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Le nuove frontiere dell’anticoagulazione nel paziente con fibrillazione atriale 14-15 Novembre 2014 Gavi Dott. Sergio Agosti Cardiologo, Ospedale Novi.

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Presentation on theme: "Le nuove frontiere dell’anticoagulazione nel paziente con fibrillazione atriale 14-15 Novembre 2014 Gavi Dott. Sergio Agosti Cardiologo, Ospedale Novi."— Presentation transcript:

1 Le nuove frontiere dell’anticoagulazione nel paziente con fibrillazione atriale Novembre 2014 Gavi Dott. Sergio Agosti Cardiologo, Ospedale Novi Ligure (AL) Prevenzione dell’ictus nella fibrillazione atriale: ancora un ruolo per ASA e VKA?

2 ASA

3 Introduction to ASA One of the most widely used drugs of the 20th century 1 Taken by millions of patients worldwide for the treatment and prevention of CVD, and is the most widely tested antiplatelet drug 1 Has been (and is still) used for stroke prevention in AF 1,2 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 stroke 1,2 However, this is not consistent with the latest treatment guidelines 2

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5 ASA?? Camm AJ et al. Eur Heart J

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

7 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 day Hart RG et al. Ann Intern Med 2007;146:857–67 RRR (%) † 100–100500–50 AFASAK (1989) SPAF (1991) EAFT (1993) ESPS II (1997) ASA betterPlacebo better LASAF (1997) 125 mg/d 125 mg QOD UK-TIA (1999) 300 mg/d 1200 mg/d JAS (2006)T All trials RRR: 19%* ( 95% CI: –1 to 35%) Only the SPAF trial showed a benefit of ASA over placebo for reducing stroke risk

8 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 acid Hart RG et al. Ann Intern Med 2007;146:857–67 8 RRR (%) † 100–100500–50 AFASAK I (1990) BAFTA (2007) EAFT (1993) PATAF (1999) Warfarin betterASA better Chinese ATAFS (2006) SPAF II (1994) Age  75 yrs Age >75 yrs All trials (4620 pt) RRR: 38%* ( 95% CI: 18-52%)

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10 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 acid Friberg L et al. Eur Hear J 2012:33: ; Pisters R et al. Chest 2010;138:1093–100 ASA (n=61 396) Major bleeding HAS-BLED total score* Bleeds/year HAS-BLED total score* Intracranial bleeding Bleeds/year OAC (n=48 599) Tot Pt 182,678

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22 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

23 Warfarin

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25 ESC 2012 Guideline recommendations 1 1. Camm et al. Eur Heart J 2012;33:2719–2747. *Class of recommendation; † Level of evidence; OAC, oral anticoagulant

26 1. Camm et al. Eur Heart J 2012;33:2719–2747. *Class of recommendation; † Level of evidence; OAC, oral anticoagulant ESC 2012 Guideline recommendations 1

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

28 Lancet, published online December 4, 2013

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

30 MAJOR BLEEDING Ruff CT,Lancet, December 4, 2013

31 EFFICACY AD SAFETY SECONDARY ENDPOINTS ICH NNT 141 Ruff CT,Lancet, December 4, 2013

32 EliquisPradaxaXarelto Condizioni di ingresso Paziente con fibrillazione atriale non valvolare (FAVN) cronica o parossistica (>65 anni) Paziente con fibrillazione atriale non valvolare (FAVN) Gruppo 1 CHA 2 DS 2 -VASC ≥1 e HAS-BLED >3 CHA 2 DS 2 -VASC ≥1 e HAS-BLED >3 CHA 2 DS 2 -VASC >3 e HAS-BLED >3 Gruppo 2TTR 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 Ai fini dell’eleggibilità bisogna rientrare in una delle seguenti condizioni (1 o 2 o 3)

33 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: Cumulative hazard ratio Dabigatran 110 mg Dabigatran 150 mg Warfarin Number at risk cTTR <57.1% cTTR 57.1–65.5% Cumulative hazard ratio Follow-up (yrs) Dabigatran 110 mg Dabigatran 150 mg Warfarin Number at risk cTTR 65.5–72.6% Follow-up (yrs) cTTR >72.6% Warfarin Dabigatran 150 mg Dabigatran 110 mg

34 TTR: ANALISI DI SOTTOGRUPPO TIME TO MAJOR BLEEDING Warfarin Dabigatran 150 mg Dabigatran 110 mg Cumulative hazard ratio Dabigatran 110 mg Dabigatran 150 mg Warfarin Number at risk cTTR <57.1% cTTR 57.1–65.5% Cumulative hazard ratio 0 Follow-up (yrs) Dabigatran 110 mg Dabigatran 150 mg Warfarin Number at risk cTTR 65.5–72.6% Follow-up (yrs) cTTR >72.6% 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:

35 Wallentin et al. Circulation 2013; 127:

36 TTR subgroup analysis: intracranial bleeding 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) P value* (interaction) <57.1% (0.19–1.00) 0.53 (0.25–1.15) 57.1– 65.5% (0.15–0.66) 0.45 (0.24–0.88) 65.5– 72.6% (0.07–0.58) 0.35 (0.15–0.82) >72.6% (0.11–0.66) (0.18–0.84) 0.89 *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 Reduced risk of intracranial bleeding with both doses vs warfarin, irrespective of centre-based INR control

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38 VALVULAR HEART DISEASE and PROSTHETIC VALVE

39 NOACs Non valvular atrial fibrillation

40 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 Valvular heart disease patients in NOACs trials

41 VHD in ARISTOTLE 4808 (26,4%) patients had a history of VHD at baseline Any VHD* % Any mitral valve disease Mitral regurgitation Mitral stenosis Any aortic valve disease Aortic stenosis Aortic regurgitation Tricuspidal regurgitation Prior valve surgery ESC Congress 2013, Dr Alvaro Avezum, Duke Clinical Research Institute

42 VHD in RE-LY 3950 VHD (21.8% of pz) Any VHD % Any mitral valve disease83,4 Mitral regurgitation ,5 Mitral stenosis1934,9 Any aortic valve disease32,6 Aortic stenosis47111,9 Aortic regurgitation81720,7 Tricuspidal regurgitation117929,8 JACC SA 325 Michael D. Ezekowitz Poster Contribution

43 NEJM, 2013 Sep, 26; 369:

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46 RE-ALIGN

47 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 1 Indication for anticoagulation 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 months of follow-up 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

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49 NOACs in RENAL FAILURE

50 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 ml/min Utilizzare 2,5 BID NOACs in RENAL FAILURE

51 DABIGATRANRIVAROXABAN ClCr <15 ml/minnon raccomandato ClCr ml/minnon raccomandato (75 mg BID in USA) ClCr ml/min110 mg BID ClCr ml/min15 mg/die ClCr >50ml/min150 mg BID20 mg/die NOACs in RENAL FAILURE

52 Pengo V. et al. Thromb Haemost 2012; 10:

53 Clearance cratinine Number of patients included in NOACs Trials

54 DRUG INTERACTIONS

55 Possible drug-drug interactions – Effect on NOAC plasma levels part 1 DabigatranApixabanEdoxabanRivaroxaban AtorvastatinP-gp/ CYP3A4+18%no data yetno effect DigoxinP-gpno effectno data yetno effect VerapamilP-gp/ wk CYP3A4 +12–180% no data yet + 53% (slow release) minor effect DiltiazemP-gp/ wk CYP3A4no effect+40%No dataminor effect QuinidineP-gp+50%no data yet+80%+50% AmiodaroneP-gp+12–60%no data yetno effectminor effect DronedaroneP-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 yetup 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

56 Possible drug-drug interactions – Effect on NOAC plasma levels part 2 InteractionDabigatranApixabanEdoxabanRivaroxaban Fluconazole CYP3A4no data +42% Cyclosporin; tacrolimus P-gpno data +50% Clarithromycin; erythromycin P-gp/ CYP3A4+15–20%no data +30–54% HIV protease inhibitors P-gp and BCRP/ CYP3A4 no datastrong increaseno dataup to +153% Rifampicin; St John’s wort; carbamezepine; phenytoin; phenobarbital P-gp and BCRP/ CYP3A4/CYP2J2 -66%-54%-35%up to -50% AntacidsGI absorption-12-30%no datano 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

57 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

58 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?

59 GRAZIE PER L’ATTENZIONE


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