When and how to combine antiplatelet agents and anticoagulant?

Transcription

1 When and how to combine antiplatelet agents and anticoagulant? Christophe Beauloye, MD, PhD Head, Division of Cardiology Cliniques Universitaires Saint-Luc Brussels, Belgium

2 Introduction Anticoagulation platelet inhibition ATRIAL FIBRILLATION the combination of Aspirin and Clopidogrel is not effective as Warfarin in patients with AF From The ACTIVE Writing Group on behalf of the ACTIVE Investigators Lancet 2006; 367: STENTING the combination of Aspirin and thienopyridine is more effective than Warfarin in patients with coronary stents From Leon et al., NEJM 1998;339:

3 Introduction Anticoagulation platelet inhibition ATRIAL FIBRILLATION the combination of Aspirin and Clopidogrel is not effective as Warfarin in patients with AF Risk of Stroke (%) From The ACTIVE Writing Group on behalf of the ACTIVE Investigators Lancet 2006; 367: ACTIVE W

4 Introduction Anticoagulation platelet inhibition STENTING the combination of Aspirin and thienopyridine is more effective than Warfarin in patients with coronary stents Death, TVR, stent thrombosis or MI (%) days STARS from Leon et al., NEJM 1998;339:

5 Introduction Anticoagulation platelet inhibition BEYOND STENTS, ACUTE CORONARY SYNDROMES the combination of Aspirin and thienopyridine is more effective than Aspirin alone CV Death, Non Fatal Myocardial Infarction or Stroke Cumulative Hazard Rate Placebo Clopidogrel (Plavix ) Loading dose 300 mg 75 mg per day from CURE, NEJM 2001:345; CURE Placebo Clopidogrel Months of Follow-up

6 Introduction Anticoagulation platelet inhibition Combination of anticoagulation and (D)APT Bleeding? DAPT Anticoagulation ACS - Stenting AF + stent Atrial fibrillation New P2Y 12 inhibitors? (N)OAC

7 Introduction Anticoagulation platelet inhibition Combination of anticoagulation and (D)APT DAPT Anticoagulation ACS - Stenting Bleeding?

8 Prolonged anticoagulation post-acs Persistent thrombin generation post-acs From Merlini et al, Circulation. 1994;90:61-68.

9 Prolonged anticoagulation post-acs Secondary prevention good compliers (> 70 % at 35 d) poor compliers (<70 % at 35 d) 25 P = P = 0.16 CV death, MI, stroke (%) P = 0.02 P = standard OAC CV death, MI, stroke, Rehospitalisation (%) standard AOC 0 good compliers poor compliers 0 good compliers Poor compliers good compliance is associated with a reduction in major ischemic cardiovascular events OASIS-2 From OASIS investigators JACC 2001;37:

10 Prolonged anticoagulation post-acs PCI Secondary prevention in-hospital follow-up 0-4 to 8 days from hospital discharge P2Y12 inhibitors! Anti-coagulant?

11 Prolonged anticoagulation post-acs Secondary prevention - Rivaroxaban phase II trial Features Rivaroxaban Apixaban Dabigatran etexilate Acronym ATLAS APRAISE REDEEM n STEMI/NSTEMI (%) 52/ / /40 Dual PLT inhibition (%) Duration (months) Dosage BID Safety outcome Dose-dependent increase in bleeding complications Based on De Caterina et al. JACC 2012;59:

12 Prolonged anticoagulation post-acs Secondary prevention - Rivaroxaban phase II trial dose escalation 3576 patients with a recent ACS stabilised 1-7 d after index event treat with thienopyridine? Stratum 1 no randomisation Stratum 2 yes randomisation Rivaroxaban placebo Rivaroxaban placebo follow-up 6 months from Mega JL et al., Lancet 2009;374:29-38

13 Prolonged anticoagulation post-acs Secondary prevention - Rivaroxaban increased risk of bleeding from Mega JL et al., Lancet 2009;374:29-38

14 Prolonged anticoagulation post-acs Secondary prevention - Rivaroxaban phase III trial patients with a recent ACS stabilised 1-7 d after index event (STEMI, NSTEMI, UA) ASA mg/d with thienopyridine (90 %) Placebo Rivaroxaban 2.5 mg 2x/d Rivaroxaban 5 mg 2x/d Efficacy: death, MI, stroke Primary endpoints Safety: TIMI major bleeding not associated with CABG Rivaroxaban for AF = 20 mg 1x/d (15 mg 1x/d) from Mega JL et al., NEJM 2012;366:9-19

15 Prolonged anticoagulation post-acs Secondary prevention - Rivaroxaban Death / MI / Stroke (%) % 8.9 % HR 0.84 ( ) P = NNT Months after Randomization ATLAS ACS 2 TIMI 51 from Mega JL et al., NEJM 2012;366:9-19

16 Prolonged anticoagulation post-acs Secondary prevention - Rivaroxaban % Stent thrombosis (%) ARC definite, probable, possible % HR 0.69 ( ) P = 0.02 Months after Randomization ATLAS ACS 2 TIMI 51 from Mega JL et al., NEJM 2012;366:9-19

17 Prolonged anticoagulation post-acs Secondary prevention - Rivaroxaban 12 CV death, MI, stroke (%) 8 4 P = % 9.1 % CV death (%) P = % 2.7 % Months after Randomization Months after Randomization ATLAS ACS 2 TIMI 51 from Mega JL et al., NEJM 2012;366:9-19

18 Prolonged anticoagulation post-acs Secondary prevention - Rivaroxaban Rivaroxaban 2.5 mg 2x/d Rivaroxaban 5 mg 2x/d Placebo TIMI major bleeding (non CABG) 1.8 % 2.4 % 0.6 % P value versus placebo < < TIMI bleeding requiring med. attention 12.9 % 16.2 % 7.5 % P value versus placebo < < Intracranial hemorrhage 0.4 % 0.7 % 0.2 % P value versus placebo Fatal bleeding 0.1 % 0.4 % 0.2 % P value versus placebo ATLAS ACS 2 TIMI 51 from Mega JL et al., NEJM 2012;366:9-19

19 Prolonged anticoagulation post-acs Secondary prevention - Rivaroxaban Rivaroxaban Low and high dose expression of inflammatory mediators In apoe-deficient mice from Zhouet al., Mediators of inflammation 2011

20 Prolonged anticoagulation post-acs Secondary prevention - Apixaban Apixaban 5 mg 2x/d Apixaban for AF = 5 mg 2x/d Probability of CV death, MI, stroke Months after Randomization APPRAISE 2 from Alexander et al., NEJM 2011;365:

21 Prolonged anticoagulation post-acs Secondary prevention - Apixaban Apixaban 5 mg 2x/d Apixaban for AF = 5 mg 2x/d Probability of TIMI major bleeding Months after Randomization Trial prematurely terminated because of an increase in major bleeding events APPRAISE 2 from Alexander et al., NEJM 2011;365:

22 Prolonged anticoagulation post-acs Anticoagulation versus Aspirin Death, MI, stroke Bleeding Events (%) None ASA ASA + clopidogrel ASA + Prasugrel ASA + Ticagrelor ASA + Clopidogrel + Rivaroxaban

23 Prolonged anticoagulation post-acs Anticoagulation versus Aspirin? 3037 patients randomized after having been started on DAPT At least Up to 48 hours 10 days Rivaroxaban 2.5mg bid ACS Event STEMI* Non-STEMI UA Clopidogrel + ASA or Ticagrelor + ASA Randomize + pre-randomization P2Y12 inhibitor* >6 months duration of therapy ASA 100mg + pre-randomization P2Y12 inhibitor* outcomes **Ticagrelor 90mg bid or Clopidogrel 75mg daily Primary: TIMI major + minor + bleeding requiring medical attention up to day 390. Exploratory ischaemic endpoints included the composite of cardiovascular death, myocardial infarction, stroke, or definite stent thrombosis; all-cause death; GEMINI - ACS from Ohman et al., Lancet 2017;in press

24 Prolonged anticoagulation post-acs Anticoagulation versus Aspirin TIMI non-cabg clinically significant bleeding (%) days GEMINI - ACS from Ohman et al., Lancet 2017;in press

25 Combination in Afib patients The problem Combination of anticoagulation and (D)APT ACS - Stenting AF + stent Atrial fibrillation New P2Y 12 inhibitors? NOAC

26 Combination in Afib patients Triple therapy double therapy Combination of anticoagulation and (D)APT? Gold Standard : Aspirin + Clopidogrel + AVK? DAPT 573 patients with long-term indication for oral anticoagulation treatment (until at least 1 year after the study), undergoing PCI PCI - ACS % - DES 65 % Anticoagulation AF 70 % Randomize Double therapy (284) Clopidogrel VKA Triple therapy (289) ASA Clopidogrel VKA WOEST From De Wilde et al., Lancet 2013; 381:

27 Combination in Afib patients Triple therapy double therapy Combination of anticoagulation and (D)APT Any bleeding (%) death, MI, stroke, target-vessel revascularisation, and stent thrombosis (%) Use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events WOEST From De Wilde et al., Lancet 2013; 381:

28 Combination in Afib patients Guidelines how? Combination of anticoagulation and (D)APT - Guidelines From Kirchhof et al., European Heart Journal (2016) 37,

29 Combination in Afib patients Guidelines how? Combination of anticoagulation and (D)APT - Guidelines From Kirchhof et al., European Heart Journal (2016) 37,

30 Combination in Afib patients Guidelines how? Combination of anticoagulation and (D)APT - Guidelines Short period of triple therapy (OAC, aspirin, clopidogrel) is recommended, followed by a period of dual therapy (OAC plus a single antiplatelet) The use of prasugrel or ticagrelor as part of triple therapy should be avoided unless there is a clear need for these agents (e.g. stent thrombosis on aspirin plus clopidogrel), given the lack of evidence and the greater risk of major bleeding compared with clopidogrel. The dose intensity of OAC should be carefully monitored with a target INR of in patients treated with VKA (with the exception of individuals with mechanical prosthetic valves in the mitral position). The lowest dose effective of (N)OAC for stroke prevention in AF should be considered. Rivaroxaban 15 mg Apixaban 2.5 mg Dabigatran 110 mg Gastric protection with a proton pump inhibitor is recommended From Kirchhof et al., European Heart Journal (2016) 37,

31 Combination in Afib patients Afib trial - Dabigatran Combination of (N)OAC and (D)APT Dabigatran etexilate 110 mg BID was noninferior to warfarin in reducing stroke and systemic embolism, whether patients received antiplatelets RE-LY From Dans et al., Circulation. 2013;127:

32 Combination in Afib patients Afib trial - Dabigatran Combination of (N)OAC and (D)APT RE-LY From Dans et al., Circulation. 2013;127: Events rate (%/year) In the time-dependent analysis, concomitant use of a single antiplatelet increased the risk of major bleeding. Dual antiplatelet increased this even more. The absolute risks were lowest on dabigatran 110 mg BID in comparison with dabigatran 150 mg BID or warfarin.

33 Combination in Afib patients (N)OAC prospective data? Combination of (N)OAC and (D)APT 2100 patients with non-valvular atrial fibrillation undergoing PCI (coronary stenting) No prior stroke/tia, GI bleeding, CrCl < 30 ml/min Randomize 1, 6 or 12 months Pre-randomization choice AVK Clopidogrel 75 mg qd Aspirin mg qd Rivaroxaban 2.5 mg bid Clopidogrel 75 mg qd Aspirin 75 mg qd Rivaroxaban 15 mg qd AVK Rivaroxaban 15 mg qd Clopidogrel 75 mg qd Aspirin mg qd Aspirin mg qd outcomes Triple therapy ATLAS like Primary: TIMI major + minor + bleeding requiring medical attention Secondary: CV death, MI, stroke WOEST like

34 Combination in Afib patients (N)OAC prospective data? Combination of (N)OAC and (D)APT CumulativeIncidenceofClinically SignificantBleeding(%) NNT 11 to 12 VKA + DAPT Riva + DAPT Riva + P2Y 12 days PIONEER AF-PCI From Gibson et al., NEJM 2016;375:

35 Combination in Afib patients (N)OAC prospective data? Combination of (N)OAC and (D)APT CumulativeIncidenceofaMajorAdverse CardiovascularEvent(%) No change in stroke Riva + P2Y 12 VKA + DAPT Riva + DAPT days PIONEER AF-PCI From Gibson et al., NEJM 2016;375:

36 Combination in Afib patients (N)OAC prospective data? Combination of (N)OAC and (D)APT From Gibson et al., NEJM 2016;375: PIONEER AF-PCI From Gibson et al., Circulation. 2017;135:

37 Combination in Afib patients (N)OAC prospective data? Combination of (N)OAC and (D)APT rehospitalisation(%) days PIONEER AF-PCI From Gibson et al., Circulation. 2017;135:

38 Conclusion Efficacy - safety balance ATRIAL FIBRILLATION PCI Double therapy Asa? Clopidogrel The lowest dose effective of (N)OAC for stroke prevention ACS PCI secondary prevention DAPT using new P2Y12 inhibitors Low dose of Rivaroxaban (without ASA?)

39 Introduction Platelets, coagulation cascade and thrombus Coagulation cascade Collagen + other mediators Platelets Anticoagulants Xa Thromboxane ADP Antiplatelets Inflammation Cellular proliferation Thrombin Thrombin Activated platelet Fibrinogen GPIIb/IIIa Fibrin Platelet aggregation Clot

40 Prolonged anticoagulation post-acs Secondary prevention - Rivaroxaban 6 All Placebo (n = 1160) 5.5% Death / MI / Stroke (%) 4 2 All Rivaroxaban (n = 2331) 3.9% HR 0.69 ( ) P = Days After Randomization 180 ATLAS-TIMI 46 from Mega JL et al., Lancet 2009;374:29-38