NOAC s post Myocardial Infarction Peter Clemmensen MD, PhD, FESC, FSCAI Chief of Cardiology

Transcription

1 NOAC s post Myocardial Infarction Peter Clemmensen MD, PhD, FESC, FSCAI Chief of Cardiology Department of Medicine Division of Cardiology Nykøbing F Hospital Denmark

2 Disclosure of Conflict of Interest The presenter has previously or currently been involved in research contracts, consulting, speakers bureau or received research and educational grants from: Abbott, AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli- Lilly, Evolva, Fibrex, Janssen, Merck, Myogen, Medtronic, Mitsubishi Pharma, The Medicines Company, Nycomed, Organon, Pfizer, Pharmacia, Regado, Sanofi, Searle, Servier.

3 STEMI: ESC guidelines 2012

4 PLATO or ATLAS TIMI 51? Drug A Control HR, p- value CV-death 4% 5.1% 0.79, p=0.001 Drug B Control HR, p- value 2.7% 4.1% 0.66, p=0.002 All-cause mortality 4.5% 5.9% 0.78, p< % 4.5% 0.68, p=0.002 ICH 0.3% 0.2% 1.87, p= % 0.2% 2.83, p=0.04 ICH fatal 0.1% 0.01% P= % 0.1% - Fatal Bleeding 0.3% 0.3% 0.87, p= % 0.2% 0.67, p=0.45

5 A daily clinical dilemma

6 The rationale of adding an anticoagulant to antiplatelet therapy

7 Thrombus formation involves both platelet activation and blood coagulation Anticoagulants Rivaroxaban Apixaban Edoxaban Inflammation Cellular proliferation Coagulation cascade Factor Xa Thrombin Collagen + other mediators Thromboxane ADP Thrombin Platelets Activated platelet Antiplatelets ASA Clopidogrel Prasugrel Ticagrelor Fibrinogen GPIIb/IIIa GPIIb/IIIa inhibitors Fibrin Platelet aggregation Mackman N. Nature, 2008 Clot

8 The late consequences of ACS: GRACE UK- Belgian study Eur Heart J 2010; 31(22):

9 Meta-analysis of anticoagulation: Efficacy of adding warfarin on top of ASA Study, year Rate ratio (95% CI) Events/ patient-years Weight (%) Warfarin ASA ATACS pilot, ( ) 0.5 0/9 1/7 ATACS main, ( ) 5.7 6/24 9/25 Williams et al., ( ) 1.3 1/6 5/5 APRICOT 2, ( ) 3.1 3/34 11/35 OASIS main, ( ) /373 52/375 OASIS pilot, ( ) 5.2 5/25 10/25 Huynh et al., ( ) 0.8 2/38 1/39 ASPECT 2, ( ) /298 14/289 Zibaeenezhad et al., ( ) 2.9 4/70 6/70 WARIS II, ( ) /4, /4,669 Overall 0.56 ( ) /5, /5, Favours warfarin 1.0 Rate ratio Recurrent MI 5.0 Favours ASA Prevent 19 MIs per 1,000 pt-years Rothberg MB, et al. Ann Int Med. 2005

10 Meta-analysis of anticoagulation: Safety of adding warfarin on top of ASA Study, year Major bleeding Rate ratio (95% CI) Events/ patient-years Weight (%) Warfarin ASA ATACS main, ( ) 1.8 3/24 0/25 Williams et al., ( ) 1.7 1/6 0/5 APRICOT 2, ( ) 4.3 2/34 2/35 OASIS main, ( ) /373 16/375 OASIS pilot, ( ) 2.9 2/25 1/25 Huynh et al., ( ) 1.7 2/38 0/39 ASPECT 2, ( ) 8.7 7/298 3/289 Zibaeenezhad et al., ( ) 6.1 5/70 2/70 WARIS II, ( ) /4,927 8/4,669 ATACS pilot, 1990 Excluded 0/9 0/7 Overall 2.48 ( ) /5,804 32/5, Favours warfarin Rothberg MB, et al. Ann Int Med Rate ratio Increase 9 bleeds per 1,000 pt-years 5.0 Favours ASA

11 WARIS II and OASIS 2: Compliance with warfarin post ACS Withdrawal from treatment (%) WARIS II 16 Aspirin (n = 1,206) 32 Warfarin (n = 1,216) 40 ASA + warfarin (n = 1,208) Patients with CVD, MI, CVA (%) Hurlen M, et al. N Engl J Med. 2002; The OASIS Investigators. J Am Coll Cardiol OASIS 2 Standard therapy 8,9 9 6,1 P = 0.02 Good complier countries OAC 7,8 P = 0.33 Poor complier countries

12 AF patients with MI (n=13,970) or PCI (n=2,909) Total 16,879 Excluded (n=4,714) 7-day run-in period No therapy Study population (n=12,165) Follow-up 1 year Mono therapy Dual therapy Triple therapy

13 Hazard ratio (95% CI) Myocardial infarction Ischemic stroke Bleeding Death VKA + clopidogrel VKA + aspirin Aspirin + clopidogrel Ref: Triple therapy

14 Non Vitamin K oral anticoagulants (NOAC s) for secondary prevention in ACS

15 Direct Oral Anticoagulants ximelagatran

16 Phase II trials: NOACs and ACS JACC 2012; 59:1413

17 Phase III trials: APPRAISE-2 and ATLAS ACS-2 JACC 2012; 59:1413

18 ATLAS ACS 2 TIMI 51 A deeper dive

19 ATLAS ACS 2 TIMI 51: a randomized, double-blind, event-driven phase III trial in patients hospitalized with ACS NO Stratum 1: ASA alone (7%) N=15,526* Physician's decision whether or not to add thienopyridine YES Stratum 2: ASA + thienopyridine (93%) Placebo (n=355) Rivaroxaban 2.5 mg bid (n=349) Rivaroxaban 5 mg bid (n=349) Placebo (n=4821) Rivaroxaban 2.5 mg bid (n=4825) Rivaroxaban 5 mg bid (n=4827) Event-driven study 983 events ASA dose: mg Patients with prior stroke were excluded from Stratum 2. *184 patients were excluded from the efficacy analyses prior to unblinding because of trial misconduct at three sites. 1. Gibson et al. Am Heart J 2011;161: e6; 2. Mega et al. N Engl J Med 2012;366:9 19; 3. FDA briefing information (May 23, 2012).

20 ATLAS ACS 2 TIMI 51: rivaroxaban (combined doses) reduced the primary efficacy endpoint vs placebo Estimated cumulative rate (%) Primary efficacy endpoint (CV death/mi/stroke) Combined rivaroxaban doses, both strata Placebo Rivaroxaban 2-year Kaplan Meier estimate 10.7% 8.9% HR=0.84 (95% CI ) ARR=1.8% 4 2 mitt p=0.008 ITT p=0.002 NNT= Months after randomization ARR, absolute risk reduction; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; ITT, intention to treat; MI, myocardial infarction; mitt, modified intention to treat; NNT, number needed to treat. Mega et al. N Engl J Med 2012;366:9 19.

21 Cumulative incidence (%) ATLAS ACS 2 TIMI 51: rivaroxaban 2.5 mg bid significantly reduced CV events and death 13 The primary efficacy endpoint reduction was driven by reduced mortality CV death/mi/stroke (primary efficacy endpoint) HR=0.84 mitt p=0.02 Placebo ITT p= % 5 Cardiovascular death HR=0.66 mitt p=0.002 ITT p=0.005 Placebo 4.1% 5 All-cause death HR=0.68 mitt p=0.002 ITT p=0.004 Placebo 4.5% 9.1% 2.7% 2.9% Rivaroxaban 2.5 mg bid Rivaroxaban 2.5 mg bid Rivaroxaban 2.5 mg bid NNT=63 NNT= Months Months Months Both strata. bid, twice daily; CV, cardiovascular; HR, hazard ratio; ITT, intention to treat; MI, myocardial infarction; mitt, modified intention to treat; NNT, number needed to treat. 1. Mega et al. N Engl J Med 2012;366:9 19; 2. Gibson et al. AHA 2011 ( NNT=63 24

22 Estimated cumulative incidence (%) ATLAS ACS 2 TIMI 51: rivaroxaban significantly reduced stent thrombosis* Both strata 3 2 Placebo Rivaroxaban (pooled) 2-year Kaplan Meier estimate 2.9% 2.3% HR=0.69 ( ) RRR=31% mitt p=0.02 ITT p= Both strata Riva. 2.5 mg bid Placebo HR (95% CI) P-value 2-year K M estimate 2.2% 2.9% 0.65 ( ) Months after randomisation *Stent thrombosis events: definite, probable or possible (Academic Research Consortium [ARC] definitions). HR, hazard ratio; ITT, intention to treat; mitt, modified intention to treat; RRR, relative risk reduction Gibson et al. J Am Coll Cardiol 2013;62:

23 2-year Kaplan Meier estimate (%) ATLAS ACS 2 TIMI 51: Bleeding 3,0 2,5 2,0 1,8 2,4 Placebo Rivaroxaban 2.5 mg bid Rivaroxaban 5 mg bid 1,5 1,0 0,5 0,0 0,6 Rivaroxaban vs placebo p=ns 0,4 0,2 0,2 0,1 Non-CABG TIMI major bleeding event Fatal bleeding events ICH Fatal ICH (principal safety outcome) *p=0.04 vs placebo; # p=0.005 vs placebo; p<0.001 vs placebo. bid, twice daily; CABG, coronary artery bypass graft; ICH, intracranial haemorrhage; NS, not significant. 1. Mega et al. N Engl J Med 2012;366:9 19; 2. Gibson et al. AHA 2011 ( * 0,4 # 0,7 Rivaroxaban vs placebo p=ns 0,1 0,1 0,2

24 Subgroup Analyses for Primary Efficacy Endpoint (mitt/all Strata/Combined doses) Hazard Ratio and 95%CI 'Xarelto' Favours Placebo Overall Age [yrs] (<55; 55; <65; 65; <75; 75) Sex (Male; Female) Race (White; Black; Asian; Other) Weight [kg] (<60; 60-<90; 90 kg) BMI [kg/m 2 ] (<25; 25-<30; 30) CrCl [ml/min] (<30; 30-<50; 50-80; >80) Index Event (STEMI; NSTEMI; Unstable angina; NSTEMI+Unstable Angina) Prior MI (yes, no) PCI for Index Event (yes, no) Elevated Cardiac Biomarker (yes, no) Congestive Heart Failure (yes, no) Prior Ischaemic Stroke/TIA (yes, no) Hypertension (yes, no) Diabetes (yes, no) Region (East Europe; Western Europe; North America; South America; Asia; Others)

25 Estimated cumulative incidence (%) Estimated cumulative incidence (%) ATLAS ACS 2 TIMI 51 - STEMI subgroup rivaroxaban 2.5 mg bid CV death/mi/stroke (primary efficacy endpoint) All-cause death 10 8 ITT: HR=0.81 (95% CI ) mitt: HR=0.85 (95% CI ) Placebo 10 8 ITT: HR=0.63 (95% CI: ) mitt: HR=0.60 (95% CI: ) 6 4 Rivaroxaban 2.5 mg bid 6 4 Placebo Months Both strata. bid, twice daily; CV, cardiovascular; HR, hazard ratio; ITT, intention to treat; MI, myocardial infarction; mitt, modified intention to treat Mega et al. J Am Coll Cardiol 2013;61: Months Rivaroxaban 2.5 mg bid

26 New antiplatelet agents vs NOACs in ACS N Engl J Med. 2012;366(1):85

27 Conclusions Warfarin + ASA versus ASA alone reduces the risk of CV events but at the expense of increased bleeding risk NOAC w/ Rivaroxaban + ASA + Clopidogrel prevents recurrent CV events in patients with ACS, including stent thrombosis and CV death DAPT with ASA + Ticagrelor or Prasugrel (or Clopidogrel) remain the dominant antithrombotic regimen after ACS Lack of knowledge: combination of NOACs with potent P2Y12 receptor inhibitors, possibly without ASA the ideal NOAC dose and antiplatelet regimen in A-fib patients undergoing PCI

28 Conclusions Low dose Rivaroxaban might be administered to high risk ACS patients with contraindications to ticagrelor or prasugrel

29 Back UP

30 In conclusion There is no place for routine use of NOACs in ACS Long term benefit is really modest, unless the lowest dose of a NOAC is selected, and the advantages are significantly limited by the excess of bleeding complications It is difficult to identify the subset of patients potentially candidate to this type of treatment and we still miss elements to better stratify patients at risk of severe hemorrhages Ideally low dose rivaroxaban might be administered to high risk patients with contraindications to antiplatelet agents more effective than clopidogrel or to the association of aspirin with a P2Y12 receptor inhibitor (single antiplatelet therapy), provided that the risk of bleeding complications is very low

31 Take-home Messages Triple therapy (OAC, clopidogrel and ASA) after PCI for ACS in AF leads to unacceptably high bleeding complications. Possibly, ASA can be skipped The most recent guidelines mandate for most patients with AF undergoing PCI triple therapy for the shortest period as clinically acceptable. The use of prasugrel or ticagrelor in this situation is discouraged In patients with AF undergoing PCI for ACS NOACs seem preferable because of their safety profile, but prospective trial data are necessary to support this 3.

32 Other key ongoing international studies Study Acronym PIONEER AF-PCI Full Study Title An open-label, randomised, controlled, multicentre study exploring two treatment strategies of Rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with Atrial Fibrillation who undergo Percutaneous Coronary Intervention X-PLORER Prospective, multi-center, randomised, heparin-controlled dose-finding trial to evaluate the efficacy and safety of rivaroxaban, a direct factor Xa inhibitor, on the background of standard dual antiplatelet therapy to support elective percutaneous coronary intervention COMPASS A randomised controlled trial of rivaroxaban for the prevention of major cardiovascular events in patients with coronary or peripheral artery disease (Short study title - Cardiovascular OutcoMes for People using Anticoagulation StrategieS) COMMANDER HF A Randomized, Double-blind, Event-driven, Multicenter Study Comparing the Efficacy and Safety of Oral Rivaroxaban With Placebo for Reducing the Risk of Death, Myocardial Infarction or Stroke in Subjects With Chronic Heart Failure and Significant Coronary Artery Disease Following a Hospitalization for Exacerbation of Heart Failure

33 X-PLORER: 'Xarelto' in patients undergoing elective PCI Objective: To investigate if 'Xarelto', with or without an additional bolus of unfractionated heparin (UFH), could suppress coagulation activation during elective PCI 'Xarelto' 20 mg* Index PCI Population: symptomatic CAD undergoing elective PCI N=108 R 'Xarelto' 10 mg* 'Xarelto' 10 mg* plus UFH 50 IU/kg bolus Up to 30 days UFH IU/kg bolus # *Single dose before index PCI procedure # Adjusted upon activated coagulation time of secs All patients on dual antiplatelet therapy. CAD, coronary artery disease; PCI, percutaneous coronary intervention; R, randomization (EudraCT )

34 COMPASS: 'Xarelto' in CAD/PAD Objective: To evaluate the efficacy and safety of 'Xarelto' vs low-dose 'Xarelto' plus ASA or ASA alone for reducing risk of MI, stroke or CV death in CAD or PAD 'Xarelto' 2.5 mg bid + ASA 100 mg od ± pantoprazole 40 mg od Population: documented CAD or PAD N~19,500 R 'Xarelto' 5.0 mg bid ± pantoprazole 40 mg od 30-day washout period Start: Q1-13 End: ~Q1-18 ASA 100 mg od ± pantoprazole 40 mg od ASA, acetylsalicylic acid; bid, twice daily; CAD, coronary artery disease; CV, cardiovascular; MI, myocardial infarction; od, once daily; PAD, peripheral artery disease; R, randomization (EudraCT )

35 COMMANDER HF: 'Xarelto' in patients with heart failure Objective: efficacy and safety of 'Xarelto' for reducing the risk of MI, stroke or death in HF with CAD 'Xarelto' 2.5 mg bid (plus standard of care) Population: HF and CAD after recent hospitalization N=5000 R ~6 30 months day follow-up Start: Q3-13 End: ~Q1-16 Placebo (plus standard of care) Global treatment end date* End of study visit *Date when 984 primary efficacy outcome events have occurred. bid, twice daily; CAD, coronary artery disease; HF, heart failure; MI, myocardial infarction; R, randomization (EudraCT )