le nuove frontiere dell’anticoagulazione nel paziente con fibrillazione atriale 14-15 novembre...
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Le nuove frontiere dell’anticoagulazione nel paziente con
fibrillazione atriale
14-15 Novembre 2014Gavi
Dott. Sergio AgostiCardiologo, Ospedale Novi Ligure (AL)agostisergio@virgilio.ithttp://www.arcaliguria.it/
Prevenzione dell’ictus nella fibrillazione atriale: ancora un ruolo
per ASA e VKA?
ASA
Introduction to ASA • One of the most widely used drugs of the 20th century1
• Taken by millions of patients worldwide for the treatment and prevention of CVD, and is the most widely tested antiplatelet drug1
• Has been (and is still) used for stroke prevention in AF1,2
ASA = acetylsalicylic acid; CVD = cardiovascular disease; VKA = vitamin K antagonist 1. Dai Y, Ge J. Thrombosis 2012;2012:245037; 2. Camm AJ et al. Eur Heart J 2012;33:2719–47 3
Traditionally considered a safe, but less effective, alternative to VKAs when anticoagulation is contraindicated, or for use in patients at low risk
of stroke1,2
However, this is not consistent with the latest treatment guidelines2
ASA??
Camm AJ et al. Eur Heart J
NICE 2014 Guidelines on the management of AF2
“Do not offer aspirin monotherapy solely for stroke prevention with atrial fibrillation”
2012 ESC Guidelines1
Current Guidelines do not recommend ASA for stroke prevention in most NVAF patients
1 Camm AJ et al. Eur Heart J 20122 NICE clinical Guideline. 2014. The management of AF
Limited efficacy of ASA in reducing stroke risk in patients with AF
Random effects model; error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic); for ischaemic stroke only, RRR was 21% (95% CI: −1 to 38%)ASA = acetylsalicylic acid; QOD = every other dayHart RG et al. Ann Intern Med 2007;146:857–67
RRR (%)†100 –10050 0 –50
AFASAK (1989)
SPAF (1991)
EAFT (1993)
ESPS II (1997)
ASA better Placebo better
LASAF (1997)125 mg/d
125 mg QOD
UK-TIA (1999)300 mg/d
1200 mg/d
JAS (2006)T
All trialsRRR: 19%*
(95% CI: –1 to 35%)
Only the SPAF trial showed a benefit of ASA over placebo for reducing stroke risk
ASA was less effective than VKA in historical trials in AF
Random effects model; error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic); ASA = acetylsalicylic acidHart RG et al. Ann Intern Med 2007;146:857–67 8
RRR (%)†
100 –10050 0 –50
AFASAK I (1990)
BAFTA (2007)
EAFT (1993)
PATAF (1999)
Warfarin better ASA better
Chinese ATAFS (2006)
SPAF II (1994)Age 75 yrsAge >75 yrs
All trials (4620 pt) RRR: 38%*(95% CI: 18-52%)
Risk of major and intracranial bleeding not significantly different between ASA and OAC
*Modified HAS-BLED score used in this study: 1 point each for systolic blood pressure >160 mmHg, renal dysfunction, liver dysfunction, stroke, bleeding, age >65 years, drugs affecting bleeding or alcohol abuse (maximum score = 7); score 0 –2 indicates low bleeding risk, ≥3 indicates high bleeding risk; ASA = acetylsalicylic acidFriberg L et al. Eur Hear J 2012:33:1500-10; Pisters R et al. Chest 2010;138:1093–100
ASA (n=61
396)
Major bleeding
0
5
10
15
20
25
0 1 2 3 4 5 6 7
HAS-BLED total score*
Ble
ed
s/year
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0 1 2 3 4 5 6 7
HAS-BLED total score*
Intracranial bleeding
Ble
ed
s/year
OAC (n=48 599)Tot Pt 182,678
ASA Conclusions
➢Antiplatelet therapy should be considered only when patients refuse any OAC, or cannot tolerate OAC for reasons
unrelated to bleeding
➢In the real world, antiplatelet therapy is still commonly prescribed for stroke prevention in AF
➢Compared with ASA, NOAs (apixaban) significantly reduced the relative risk of stroke or systemic embolism by 55% while the risk of major bleeding was not significantly increased
➢The evidence demonstrated that oral anticoagulation should be the preferred option in NVAF patients at risk of stroke
Warfarin
ESC 2012 Guideline recommendations1
1. Camm et al. Eur Heart J 2012;33:2719–2747.
*Class of recommendation; †Level of evidence; OAC, oral anticoagulant
1. Camm et al. Eur Heart J 2012;33:2719–2747.
*Class of recommendation; †Level of evidence; OAC, oral anticoagulant
ESC 2012 Guideline recommendations1
Hart RG et al. Ann Intern Med 2007;146:857–67
-60% RR
Lancet, published online December 4, 2013
STROKE OR SYSTEMIC EMBOLISM
Ruff CT,Lancet, December 4, 2013
NNT 173
MAJOR BLEEDING
Ruff CT,Lancet, December 4, 2013
EFFICACY AD SAFETYSECONDARY ENDPOINTS
ICH NNT 141
Ruff CT,Lancet, December 4, 2013
Eliquis Pradaxa Xarelto
Condizioni di ingresso
Paziente con fibrillazione atriale non valvolare (FAVN) cronica o parossistica (>65 anni)
Paziente con fibrillazione atriale non valvolare (FAVN)
Paziente con fibrillazione atriale non valvolare (FAVN)
Gruppo 1 CHA2DS2-VASC ≥1 eHAS-BLED >3
CHA2DS2-VASC ≥1 eHAS-BLED >3
CHA2DS2-VASC >3 eHAS-BLED >3
Gruppo 2 TTR negli ultimi 6 mesi <70%
TTR negli ultimi 6 mesi <70%
TTR negli ultimi 6 mesi <60%
Gruppo 3 Il trattamento anticoagulante non è attuabile per difficoltà oggettive ad eseguire i controlli INR
Il trattamento anticoagulante non è attuabile per difficoltà oggettive ad eseguire i controlli INR
Il trattamento anticoagulante non è attuabile per difficoltà oggettive ad eseguire i controlli INR
Ai fini dell’eleggibilità bisogna rientrare in una delle seguenti condizioni (1 o 2 o 3)
TTR: ANALISI DI SOTTOGRUPPO TIME TO PRIMARY OUTCOME
TTR = time in therapeutic range; cTTR = centre mean TTR.Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.Wallentin L, et al. Lancet 2010;376:975-983.
Cu
mu
lati
ve h
aza
rd r
ati
o
0.01
0.03
0.04
0.05
0.06
0
0.02
0 0.5 1.0 1.5 2.0 2.5
1497 1450 1411 1144 649 274Dabigatran 110 mg1509 1469 1427 1164 699 283Dabigatran 150 mg1504 1445 1395 1094 640 242Warfarin
Number at risk
cTTR <57.1%
0.01
0.03
0.04
0.05
0.06
0
0.02
0 0.5 1.0 1.5 2.0 2.5
1524 1477 1440 1169 783 3791526 1493 1453 1192 801 3941514 1476 1438 1175 752 351
cTTR 57.1–65.5%
Cu
mu
lati
ve h
aza
rd r
ati
o
0.01
0.03
0.04
0.05
0.06
0
0.02
0Follow-up (yrs)
0.5 1.0 1.5 2.0 2.5
1474 1456 1420 1142 760 370Dabigatran 110 mg1484 1419 1419 1153 761 369Dabigatran 150 mg1487 1458 1436 1150 755 359Warfarin
Number at risk
cTTR 65.5–72.6%
0.01
0.03
0.04
0.05
0.06
0
0.02
0 0.5 1.0 1.5 2.0 2.5
1482 1444 1405 1108 730 3471514 1487 1437 1135 750 3671509 1476 1440 1166 737 366
Follow-up (yrs)
cTTR >72.6%
WarfarinDabigatran 150 mg Dabigatran 110 mg
TTR: ANALISI DI SOTTOGRUPPO TIME TO MAJOR BLEEDING
WarfarinDabigatran 150 mg Dabigatran 110 mgC
um
ula
tive h
aza
rd r
ati
o
0 0.5 1.0 1.5 2.0 2.5
Dabigatran 110 mgDabigatran 150 mgWarfarin
Number at risk
cTTR <57.1%
0
0.02
0.06
0.08
0.10
0.12
0.04
149715091504
144314481430
139813991371
113511351065
647680614
274276231
0 0.5 1.0 1.5 2.0 2.5
cTTR 57.1–65.5%
0
0.02
0.06
0.08
0.10
0.12
0.04
152415261514
146514671460
141614161403
113911601140
753774729
362377333
Cu
mu
lati
ve h
aza
rd r
ati
o
0Follow-up (yrs)
0.5 1.0 1.5 2.0 2.5
Dabigatran 110 mgDabigatran 150 mgWarfarin
Number at risk
cTTR 65.5–72.6%
0
0.02
0.06
0.08
0.10
0.12
0.04
1474 1445 1392 1108 736 3641484 1415 1372 1105 715 3431487 1445 1398 1121 725 344
0 0.5 1.0 1.5 2.0 2.5Follow-up (yrs)
cTTR >72.6%
0
0.02
0.06
0.08
0.10
0.12
0.04
1482 1438 1385 1087 706 3361514 1455 1399 1109 716 3501509 1452 1411 1129 714 354
TTR = time in therapeutic range; cTTR = centre mean TTR; HR = hazard ratio; CI = confidence interval.Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation outside the US and Canada.Wallentin L, et al. Lancet 2010;376:975-983.
Wallentin et al. Circulation 2013; 127: 2166-76
TTR subgroup analysis: intracranial bleeding
cTTR
Dabigatran
110 mg
Dabigatran
150 mgWarfarin
Dabigatran 110 mgvs warfarin
Dabigatran 150 mgvs warfarin
Rate per100
person-yrs
Rate per100
person-yrs
Rate per100
person-yrs
HR(95% CI)
P value*(interactio
n)
HR (95% CI)
P value*(interaction
)
<57.1%
0.28 0.34 0.64 0.43(0.19–1.00)
0.53 (0.25–1.15)
57.1–65.5%
0.30 0.42 0.93 0.31(0.15–0.66)
0.45(0.24–0.88)
65.5–72.6%
0.13 0.24 0.67 0.20(0.07–0.58)
0.35(0.15–0.82)
>72.6%
0.21 0.30 0.77 0.27(0.11–0.66)
0.71 0.39(0.18–0.84)
0.89
*Interaction P value evaluated by a multivariate approach with centre-based TTR as a continuous variablecTTR = centre mean TTR; HR = hazard ratio; INR = international normalized ratio; TTR = time in therapeutic range Wallentin L et al. Lancet 2010;376:975–83
Reduced risk of intracranial bleeding with both doses vs warfarin, irrespective of centre-based INR control
VALVULAR HEART DISEASE and PROSTHETIC VALVE
NOACs
Non valvular atrial fibrillation
PATIENTS EXCLUDED
ARISTOTELE: moderate or severe mitral stenosis
ENGAGE TIMI 38: moderate or severe mitral stenosis
RE-LY: mitral stenosishemodynamically relevant valve disease that is expected to
require surgical intervention during the course of the study
ROCKET AF: Hemodynamically significant mitral valve stenosis
VHD PATIENTS
ARISTOTELE: 4808 (26,4%) patients had a history of VHD at baseline
RE-LY: 21,8% dei pz con VHD
ROCKET AF: 14,1% had severe valvular disease
ENGAGE TIMI 38: mancanza di dati pubblicati
Valvular heart disease patients in NOACs trials
VHD in ARISTOTLE4808 (26,4%) patients had a history of VHD
at baseline
Any VHD* 4.808 100.0%Any mitral valve disease
3.578 74.4
Mitral regurgitation 3.526 73.3
Mitral stenosis 131 2.7
Any aortic valve disease
1.150 23.9
Aortic stenosis 887 18.4
Aortic regurgitation 384 8.0
Tricuspidal regurgitation
2.124 44.2
Prior valve surgery 251 5.2
ESC Congress 2013, Dr Alvaro Avezum, Duke Clinical Research Institute
VHD in RE-LY3950 VHD (21.8% of 18113 pz)
Any VHD 3950 100.0%Any mitral valve disease
83,4
Mitral regurgitation 3.101 78,5
Mitral stenosis 193 4,9
Any aortic valve disease
32,6
Aortic stenosis 471 11,9
Aortic regurgitation 817 20,7
Tricuspidal regurgitation
1179 29,8
JACC 2014 63 SA 325 Michael D. Ezekowitz Poster Contribution
NEJM, 2013 Sep, 26; 369:1206-14
NEJM, 2013 Sep, 26; 369:1206-14
NEJM, 2013 Sep, 26; 369:1206-14
NEJM, 2013 Sep, 26; 369:1206-14
RE-ALIGN
ATLANTIS trial: Apixaban in patients who underwent a clinically successful TAVI procedure
* Standard of Care
** 2.5mg bid if creatinine clearance 15-29mL/min or if two of the following criteria: age ≥80 years, weight ≤ 60kg or creatinine ≥1,5mg/dL (133µMol)
1509 patients after successful TAVI procedure Stratum 2
No indication for anticoagulation
Stratum 1Indication for anticoagulatio
n
R 1:1
R 1:1
Primary endpoint composite of death, myocardial Infarction, stroke/TIA/systemic emboli, intracardiac or bioprosthesis thrombus, episode of deep vein thrombosis or pulmonary embolism, major bleedings over 6 months of follow-up
6 m
on
ths o
f fo
llow
-u
p
Apixaban 5mg twice daily
2.5 mg twice daily in select patients**
SOC*-VKA
SOC-DAPT/ SAPT
Design and execution of this trial is not yet finalized and may be subject to further changes
NOACs in RENAL FAILURE
APIXABAN
Se due di tre:• età >80 anni• Creatinina > 1,5 mg/dl• peso <60 Kg
Utilizzare 2,5 mg BID
Altrimenti 5 mg BID
ClCr 15-29 ml/min Utilizzare 2,5 BID
NOACs in RENAL FAILURE
DABIGATRAN RIVAROXABAN
ClCr <15 ml/min non raccomandato non raccomandato
ClCr 15-30 ml/min non raccomandato (75 mg BID in USA)
ClCr 30-50 ml/min 110 mg BID
ClCr 15-50 ml/min 15 mg/die
ClCr >50ml/min 150 mg BID 20 mg/die
NOACs in RENAL FAILURE
Pengo V. et al. Thromb Haemost 2012; 10:1979-87
Clearance cratinineNumber of patients included in NOACs Trials
DRUG INTERACTIONS
Possible drug-drug interactions – Effect on NOAC plasma levels part 1
Dabigatran Apixaban Edoxaban Rivaroxaban
Atorvastatin P-gp/ CYP3A4 +18%no data
yetno effect no effect
Digoxin P-gp no effectno data
yetno effect no effect
Verapamil P-gp/ wk CYP3A4+12–180% no data
yet
+ 53% (slow release) minor effect
Diltiazem P-gp/ wk CYP3A4 no effect +40% No data minor effect
Quinidine P-gp +50%no data
yet+80% +50%
Amiodarone P-gp +12–60%no data
yetno effect minor effect
Dronedarone P-gp/CYP3A4 +70–100%no data
yet+85% no data yet
Ketoconazole; itraconazole; voriconazole; posaconazole;
P-gp and BCRP/ CYP3A4
+140–150% +100% no data yet up to +160%
Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present; hatching – no data available; recommendation made from pharmacokinetic considerations
EHRA GL 2013
Possible drug-drug interactions – Effect on NOAC plasma levels part 2
Interaction Dabigatran Apixaban Edoxaban Rivaroxaban
Fluconazole CYP3A4 no data no data no data +42%
Cyclosporin; tacrolimus
P-gp no data no data no data +50%
Clarithromycin; erythromycin
P-gp/ CYP3A4 +15–20% no data no data +30–54%
HIV protease inhibitors
P-gp and BCRP/ CYP3A4
no data strong increase no data up to +153%
Rifampicin; St John’s wort; carbamezepine; phenytoin; phenobarbital
P-gp and BCRP/ CYP3A4/CYP2J2
-66% -54% -35% up to -50%
Antacids GI absorption -12-30% no data no effect no effect
Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present; hatching – no data available; recommendation made from pharmacokinetic considerations
EHRA GL 2013
Warfarin Conclusions
➢Warfarin will continue to be used in patients with mecanical prosthetic heart valve and patients with rheumatic valve disease
➢Warfarin will continue to be used in patients with severe renal failure
➢Warfarin will continue to be used in patients with drug-drug interactions
➢NOAs should be considered rather than adjusted-dose VKA for most patietns with NVAF, based on their net clinical benefit
Assume that NAOs have been on the market for 5 year
➢A new drug comes to the market. Compared to NAOs, the new drug has:
- cheaper- antidote- requirement for monthly monitoring to adjust dose- many food and drug interactions- 25% increased relative risk of stroke/systemic embolism- nearly 50% increased relative risk of major bleeding- approx. 2.5 times the rate of ICH- 10% increased relative risk of mortality
➢Would Warfarin be approved by regulatory authorities now?
GRAZIE PER L’ATTENZIONE
www.docvadis.it/agostisergio
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