Le nuove frontiere dell’anticoagulazione nel paziente con fibrillazione atriale 14-15 Novembre 2014 Gavi Prevenzione dell’ictus nella fibrillazione atriale: ancora un ruolo per ASA e VKA? Risposta a BMJ: capire se monitoraggio possa migliorare i dati di outcome, intanto accontentiamoci del fatto che con due dosaggi fissi somministrati in fx dell fx renale i risultati sono stati superiori in termini di efficacia e sicurezza al warfarin. I risultati attuali non dimostrano ancora come modulare la posologia di pradaxa in base ai valori ematici si rifletta su un miglioramento di outcome clinici forti… quindi nao sebbene perfettibile sia attualmente il gold standard… noi non usiamo ancora i nao che già vorremmo avere qualcosa che funziona meglio… Dott. Sergio Agosti Cardiologo, Ospedale Novi Ligure (AL) agostisergio@virgilio.it http://www.arcaliguria.it/

ASA

However, this is not consistent with the latest treatment guidelines2 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 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 = 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

ASA?? Camm AJ et al. Eur Heart J

Current Guidelines do not recommend ASA for stroke prevention in most NVAF patients 2012 ESC Guidelines1 NICE 2014 Guidelines on the management of AF2 “Do not offer aspirin monotherapy solely for stroke prevention with atrial fibrillation” 1 Camm AJ et al. Eur Heart J 2012 2 NICE clinical Guideline. 2014. The management of AF

Limited efficacy of ASA in reducing stroke risk in patients with AF RRR (%)† 100 –100 50 –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 trials Only the SPAF trial showed a benefit of ASA over placebo for reducing stroke risk A meta-analysis of study data showed that ASA had a limited and non-significant effect on stroke risk in patients with AF. Analysis of data from 7 trials involving 3990 patients that compared ASA alone with placebo or no treatment showed that ASA was associated with a 19% (95% CI, –1% to 35%) reduction in the incidence of stroke. When only strokes classified as ischaemic were considered (5 trials), ASA treatment resulted in a 21% (CI, –1% to 38%) reduction in strokes. Only one study, the SPAF trial, showed a significant benefit of ASA over placebo in reducing stroke risk, with a 44% risk reduction. Hart RG et al. Ann Intern Med 2007;146:857–67 RRR: 19%* (95% CI: –1 to 35%) 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 day Hart RG et al. Ann Intern Med 2007;146:857–67

ASA was less effective than VKA in historical trials in AF RRR (%)† 100 –100 50 –50 AFASAK I (1990) BAFTA (2007) EAFT (1993) PATAF (1999) Warfarin better ASA better Chinese ATAFS (2006) SPAF II (1994) Age 75 yrs Age >75 yrs All trials (4620 pt) Meta-analysis of data from 8 studies comparing ASA with adjusted-dose warfarin (n=3647) showed that warfarin provided a 38% (95% CI, 18 to 52%) reduction in stroke risk. Thus, ASA was shown to be statistically inferior to warfarin for stroke prevention in AF. Hart RG et al. Ann Intern Med 2007;146:857–67 RRR: 38%* (95% CI: 18-52%) Random effects model; error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes (ischaemic and haemorrhagic); ASA = acetylsalicylic acid Hart RG et al. Ann Intern Med 2007;146:857–67

Intracranial bleeding Risk of major and intracranial bleeding not significantly different between ASA and OAC Tot Pt 182,678 ASA (n=61 396) OAC (n=48 599) 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 3 4 5 6 7 HAS-BLED total score* Intracranial bleeding Bleeds/year Major bleeding 5 10 15 20 25 1 2 3 4 6 7 HAS-BLED total score* Bleeds/year The risk of major and intracranial bleeding does not differ significantly between treatment with ASA and OACs. This study stratified 182,678 patients by their modified HAS-BLED score, which assesses their risk of bleeding from the number of risk factors present (hypertension, renal dysfunction, stroke, bleeding, age >65 years, drugs affecting bleeding or alcohol abuse).1,2 The rates of major and intracranial bleeding were similar for patients using ASA or OACs.2 Bleeding risk increased with increasing HAS-BLED scores, irrespective of whether the patient was taking ASA, OAC, OAC plus ASA, or no antithrombotic therapy.2 Pisters R et al. Chest 2010;138:1093–100 Friberg L et al. Eur Hear J 2012:33:1500-10; *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 acid Friberg L et al. Eur Hear J 2012:33:1500-10; Pisters R et al. Chest 2010;138:1093–100

Quando pubblicato…??

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 CHA2DS2-VASc Recommendation Class* Level† No antithrombotic therapy I B 1 OAC therapy with Adjusted-dose VKA (INR 2–3); or A direct thrombin inhibitor (dabigatran); or An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban) …should be considered IIa A ≥2 An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban) …is recommended *Class of recommendation; †Level of evidence; OAC, oral anticoagulant 1. Camm et al. Eur Heart J 2012;33:2719–2747.

ESC 2012 Guideline recommendations1 Recommendations for prevention of thromboembolism in NVAF—NOACs Class* Level† Where OAC is recommended, one of the NOACs, either: A direct thrombin inhibitor (dabigatran); or An oral factor Xa inhibitor (e.g. rivaroxaban, apixaban) …should be considered rather than adjusted-dose VKA (INR 2–3) for most patients with NVAF, based on their net clinical benefit IIa A *Class of recommendation; †Level of evidence; OAC, oral anticoagulant 1. Camm et al. Eur Heart J 2012;33:2719–2747.

-60% RR Hart RG et al. Ann Intern Med 2007;146:857–67

Lancet, published online December 4, 2013

STROKE OR SYSTEMIC EMBOLISM NNT 173 Ruff CT,Lancet, December 4, 2013

MAJOR BLEEDING Ruff CT,Lancet, December 4, 2013

EFFICACY AD SAFETY SECONDARY ENDPOINTS NNT PER ICH è 140 ICH NNT 141 Ruff CT,Lancet, December 4, 2013

Condizioni di ingresso 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) Ai fini dell’eleggibilità bisogna rientrare in una delle seguenti condizioni (1 o 2 o 3) Gruppo 1 CHA2DS2-VASC ≥1 e HAS-BLED >3 CHA2DS2-VASC >3 Gruppo 2 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

TTR: ANALISI DI SOTTOGRUPPO TIME TO PRIMARY OUTCOME Dabigatran 150 mg Dabigatran 110 mg Warfarin 0.06 0.06 cTTR <57.1% cTTR 57.1–65.5% 0.05 0.05 0.04 0.04 Cumulative hazard ratio 0.03 0.03 0.02 0.02 0.01 0.01 Number at risk 0.5 1.0 1.5 2.0 2.5 0.5 1.0 1.5 2.0 2.5 Dabigatran 110 mg 1497 1450 1411 1144 649 274 1524 1477 1440 1169 783 379 Dabigatran 150 mg 1509 1469 1427 1164 699 283 1526 1493 1453 1192 801 394 Warfarin 1504 1445 1395 1094 640 242 1514 1476 1438 1175 752 351 0.06 0.06 cTTR 65.5–72.6% cTTR >72.6% 0.05 0.05 0.04 0.04 Cumulative hazard ratio 0.03 0.03 0.02 0.02 0.01 0.01 0.5 1.0 1.5 2.0 2.5 0.5 1.0 1.5 2.0 2.5 Number at risk Follow-up (yrs) Follow-up (yrs) Dabigatran 110 mg 1474 1456 1420 1142 760 370 1482 1444 1405 1108 730 347 Dabigatran 150 mg 1484 1419 1419 1153 761 369 1514 1487 1437 1135 750 367 Warfarin 1487 1458 1436 1150 755 359 1509 1476 1440 1166 737 366 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.

TTR: ANALISI DI SOTTOGRUPPO TIME TO MAJOR BLEEDING Dabigatran 150 mg Dabigatran 110 mg Warfarin Cumulative hazard ratio 0.5 1.0 1.5 2.0 2.5 Dabigatran 110 mg Dabigatran 150 mg Warfarin Number at risk cTTR <57.1% 0.02 0.06 0.08 0.10 0.12 0.04 1497 1509 1504 1443 1448 1430 1398 1399 1371 1135 1065 647 680 614 274 276 231 0.5 1.0 1.5 2.0 2.5 cTTR 57.1–65.5% 0.02 0.06 0.08 0.10 0.12 0.04 1524 1526 1514 1465 1467 1460 1416 1403 1139 1160 1140 753 774 729 362 377 333 Cumulative hazard ratio Follow-up (yrs) 0.5 1.0 1.5 2.0 2.5 Dabigatran 110 mg Dabigatran 150 mg Warfarin Number at risk cTTR 65.5–72.6% 0.02 0.06 0.08 0.10 0.12 0.04 1474 1445 1392 1108 736 364 1484 1415 1372 1105 715 343 1487 1398 1121 725 344 0.5 1.0 1.5 2.0 2.5 Follow-up (yrs) cTTR >72.6% 0.02 0.06 0.08 0.10 0.12 0.04 1482 1438 1385 1087 706 336 1514 1455 1399 1109 716 350 1509 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 Nell’ir nao utili in tutti i gradi di ir - sottopopolazioni, no in ir avanzata… Wallentin et al. Circulation 2013; 127: 2166-76

TTR subgroup analysis: intracranial bleeding Reduced risk of intracranial bleeding with both doses vs warfarin, irrespective of centre-based INR control cTTR Dabigatran 110 mg Dabigatran 150 mg Warfarin Dabigatran 110 mg vs warfarin Dabigatran 150 mg vs warfarin Rate per 100 person-yrs HR (95% CI) P value* (interaction) HR (95% CI) <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 0.77 0.27 (0.11–0.66) 0.71 0.39 (0.18–0.84) 0.89 Non è stato ristretta indicazione perché su emorragia intracranica non c’è differenza per TTR. Mi serve diapo dove ci sia rappresentazione grafica intuitiva dell’HR delle sottopopolazioni TTR per l’emorragia intracranica. Vorrei far passare il concetto che anche se il beneficio in termini di endpoint primario si riduce al confronto con un Coumadin con TTR molto alto, il sanguinamento intracranico risulta progressivamente più a favore di dabigatran anche nella sottopolazione con TTR più elevato. *Interaction P value evaluated by a multivariate approach with centre-based TTR as a continuous variable cTTR = centre mean TTR; HR = hazard ratio; INR = international normalized ratio; TTR = time in therapeutic range Wallentin L et al. Lancet 2010;376:975–83

Interazioni farmacologiche

VALVULAR HEART DISEASE and PROSTHETIC VALVE

Non valvular atrial fibrillation NOACs Non valvular atrial fibrillation

Valvular heart disease patients in NOACs trials PATIENTS EXCLUDED ARISTOTELE: moderate or severe mitral stenosis ENGAGE TIMI 38: moderate or severe mitral stenosis RE-LY: mitral stenosis hemodynamically 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

ESC Congress 2013, Dr Alvaro Avezum, Duke Clinical Research Institute VHD in ARISTOTLE 4808 (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-LY 3950 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

Studio di fase II. Tre dosaggi in base a cl cr 150x2, 220x2, 300x2 fino a raggiungere dosaggio ematico di dabigatran pari a 50 ng (dosaggio efficace nel rely). Due gruppi: popolazione A ha iniziato D entro una sett dall’intervento, popol B ha iniziato D a 3 mesi dall’intervento. Gli eventi ischemici cerebrali e le emorragie maggiori (emopericardio) sono stati nella popolaz A. Anche se TIA e sanguinam minori sono stati maggiori nella popolaz B vs Warfarin NEJM, 2013 Sep, 26; 369:1206-14

NEJM, 2013 Sep, 26; 369:1206-14

NEJM, 2013 Sep, 26; 369:1206-14

RE-ALIGN NEJM, 2013 Sep, 26; 369:1206-14

1509 patients after successful TAVI procedure ATLANTIS trial: Apixaban in patients who underwent a clinically successful TAVI procedure SOC*-VKA Stratum 1 Indication for anticoagulation R 1:1 Apixaban 5mg twice daily 2.5 mg twice daily in select patients** 1509 patients after successful TAVI procedure 6 months of follow-up Stratum 2 No indication for anticoagulation R 1:1 SOC-DAPT/ SAPT Phase 4, randomised, open label, parallel group (N-1500) To asses whether anticoagulation with apixaban is not less safe than standard of care therapy in patients with valvular heart disease following transcatheter aortic valve implantation (TAVI) 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 * 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) Design and execution of this trial is not yet finalized and may be subject to further changes

NOACs in RENAL FAILURE

NOACs in RENAL FAILURE Se due di tre: età >80 anni 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 ClCr 15-30 ml/min (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

Scala di jadad 3 per rely e 4 per aristotele e rocket… valutazione della qualità dei trials… (da 1 a 5) Pengo V. et al. Thromb Haemost 2012; 10:1979-87

Number of patients included in NOACs Trials Clearance cratinine Number 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 yet no effect Digoxin P-gp Verapamil P-gp/ wk CYP3A4 +12–180% + 53% (slow release) minor effect Diltiazem +40% No data Quinidine +50% +80% Amiodarone +12–60% Dronedarone P-gp/CYP3A4 +70–100% +85% Ketoconazole; itraconazole; voriconazole; posaconazole; P-gp and BCRP/ CYP3A4 +140–150% +100% 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 Dabigatran Apixaban Edoxaban Rivaroxaban Fluconazole CYP3A4 no data +42% Cyclosporin; tacrolimus P-gp +50% Clarithromycin; erythromycin P-gp/ CYP3A4 +15–20% +30–54% HIV protease inhibitors P-gp and BCRP/ CYP3A4 strong increase 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 effect Non dimentichiamo che apixaban e rivarox hanno un metabolismo da parte del citocromo P 450 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