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Triple Antithrombotic Therapy in Cardiac Patients Elizaveta P. Panchenko, MD,PhD Cardiology Research and Production Center Moscow Russian Federation September.

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Presentation on theme: "Triple Antithrombotic Therapy in Cardiac Patients Elizaveta P. Panchenko, MD,PhD Cardiology Research and Production Center Moscow Russian Federation September."— Presentation transcript:

1 Triple Antithrombotic Therapy in Cardiac Patients Elizaveta P. Panchenko, MD,PhD Cardiology Research and Production Center Moscow Russian Federation September 17, 2014

2 Disclosures Consultancy fees or honoraria from SANOFI, Takeda-NYCOMED, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Bayer, Lilly, AstraZeneca, GlaxoSmithKline, MEDICINES

3 Triple antithrombotic therapy 1.Aspirin 2.Р 2 Y 12 antagonists: clopidogrel, prasugrel, ticagrelor 3.Oral anticoagulants: vitamin K antagonists, dabigatran, apixaban, rivaroxaban

4 Cardiac Patients Who Need Triple Antithrombotic Therapy  Patients with indications for long anticoagulant therapy: atrial fibrillation, venous thromboembolism, mechanical valve surgery, thrombosis of left ventricle If they have acute coronary syndrom (ACS) If they need elective PCI because of angina pectoris

5 1.Analysis of 261 consecutive pts with AF undergoing CAG: The rate of CAD – 34% The need of PCI /CABG – 21% 2.The frequency of AF (Meta-analysis pts from 10 clinical trials) - in pts with STEMI – 8% - in pts with NSTE-ACS - 6,4% % of pts with ACS have AF 1 -Kralev et al., PLoSOne.2011;6:e Lopes et al. Heart.2008;94: Schmitt et al., EHJ.2009; 30: COEXISTENCE OF CORONARY ARTERY DISEASE AND ATRIAL FIBRILLATION

6 BOTH DISEASES DEMAND ANTITHROMBOTIC THERAPY Acute Coronary Syndrome Aspirin (forever) Р 2 Y 12 inhibitor: Clopidogrel, Prasugrel, Ticagrelor (12 months) Atrial Fibrillation Warfarin Dabigatran Rivaroxaban Apixaban Aspirin Aspirin+Clopidogrel Dual antiplatelet therapyAnticoagulant

7 Bleedings worsen the outcomes in patients receiving the antithrombotic therapy Achilles' heel

8 BLEEDINGS SIGNIFICANTLY INCREASE THE RISK OF DEATH OASIS-5 dataset

9 What do we know about the frequency of bleedings in patients with antithrombotic therapy?

10 Major Bleedings In AF Patients Receiving Antithrombotic Therapy AspirinAspirin + ClopidogrelWarfarin 1,3%(ACTIVE-A) 1,2%(AVERROES) 2,0% (ACTIVE-W)1,5-3,0% Randomized trials

11 ANTITHROMBOTIC THERAPY AND RISK OF BLEEDINGS IN PATIENTS WITH ATRIAL FIBRILLATION Antithrombotic therapyHR95% CI Warfarin2,081,95-2,23 Clopidogrel1,571,37-1,81 Aspirin1,251,17-1,34 Aspirin + Clopidogrel1,681,44-1,97 Warfarin+Aspirin2,872,58-3,19 Warfarin+Clopidogrel2,742,14-3,51 Warfarin+Aspirin+Clopidogrel3,752,7-5,19  70,760 patients with AF (UKGPRD registry)  years follow up  10,850 patients had bleedings during follow up

12 Fatal and nonfatal bleedings* according to antithrombotic regimen in time periods following inclusion (Denmark register) Lamberts M et al. Circulation. 2012;126:  pts with AF and MI/PCI between y.  Mean age -75,6 y.  Male -60,9% *- reguiring hospitalisation Triple-22,6% VKA+ ASP/CLOPI - 20,3% VKA

13 HOW TO MINIMIZE THE RISK OF BLEEDINGS? 1. To decrease the number of antithrombotic drugs

14 What do we know about efficacy and safety of antiplatelet drugs in prevention of stroke in AF patients?

15 ASPIRIN IS SUPERIOR TO PLACEBO STROKE PREVENTION IN ATRIAL FIBRILLATION

16 Major bleedings ОР (95%CI) 1,56 ( ) р=0,07 % RR (95%CI) 1,57 (1.29-1,92) р<0,001 2,0 % 1,3% 0,2% 0,3% RR 11% р=0,01 RR 28% р<0,001 RR 22% р=0,08 %  7,554 pts with AF, those didn’t wish or couldn’t intake warfarin  33 countries, follow-up – 3,6 years ASP+CLOPI are superior to ASP, STROKE PREVENTION IN AF PATIENTS ACTIVE-A but induce more bleedings… Connolly et all, N Engl J Med 2009;360:

17 WARFARIN IS SUPERIOR TO ASPIRIN STROKE PREVENTION IN ATRIAL FIBRILLATION  VKA therapy is more effective than aspirin, relative risk reduction of stroke/SE on warfarin is 39%  In AF patients with high risk of stroke/SE (>6% per year) RRR is more higher - 50%

18 The ACTIVE Writing Group Lancet 2006; 367: Stroke + SE +MI +CVD Warfarin is superior to CLOPI+ASP Warfarin Clopi+Asp STROKE PREVENTION IN ATRIAL FIBRILLATION ACTIVE-W

19 Ха Thrombin Rivaroxaban Apixaban Dabigatran Edoxaban Fibrin  The NOACs fall into two classes: the oral direct thrombin inhibitors (dabigatran) and oral direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)  In contrast to VKAs, which block the formation of multiple active vitamin K dependent coagulation factors (factors II,VII,IX and X), NOACs target selectively the individual step in coagulation cascade VKA

20 Apixaban is Superior to Aspirin AVERROES Stroke or Systemic EmbolismMajor Bleeding Cumulative Hazard STROKE PREVENTION IN ATRIAL FIBRILLATION  5,599 pts with AF at increased risk of stroke to whom VKA therapy was unsuitable  Randomization Apixaban 5mg twice daily or Aspirin mg per day  Mean follow up period 1,1 year

21  All NOACs have demonstrated non-inferiority compare to warfarin with better safety by consistently limiting the number of ICH  Guideline now recommends them as broadly preferable to VKA in the vast majority of patients with NVAF

22

23 What do we know about efficacy and safety of warfarin in patients survived acute coronary syndrome?

24 Warfarin (INR 2,0-2,5) in addition to Aspirin 80 mg per day   the risk of cardio-vascular events (ASPECT-2, OASIS-2, WARIS-II),   the risk of re-occlusion of IRA in patients with MI and thrombolysis (APRICOT-2)  no increase of major bleeding (ASPECT-2, OASIS-2) Warfarin (INR 2,8-3,2) is superior to Aspirin 80 mg  the risk of cardio-vascular events (ASPECT-2, WARIS-II) WARFARIN in Patients Survived Acute Coronary Syndrome Conservative strategy of treatment, before «clopidogrel era» Major bleeding WARIS II CURE AspirinAspirin + Warfarin (INR 2,2) Warfarin (INR 2,8) Aspirin + Clopidogrel 0,15% per year 0,52% per year 0,58% per year 3,6% per 9 months

25 WARFARIN AND ANTIPLATELET DRUG IN PATIENTS SURVIVED ACUTE CORONARY SYNDROM WARFARIN +ASPIRIN are better than ASPIRIN in prevention of recurrent events, moreover, benefits are more than risk of bleeding in patients with medium and low bleeding risk (WARIS-2) CONSERVATIVE STATEGY

26 HOW TO MINIMIZE THE RISK OF BLEEDINGS? 1.To decrease the number of antithrombotic drugs 2.To choose the optimal combination of anticoagulant (VKA or novel oral anticoagulant) and antiplatelet drugs (aspirin or clopidogrel or aspirin+clopidogrel)

27 Is it suitable to withdraw aspirin from triple therapy (asp+clopi+VKA) in patients after PCI?

28 Incidence of any bleeding Cumulative incidence of death, MI, Stroke, TVR and stent thrombosis W JM Dewilde et al., for the WOEST study investigators Clopidogrel+VKA versus Clopidogrel+VKA+Aspirin in PCI Patients  An open-labelled, multicentred, randomised, controlled trial  573 on VKA were enrolled, 279 pts assigned double therapy and 284 assigned triple therapy  Indication for oral anticoagulation (AF-67%, Mechanical valve-11%, Other.-20%)  ACS-25-30%; EF-13-15%; Radial access-25-27%

29 ESC, Hotline III, Munchen, August 28th, 2012 Death, MI, Stroke, TVR and stent thrombosis (subgroup analysis) WOEST HR

30 All-Cause Mortality Days Cumulative incidence of death % 2.5 % 5 % 7.5 % n at risk: % 2.6% HR= %CI[ ] p=0.027 Triple therapy group Double therapy group WOEST ESC, Hotline III, Munchen, August 28th, 2012

31 WARFARIN AND ANTIPLATELET DRUG IN PATIENTS SURVIVED ACUTE CORONARY SYNDROM WOEST WARFARIN + CLOPIDOGREL are better than WARFARIN +ASPIRIN +CLOPIDOGREL in the frequency of bleeding complications and similar in the rate of thrombotic events PCI TREATMENT

32 What about adding novel oral anticoagulant to dual antiplatelet therapy in patients survived acute coronary syndrome?

33 Apixaban with Antiplatelet therapy after Acute Coronary Syndrome (APPRAISE-2) Probability of TIMI major bleeding Probability of CVD/MI/Stroke  Randomized, double-blind controlled clinical trial comparing apixaban, at dose of 5 mg twice daiy with placebo in addition to standard antiplatelet therapy in pts with a recent ACS and at least 2 additional RF for recurrent ischemic events

34 Probability of major and clinically relevant minor bleedings Dabigatran vs. placebo in ACS patients with dual antiplatelet therapy A randomized, double-blind, phase II trial  Dabigatran, in a dose dependent manner, increases bleeding events during dual antiplatelet therapy

35 98,7% -intake aspirin 92,6% -intake clopidogrel This dose is less than dose for patients with AF BLEEDINGS2,5 twice daily N=5114 Placebo N=5113 TIMI major not associated with CABG 65 (1,8%)19 (0,6%) TIMI minor32 (0,9%)20 (0,5%) Intracranial14 (0,4%)5 (0,2%) Fatal6 (0,1%)9 (0,2%) Rivaroxaban in Patients with a Recent Acute Coronary Syndrome (ATLAS ACS 2-TIMI 51)  Double-blind, placebo-controlled trial  Patients with recent ACS, n=15526 (Api 2,5mg twice daily or Api 5 mg twice daily or placebo)  Mean follow-up - 13 months  Primary efficacy end point – CVD/MI/Stroke  In pts with recent ACS Riva reduced risk of death from cardiovascular causes, MI or stroke.  Riva increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding

36 NEW ORAL ANTICOAGULANTS AS COMPONENTS OF TRIPLE THERAPY

37  18,113 pts with AF in RELY  6,952 pts (38,4%) also received an antiplatelet therapy during the study  5,789 pts on aspirin alone  351 pts on clopidogrel alone  812 pts on both drugs Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in RELY Trial WARF D-150 D Major bleeding rate (%/year)  Concomitant antiplatelet drugs appeared to increase the risk of major bleedings in RELY with no advantage of dabigatran over warfarin

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39 These recent recommendations are based on expert consensus and observational trials and ma ny questions do remain unanswered…

40 GENERAL RECOMMENDATIONS ClassLevel 1. In AF patients stroke risk must be assessed using the CHA2DS2VASc score, and bleeding risk assessed using the HAS-BLED score. Risk stratification must be performed at regular intervals. a) HAS-BLED score should be used to identify and correct potentially reversible bleeding risk factors b) GRACE score should be used to stratify ACS risk IC 2. If VKA is used good quality anticoagulation control is recommended with TTR>70% IA 3. When VKA is given in combination with clopidogrel and/or aspirin target INR 2,0-2,5 IIaC 4. Where a NOAC is used in combination with clopidogrel and/or low dose aspirin, the lower tested dose for stroke prevention in AF may be considered (dabi- 110mg b.I.d., riva- 15mg o.d., api-2,5 mg b.i.d.) IIbC 5. In pts with AF and stable vascular disease (free from any acute ischaemic event or repeat revascularization >1 year) the patient should be managed with OAC alone (whether NOAC or VKA) IIaB 6. Radial access should be considered as the default for CAG/PCI to minimize the risk of access related bleeding depending on operator expertise and preference IIaC 7. New generation DES may be preferred over BMS in pts at low risk of bleeding (HAS-BLED 0-2) IIbC 8.Novel P2Y12 receptor inhibitors (prasugrel and ticagrelor) should not be part of triple therapy in pts with AF IIIC

41 SCHEME OF ANTITHROMBOTIC THERAPY IN PATIENTS WITH AF *- Dual therapy with OAC+Clopi may be considered in selected pts **- Asp may be considered in pts on dual therapy ***- Dual therapy (OAC+Asp/Clopi) may be considered in pts at very high risk of coronary event

42 SCHEME OF ANTITHROMBOTIC THERAPY IN PATIENTS WITH AF *- Dual therapy with OAC+Clopi may be considered in selected pts **- Asp may be considered in pts on dual therapy ***- Dual therapy (OAC+Asp/Clopi) may be considered in pts at very high risk of coronary event

43 NOAC trials are ongoing

44  The period of triple therapy should be as short as possible  The duration of triple therapy depends on a number of considerations: acute or elective PCI, HAS-BLED score, type of stent with preference for new generation of DES or BMS  Use aspirin in low doses: mg daily  Use clopidogrel as preferred P2Y12 inhibitor to more potent ticagrelor or prasugrel  OAC – well-controlled adjusted dose warfarin (INR 2,0-2,5; TTR>70%) or NOAC  Use BMS*, thus minimizing the duration of triple therapy  Use the radial approach thus minimizing the risk of bleeding at the access site The optimal NOAC regimen for patients with AF and ACS or undergoing PCI has not been addressed by RCT * - It is uncertain whether BMS use requires a shorter duration of dual therapy than new generation DES. New data on dual therapy cessation shows no difference between BMS and DES, especially with new generation stents. CONCLUSIONS

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46 Recommendation on the Management of patients on Oral Anticoagulation With ACS and/or Undergoing PCI I.Risk Stratification and Balance (CHA 2 DS 2 -Vasc risk scores) for assessing the risk of stroke, and HAS-BLED to assess bleeding risk in pts with AF)

47 PHARMACOLOGY OF THE NOVEL ANTICOAGULANTS

48 Is it always necessary to avoid aspirin from the combinatory therapy?


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