs) in heart

failurefailure ARBs can be considered ARBs can be considered in combinationin combination

with ACE-I in patients who remain with ACE-I in patients who remain symptomatic, to reduce mortality (Class IIa, symptomatic, to reduce mortality (Class IIa, level B) and hospital admissions for HF level B) and hospital admissions for HF (Class I, level A)(Class I, level A)

Concerns raised by initial studies about a Concerns raised by initial studies about a potential negative interaction between potential negative interaction between ARBs and beta-blockers ARBs and beta-blockers have not been have not been confirmedconfirmed by recent studies in post-MI or by recent studies in post-MI or CHF (Class I, level A)CHF (Class I, level A)


plaqueplaque

VPI

TNFαA

MMPI

STATIN

BB

ARBs

ACE-I

APA

AP

Proven effect

Benefits of statin therapyBenefits of statin therapy

Dyslipidaemiatherapy

Secondary prevention

of CVE

Angioprotectiveeffect

Significance ofSignificance of S Scandinavian candinavian SSimvastatin imvastatin SSurvival urvival SStudy (tudy (44SS) )

19931993 Simvastatin Simvastatin ((10-4010-40mg/d) vs placebomg/d) vs placebo

Patients (Patients (n=4444n=4444) with CAD/post MI and ) with CAD/post MI and total cholesterol concentrations total cholesterol concentrations 5,5-5,5-8mmol/L8mmol/L

Prospective, randomized, double-blind, multicenter Prospective, randomized, double-blind, multicenter studystudy

Aim of study: to establish the benfit of simvastatin Aim of study: to establish the benfit of simvastatin therapy on cardiovascular morbidity and overall therapy on cardiovascular morbidity and overall mortality.mortality.

Significance ofSignificance of S Scandinavian candinavian SSimvastatin imvastatin SSurvival urvival SStudy (tudy (44SS))

Results: significant reduction of Results: significant reduction of relative riskrelative riskSimvastatin vs placeboSimvastatin vs placebo RRR RRR

Overall mortalityOverall mortality 33%33%

CV deathCV death 42%42%

Serious cardiovascular events (AMI, SCD, Serious cardiovascular events (AMI, SCD, cardiovascular death)cardiovascular death)

34%34%

Need for revascularisationNeed for revascularisation 37%37%

Cost of hospitalisationCost of hospitalisation 32%32%

Beneficial effect was observed also in patients with diabetes and in elderly

Pravastatin trials Pravastatin trials

LIPID LIPID 1995y1995y Patients with CAD/MI Patients with CAD/MI

pravastatin pravastatin 4040mg/d vs mg/d vs placeboplacebo

NN=9014=9014 Results: reduction of RRResults: reduction of RR

CV death CV death 25%25%

ovarall mortality ovarall mortality 22%22% reinfarction reinfarction 29%29% CABG CABG 22%22%Stroke Stroke 19%19%

CARE CARE 1996y.1996y. Patients post MIPatients post MI

pravastatin pravastatin 4040mg/d vs mg/d vs placeboplacebo

NN=4159=4159 Results: reduction of RRResults: reduction of RR

CV death CV death 24%24%reinfarction reinfarction 25%25%CABG CABG 26%26%PTCA PTCA 23%23%Stroke Stroke 32%32%TIA TIA 27%27%

Beneficial effects of statin Beneficial effects of statin despite normal lipidogram?despite normal lipidogram?

HPSHPS ( (Heart Protection StudyHeart Protection Study) ) 20022002British multicenter study (British multicenter study (5555 hospitals) hospitals) N=N=20536 20536 patients (patients (40-80 years old40-80 years old) with CAD) with CAD

or AO or AO or or after Stroke/TIAafter Stroke/TIA or or Diabetes (type 2)Diabetes (type 2)

Total cholesterol concentration > Total cholesterol concentration > 135135mg% mg% Follow-up: 5 years Follow-up: 5 years Arms of study: Arms of study: simvastatin simvastatin vs placebovs placebo

simvastatin simvastatin vsvs antioxidants antioxidants antioxidants antioxidants vs placebovs placebo placebo vs placeboplacebo vs placebo

HPSHPS ( (Heart Protection StudyHeart Protection Study))

Results:Results:

No effects on CV events after antioxidants No effects on CV events after antioxidants administration (Vit. C administration (Vit. C 250250mg/d, vit. E mg/d, vit. E 600600mg/d, beta-caroten mg/d, beta-caroten 2020mg/d)mg/d)

SimvastatinSimvastatin therapy was associated with therapy was associated with significant risk reduction of:significant risk reduction of:

CV death CV death 1818%% all-cause death all-cause death 1313%% overall death, MI, stroke, overall death, MI, stroke, need for revascularisation need for revascularisation 2424%%

What LDL concentration is What LDL concentration is optimal?optimal?

In the Pravastatin or Atorvastatin Evaluation and In the Pravastatin or Atorvastatin Evaluation and Infection Therapy (Infection Therapy (PROVE-ITPROVE-IT) trial, standard statin ) trial, standard statin therapy (therapy (pravastatinpravastatin 4040mg/d) was compared with mg/d) was compared with intensive therapy (intensive therapy (atorvastatinatorvastatin 8080mg/d)mg/d)

Patients (n=Patients (n=41624162) within ) within 1010 days of an ACS days of an ACS Mean follow-up Mean follow-up 2424 months months Results: more intensive therapy (achived mean LDL Results: more intensive therapy (achived mean LDL

1,6mmol/L) was associated with a significant 1,6mmol/L) was associated with a significant 16%16% risk risk reduction in CVE, compred with standard therapy reduction in CVE, compred with standard therapy (mean LDL (mean LDL 2,52,5mmol/lmmol/l

Intensive vs standard statin Intensive vs standard statin therapytherapy

Treat to New Targets Trial (Treat to New Targets Trial (TNTTNT))

Comparision of intensive statin therapy Comparision of intensive statin therapy ((atorvastainatorvastain 8080mg/d) and standard statin mg/d) and standard statin therapy (therapy (atorvastain atorvastain 1010mg/d)mg/d)

Patients (n=Patients (n=1000110001) with stable CAD) with stable CAD Results:Results:

Atorvastatin Atorvastatin 1010mg/dmg/d

Atorvastatin Atorvastatin 8080mg/dmg/d

Mean LDL ChMean LDL Ch 101mg/dL101mg/dL 77mg/dL77mg/dL

SCESCE 10,9%10,9% 8,7% (RRR=22%)8,7% (RRR=22%)


plaqueplaque

VPI

TNFαA

MMPI

STATIN

BB

ARBs

ACE-I

APA

AP

Proven effect

The use of aniplatelet agents in The use of aniplatelet agents in patients with atherosclerotic patients with atherosclerotic

cardiovasular diseasecardiovasular disease ESC Expert Consensus DocumentESC Expert Consensus Document

European Heart Journal 2004;25, 166-181European Heart Journal 2004;25, 166-181

Sixth American College of Chest Sixth American College of Chest Physicians (ACCP) Consensus Physicians (ACCP) Consensus Conference on Antithrombotic Conference on Antithrombotic TherapyTherapy Chest 2001; 119: 39S-63SChest 2001; 119: 39S-63S

Antithrombotic Trialists’ (ATT) Antithrombotic Trialists’ (ATT) CollaborationCollaboration BMJ 2002; 324: 71-86BMJ 2002; 324: 71-86

Antiplatelet drugs that may Antiplatelet drugs that may prevent atherothrombosisprevent atherothrombosis

Approximately 20 different agents have been shown to inhibit platelet aggregation through different mechanisms of action

However, inhibition of platelet aggreagation does not necessarily translate into prevention of atherothrombosis

Antiplatelet drugs that have been successfully tested against placebo in adequately large randomized clinical trials include:

* for chronic oral dosing: aspirin, ticlopidine and clopidogrel

* for short-term intravenous administration: abciximab, tirofiban and eptifibatide

Patients that may benefit from Patients that may benefit from antiplatelet therapyantiplatelet therapy

Allocation of high-risk patients to a prolonged course of antiplatelet therapy reduced the combined outcome of nonfatal myocardial infarction, nonfatal stroke or vascular death (serious vascular events-SVA) by about 25%

Absolute reductions in the risk of having a SVA:

In each of these high-risk categories, the absolute benefits substentially outweighed the absolute risk of major bleeding complications

36/1000 2 years Previous myocardial infarction (MI)

38/1000 1 month Acute myocardial infarction (AMI)

36/1000 2 years Previous stroke/TIA

9/1000 1 month Acute ischaemic stroke

22/1000 2 years Stabile angina (AP), peripheral arterial disease and atrial fibrillation (AF)

Clinical trial evidence in patients Clinical trial evidence in patients with ischaemic heart diseasewith ischaemic heart disease

Ticlopidine and clopidogrel vs aspirin in patients with AMI non-significantly lower rates of SVA in the aspirine-treated arm

In patients with chronic stable angina (AP), aspirin (75mg/d) significantly reduced the occurence of the primary end-point (MI, SCD) by 34% (median duration of follow-up of 50 months)

In patients with unstable angina (API) aspirin (75-1300mg/d in 4 placebo-controlled trials) and ticlopidine have been shown to reduce by~50% the rate of MI and death

Clinical trial evidence in patients Clinical trial evidence in patients with ischaemic heart diseasewith ischaemic heart disease

Aspirin + ClopidigrelAspirin + Clopidigrel produced additive effects in produced additive effects in patients with NSTEMI by reducing the rate of patients with NSTEMI by reducing the rate of the first primary outcome (a composite of the first primary outcome (a composite of cardiovascular death (CVD), non fatal MI or cardiovascular death (CVD), non fatal MI or stroke) by stroke) by ~~20% 20% vs aspirin alone (12months of vs aspirin alone (12months of follow-up)follow-up)

The efficacy and safety of this combined The efficacy and safety of this combined antiplatelet strategy is currently being tested in antiplatelet strategy is currently being tested in patients with AMI, a clinical setting where patients with AMI, a clinical setting where aspirin aloneaspirin alone (162,5mg (162,5mg started within started within 2424h of the h of the onset of symptoms) reduced the primary end-onset of symptoms) reduced the primary end-piontpiont of CVD byof CVD by ~~23% 23% and non-fatal SVA byand non-fatal SVA by ~~50% 50%

Anitiplatelet therapy in Anitiplatelet therapy in diabetic patients with CADdiabetic patients with CAD

AspirinAspirin should be given for the same should be given for the same indications and in indications and in similar dosagessimilar dosages to to diabetic and non-diabetic patients diabetic and non-diabetic patients (Class IIa, level B)(Class IIa, level B)

ADP receptor-dependent platelet ADP receptor-dependent platelet aggregation inhibitor (aggregation inhibitor (clopidogrelclopidogrel) may be ) may be considered in diabetic patients with ACS considered in diabetic patients with ACS in addition to aspirinin addition to aspirin (Class IIa, level C) (Class IIa, level C)

Guidelines on diabetes, pre-diabetes, and cardiovascular disease (ESC and EASD) Eur Heart J 2007: 28, 88-136

Balance of benefits and risks of Balance of benefits and risks of antiplatelet therapyantiplatelet therapy

The absolute benefits of The absolute benefits of aspirin aspirin therapy therapy substantially outweigh the absolute risks of major substantially outweigh the absolute risks of major bleeding [particulary, gastrointestinal (GI)] bleeding [particulary, gastrointestinal (GI)] complications in a variety of clinical settings complications in a variety of clinical settings characterized by characterized by moderate moderate to to high riskhigh risk of of occlusive vascular events. However, in low-risk occlusive vascular events. However, in low-risk individuals the benfit/risk profile of such a individuals the benfit/risk profile of such a preventive strategy is uncertain.preventive strategy is uncertain.

A meta-anlysis of four primary prevention trials A meta-anlysis of four primary prevention trials suggests that suggests that aspirinaspirin treatment is safe and treatment is safe and worthwhile at coronary event risk ≥ worthwhile at coronary event risk ≥ 1,5%1,5% per year per year

Recommendations concerning Recommendations concerning individual antiplatelet agentsindividual antiplatelet agents

AspirinAspirin TiclopidineTiclopidine ClopidogrelClopidogrel DipyridamolDipyridamol Abciximab, tirofiban, eptifibatideAbciximab, tirofiban, eptifibatide Other antiplatelet drugsOther antiplatelet drugs

ASPIRINASPIRIN

Aspirin once daily is recommended in all clinical Aspirin once daily is recommended in all clinical conditions in wich antiplatelet prophylaxis has a conditions in wich antiplatelet prophylaxis has a favourable benefit/risk profile.favourable benefit/risk profile.

Because of GI toxicity and its potential impact on Because of GI toxicity and its potential impact on compliance, physicians are encouraged to use compliance, physicians are encouraged to use the lowest dose of aspirin that was shown to be the lowest dose of aspirin that was shown to be effective in each clinical setting.effective in each clinical setting.

ASPIRINASPIRIN

The available evidence supports daily dose od The available evidence supports daily dose od aspirinaspirin in the range of in the range of 75-100 75-100 mgmg for the long for the long term prevention of SVE in high-risk patients (i.e. term prevention of SVE in high-risk patients (i.e. ≥ ≥ 3%3% per year). per year).

In clinical situations where an immediate In clinical situations where an immediate antithrombotic effect is required (such as in ACS antithrombotic effect is required (such as in ACS or acute ischaemic stroke), a loading dose of or acute ischaemic stroke), a loading dose of 160160 mgmg should be given at diagnosis (rapid and should be given at diagnosis (rapid and complete inhibition of TXAcomplete inhibition of TXA22- dependent platelet - dependent platelet aggregation)!!!aggregation)!!!

ASPIRINASPIRIN

No test of platelet function is recommended to No test of platelet function is recommended to assess the antiplatelet effect of aspirin in the assess the antiplatelet effect of aspirin in the individual patientindividual patient

The routine use of proton pump inhibitors or The routine use of proton pump inhibitors or cytoprtotecive agents is not recommended in cytoprtotecive agents is not recommended in patients taking daily dose of aspirin in the range patients taking daily dose of aspirin in the range of of 75-10075-100 mg, because of lack of randomized trials mg, because of lack of randomized trials demonstrating the efficiacy of such protective demonstrating the efficiacy of such protective strategies in this settingstrategies in this setting

ASPIRINASPIRIN

Non-steroidal anti-inflammatory drugsNon-steroidal anti-inflammatory drugs (NSAIDs) (NSAIDs) have been investigated inadequately in terms of have been investigated inadequately in terms of their potential cardiovacular effects. Thus, their potential cardiovacular effects. Thus, physicians prescibing these drugs to arthritic physicians prescibing these drugs to arthritic patients with prior vascular complications should patients with prior vascular complications should not discontinue treatment with low-dose aspirinnot discontinue treatment with low-dose aspirin

Because of potential pharmacodynamic Because of potential pharmacodynamic interactions between traditional interactions between traditional NSAIDs and NSAIDs and aspirinaspirin, patients treated with low-dose aspirin , patients treated with low-dose aspirin requiring NSAID therapy may benfit from the use requiring NSAID therapy may benfit from the use of selective of selective COX-COX-22 inhibitors inhibitors..

TICLOPIDINETICLOPIDINE

The role of The role of ticlopidineticlopidine in the present therapeutic in the present therapeutic armamentarium armamentarium is uncertainis uncertain. Now that ticlopidine is . Now that ticlopidine is available as a generic drug in many countries, its available as a generic drug in many countries, its lower cost as compared to clopidogrel is being lower cost as compared to clopidogrel is being emphasized within a broad-cost containment emphasized within a broad-cost containment strategy.strategy.

Although there are no large head-to-head Although there are no large head-to-head comparisions between the two thienopyridines, comparisions between the two thienopyridines, indirect comparisions are highly suggestive of a indirect comparisions are highly suggestive of a lower burden of lower burden of serious bone-marrow toxicityserious bone-marrow toxicity with with clopidogrelclopidogrel as compared to as compared to ticlopidineticlopidine

In contrast to clopidogrel, In contrast to clopidogrel, ticlopidineticlopidine does not havedoes not have an approved indication for patients with a AMIan approved indication for patients with a AMI

CLOPIDOGRELCLOPIDOGREL

Although Although clopidogrel clopidogrel may be slightly more may be slightly more effecive than aspirin, the size of any additional effecive than aspirin, the size of any additional benefit is statistically benefit is statistically uncertainuncertain and the drug has and the drug has not been granted a claim of not been granted a claim of superiority vs superiority vs aspirinaspirin by regulatory authorities.by regulatory authorities.

ClopidogrelClopidogrel, , 7575mg daily, is an approppriate mg daily, is an approppriate alternative for high-risk patients with coronary, alternative for high-risk patients with coronary, cerebrovascular or peripheral arterial disease cerebrovascular or peripheral arterial disease who have a who have a contraindication to low-dose aspirincontraindication to low-dose aspirin

CLOPIDOGRELCLOPIDOGREL

The results of the The results of the CURECURE trial have led to trial have led to approval of a new indication for clopidogrel in approval of a new indication for clopidogrel in patients with NSTEMI ACSpatients with NSTEMI ACS

A loading dose of A loading dose of 300300 mg mg clopidogrelclopidogrel should be should be used in this setting followed by used in this setting followed by 7575 mg daily. mg daily.

Revision of the existing guidelines will need a Revision of the existing guidelines will need a consensus agreement by the experts with respect consensus agreement by the experts with respect to timing of percutaneous coronary intervention to timing of percutaneous coronary intervention (PCI), length of clopidogrel treatment, and (PCI), length of clopidogrel treatment, and combination with GPIIb/IIIa anatagonists.combination with GPIIb/IIIa anatagonists.

DIPYRIDAMOLDIPYRIDAMOL

The combination of low-dose aspirin and extended-relase dipyridamol (200mg bid) is considered an acceptable option for initial therapy of patients with non-cardioembolic cerebral ischaemic events.(ESPS-2 trial)

There is no basis to recommend this combination in patients with ischaemic heart disease.

Abciximab, eptifibatide and Abciximab, eptifibatide and tirofibantirofiban

The benefit/risk profile of currently available The benefit/risk profile of currently available GPIIb/IIIa antagonists is substentially GPIIb/IIIa antagonists is substentially uncertain uncertain for patients with ACS who are not routinely for patients with ACS who are not routinely scheduled for early revascularisation (scheduled for early revascularisation (GUSTO IV, GUSTO IV, ACS, PARAGON-BACS, PARAGON-B))

In contrast, for patients undergoingIn contrast, for patients undergoing PCI PCI, , intensification of antiplatelet therapy by adding intensification of antiplatelet therapy by adding an intravenous GPIIb/IIIa blocker is an an intravenous GPIIb/IIIa blocker is an appropriate strategy appropriate strategy to reduce the risk of to reduce the risk of procedure-related thrombotic complications.procedure-related thrombotic complications.

Other antiplatelet drugsOther antiplatelet drugs

Indobufen, triflusal and picotamideIndobufen, triflusal and picotamide are are commercially available in a few European commercially available in a few European countries, based on relatively limited evidence countries, based on relatively limited evidence for efficacy and safety.for efficacy and safety.

Because of substantial statistical uncertainty Because of substantial statistical uncertainty surrounding the direct randomized comparisions surrounding the direct randomized comparisions of these agents vs aspirin and inadequate of these agents vs aspirin and inadequate statistical power of the studies to assess reliably statistical power of the studies to assess reliably any difference in SVE, the use of any difference in SVE, the use of indobufen, indobufen, triflusal and picotamidetriflusal and picotamide instead ofinstead of aspirinaspirin is not is not recommendedrecommended

ACS STEMI without PCI-ACS STEMI without PCI-secondary preventionsecondary prevention

ACE-I

ASA

BB

STATIN

STEMIACS

ACS STEMI post PCI (stent)ACS STEMI post PCI (stent)

clopidogrel

ACE-I ASA

BB

STATIN

STEMIACS

ACS NSTEMI with or without ACS NSTEMI with or without PCI –secondary prevention PCI –secondary prevention

clopidogrel

ACE-I ASA

BB

STATIN

NSTEMIACS

Stroke/TIA –secondary Stroke/TIA –secondary preventionprevention

APA STATIN

ACE-I

STROKE

Peripheral artery diseasePeripheral artery disease–secondary prevention–secondary prevention

APA STATIN

ACE-I

PAD

zofia oko-sarnowska department of clinical pharmacology

Documents

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aceiheart failure

hypertensionuse of ace

hfheart failure

heart failure studies

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low risk patientsuse

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