4Cardiac Patients Who Need Triple Antithrombotic Therapy Patients with indications for long anticoagulant therapy: atrial fibrillation, venous thromboembolism, mechanical valve surgery, thrombosis of left ventricleIf they have acute coronary syndrom (ACS)If they need elective PCI because of angina pectorisLong –term treatment with oral anticoagulant is necessary in pts with AF, VTE, mechanical heart valves and other clinical situations. Up to 20-30% of pts on VKA have the concomitant diagnosis of CAD and thus are potential candidates for percutaneous coronary intervention (PCI) with stenting. In these cases, double antiplatelet therapy is indicated to prevent stent thrombosis.
5COEXISTENCE OF CORONARY ARTERY DISEASE AND ATRIAL FIBRILLATION Analysis of 261 consecutive pts with AF undergoing CAG:The rate of CAD – 34%The need of PCI /CABG – 21%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 AF1-Kralev et al., PLoSOne.2011;6:e24964.2-Lopes et al. Heart.2008;94:3-Schmitt et al., EHJ.2009; 30:
6BOTH DISEASES DEMAND ANTITHROMBOTIC THERAPY Acute Coronary SyndromeAspirin (forever)Р2Y12 inhibitor: Clopidogrel, Prasugrel, Ticagrelor (12 months)Atrial FibrillationWarfarinDabigatranRivaroxabanApixabanAspirinAspirin+ClopidogrelAccording to modern recommendations both diseases demand administration of antithrombotic therapy. ACS patients need of two antiplatelet agents: aspirin and one of P2Y12 inhibitors (clopidogrel or prasugrel or ticagrelor). And patients with AF are needed in oral anticoagulant (warfarin, or one of new anticoagulants). Efficacy of aspirin and dual antiplattlet therapy is significant lower than anticoagulants in stroke prevention.Dual antiplatelet therapyAnticoagulant
7Achilles' heelBleedings worsen the outcomes in patients receiving the antithrombotic therapyNow is well established that severe bleeding may have deleterious effects on mortality.
8BLEEDINGS SIGNIFICANTLY INCREASE THE RISK OF DEATH The OASIS -5 study was the first demonstrated this position. In this study enoxaparin was compared with fondaparinux in ACS pts. The study demonstrated that there were less bleeding complications in fonda group and bleeding increases risk of death significantlyOASIS-5 dataset
9What do we know about the frequency of bleedings in patients with antithrombotic therapy?
10Major Bleedings In AF Patients Receiving Antithrombotic Therapy Randomized trialsAspirinAspirin + ClopidogrelWarfarin1,3%(ACTIVE-A)1,2%(AVERROES)2,0% (ACTIVE-W)1,5-3,0%
11Antithrombotic therapy ANTITHROMBOTIC THERAPY AND RISK OF BLEEDINGS IN PATIENTS WITH ATRIAL FIBRILLATION70,760 patients with AF (UKGPRD registry)years follow up10,850 patients had bleedings during follow upAntithrombotic therapyHR95% CIWarfarin2,081,95-2,23Clopidogrel1,571,37-1,81Aspirin1,251,17-1,34Aspirin + Clopidogrel1,681,44-1,97Warfarin+Aspirin2,872,58-3,19Warfarin+Clopidogrel2,742,14-3,51Warfarin+Aspirin+Clopidogrel3,752,7-5,19As you can see from the results of this register, which reflects the real clinical practice, addition of both aspirin and clopidogrel to the drug regimen of patients already on anticoagulants increases the risk of bleeding.
12Fatal and nonfatal bleedings Fatal and nonfatal bleedings* according to antithrombotic regimen in time periods following inclusion (Denmark register)11480 pts with AF and MI/PCI between y.Mean age -75,6 y.Male -60,9%Triple-22,6%VKA+ ASP/CLOPI - 20,3%VKACrude incidence rates of fatal and nonfatal bleeding according to antithrombotic regimen in time periods following inclusion. Error bars show standard errors. Triple therapy includes aspirin, clopidogrel, and vitamin K antagonists (VKAs); VKA+single antiplatelet therapy includes VKA+aspirin or clopidogrel; dual antiplatelet therapy includes aspirin and clopidogrel; VKA monotherapy includes only VKA; single antiplatelet therapy includes aspirin or clopidogrel.*- reguiring hospitalisationLamberts M et al. Circulation. 2012;126:
13HOW TO MINIMIZE THE RISK OF BLEEDINGS? To decrease the number of antithrombotic drugs
14What do we know about efficacy and safety of antiplatelet drugs in prevention of stroke in AF patients?
15STROKE PREVENTION IN ATRIAL FIBRILLATION ASPIRIN IS superior to PLACEBO
16STROKE PREVENTION IN AF PATIENTS ACTIVE-AASP+CLOPI are superior to ASP,but induce more bleedings…Major bleedings7,554 pts with AF, those didn’t wish or couldn’t intake warfarin33 countries, follow-up – 3,6 years%RR11%р=0,0128%р<0,00122%р=0,08%2,0%1,3%ОР (95%CI)1,56 ( )р=0,07RR (95%CI)1,57 (1.29-1,92)р<0,0010,3%0,2%Connolly et all, N Engl J Med 2009;360:
17STROKE PREVENTION IN ATRIAL FIBRILLATION Warfarin Is SUPERIOR TO aspirinVKA 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%
18STROKE PREVENTION IN ATRIAL FIBRILLATION ACTIVE-WWarfarin is superior to CLOPI+ASPStroke + SE +MI +CVDWarfarinClopi+AspOral anticoagulation is superior to clopidogrel plus ASA in prevention of vascular events. Rates of major hemorrhage are similar.In warfarin naïve patients curves began to diverge after 6-months lag-period, so warfarin is very effective anticoagulant but with slow beginning of clinical effectThe ACTIVE Writing Group Lancet 2006; 367:
19VKAХаThrombinRivaroxabanApixabanDabigatranEdoxabanThe 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 cascadeVKAVKAVKAFibrin
20STROKE PREVENTION IN ATRIAL FIBRILLATION Apixaban is Superior to Aspirin5,599 pts with AF at increased risk of stroke to whom VKA therapy was unsuitableRandomization Apixaban 5mg twice daily or Aspirin mg per dayMean follow up period 1,1 yearAVERROESStroke or Systemic EmbolismMajor BleedingCumulative Hazard
21All NOACs have demonstrated non-inferiority compare to warfarin with better safety by consistently limiting the number of ICHGuideline now recommends them as broadly preferable to VKA in the vast majority of patients with NVAFAll NOACs have demonstrated noninferiority compare to warfarin with better safety by consistently limiting the number of ICHOn this basis guideline now
23What do we know about efficacy and safety of warfarin in patients survived acute coronary syndrome?
24Aspirin + Warfarin (INR 2,2) WARFARIN in Patients Survived Acute Coronary Syndrome Conservative strategy of treatment, before «clopidogrel era»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)Major bleedingWARIS IICUREAspirinAspirin + Warfarin (INR 2,2)Warfarin (INR 2,8)Aspirin + Clopidogrel0,15% per year0,52% per year0,58% per year3,6% per 9 months
25WARFARIN 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
26HOW TO MINIMIZE THE RISK OF BLEEDINGS? To decrease the number of antithrombotic drugsTo choose the optimal combination of anticoagulant (VKA or novel oral anticoagulant) and antiplatelet drugs (aspirin or clopidogrel or aspirin+clopidogrel)
27Is it suitable to withdraw aspirin from triple therapy (asp+clopi+VKA) in patients after PCI?
28Clopidogrel+VKA versus Clopidogrel+VKA+Aspirin in PCI Patients An open-labelled, multicentred, randomised, controlled trial573 on VKA were enrolled, 279 pts assigned double therapy and 284 assigned triple therapyIndication for oral anticoagulation (AF-67%, Mechanical valve-11%, Other.-20%)ACS-25-30%; EF-13-15%; Radial access-25-27%Cumulative incidence of death, MI, Stroke, TVR and stent thrombosisIncidence of any bleedingThere is only one prospective randomised study WOEST comparing VKA plus clopidogrel with triple therapy in patients undergoing PCI. As you can see from this figure dual therapy was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events. This study was not powered to detect differences in stent thrombosis occurrence.W JM Dewilde et al., for the WOEST study investigators
29Death, MI, Stroke, TVR and stent thrombosis (subgroup analysis) WOESTDeath, MI, Stroke, TVR and stent thrombosis (subgroup analysis)HRage75malet0acsoacind3catdesOverallFALSETRUEnoyesAF/AFlutMechanical valveOtherNoDES2007950234195861622547901942848265214207691642448941842790.91570.82170.7210.11160.77610.7894FactorAgeGenderACSIndicationOACStenttypeSubgroup<75 years>75 yearsfemaleMechanicalvalveBMSTripleVKA+ClopiP-value for interaction0.7210double therapy better <=> triple therapy better0.10.41ESC, Hotline III, Munchen, August 28th, 2012
30All-Cause Mortality WOEST Triple therapy group Double therapy group DaysCumulative incidence of death3060901201802703650 %2.5 %5 %7.5 %284281280279277252n at risk:2782762752742566.4%2.6%HR= %CI[ ]p=0.027Triple therapy groupDouble therapy groupESC, Hotline III, Munchen, August 28th, 2012
31WARFARIN AND ANTIPLATELET DRUG IN PATIENTS SURVIVED ACUTE CORONARY SYNDROM WOESTWARFARIN + CLOPIDOGREL are better than WARFARIN +ASPIRIN +CLOPIDOGREL in the frequency of bleeding complications and similar in the rate of thrombotic eventsPCI TREATMENT
32What about adding novel oral anticoagulant to dual antiplatelet therapy in patients survived acute coronary syndrome?
33Probability of TIMI major bleeding Probability of CVD/MI/Stroke Apixaban with Antiplatelet therapy after Acute Coronary Syndrome (APPRAISE-2)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 eventsProbability of TIMI major bleedingProbability of CVD/MI/Stroke
34Dabigatran vs. placebo in ACS patients with dual antiplatelet therapy A randomized, double-blind, phase II trialProbability of major and clinically relevant minor bleedingsDabigatran, in a dose dependent manner, increases bleeding events during dual antiplatelet therapy
35This dose is less than dose for patients with AF Rivaroxaban in Patients with a Recent Acute Coronary Syndrome (ATLAS ACS 2-TIMI 51)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 bleedingDouble-blind, placebo-controlled trialPatients with recent ACS, n=15526 (Api 2,5mg twice daily or Api 5 mg twice daily or placebo)Mean follow-up - 13 monthsPrimary efficacy end point – CVD/MI/StrokeBLEEDINGS2,5 twice dailyN=5114PlaceboN=5113TIMI major not associated with CABG65 (1,8%)19 (0,6%)TIMI minor32 (0,9%)20 (0,5%)Intracranial14 (0,4%)5 (0,2%)Fatal6 (0,1%)9 (0,2%)This dose is less than dose for patients with AF98,7% -intake aspirin92,6% -intake clopidogrel
36NEW ORAL ANTICOAGULANTS AS COMPONENTS OF TRIPLE THERAPY
37Major bleeding rate (%/year) Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in RELY TrialWARF D D-110Major bleeding rate (%/year)18,113 pts with AF in RELY6,952 pts (38,4%) also received an antiplatelet therapy during the study5,789 pts on aspirin alone351 pts on clopidogrel alone812 pts on both drugsConcomitant antiplatelet drugs appeared to increase the risk of major bleedings in RELY with no advantage of dabigatran over warfarin
39These recent recommendations are based on expert consensus and observational trials and many questions do remain unanswered…
40GENERAL RECOMMENDATIONS ClassLevel1.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.HAS-BLED score should be used to identify and correct potentially reversible bleeding risk factorsGRACE score should be used to stratify ACS riskIC2.If VKA is used good quality anticoagulation control is recommended with TTR>70%A3.When VKA is given in combination with clopidogrel and/or aspirin target INR 2,0-2,5IIa4.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.)IIb5.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)B6.Radial access should be considered as the default for CAG/PCI to minimize the risk of access related bleeding depending on operator expertise and preference7.New generation DES may be preferred over BMS in pts at low risk of bleeding (HAS-BLED 0-2)8.Novel P2Y12 receptor inhibitors (prasugrel and ticagrelor) should not be part of triple therapy in pts with AFIII
41SCHEME OF ANTITHROMBOTIC THERAPY IN PATIENTS WITH AF In pts with stable angina and AF undergoing PCI at low bleeding risk TT should be given for a minimum of 4 weeks and no longer than 6 months after PCI, following with dual therapy with OAC(whether new or VKA) and clopidogrel (or aspirin) up to 12 month*- 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
42SCHEME 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
44CONCLUSIONSThe period of triple therapy should be as short as possibleThe 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 BMSUse aspirin in low doses: mg dailyUse clopidogrel as preferred P2Y12 inhibitor to more potent ticagrelor or prasugrelOAC – well-controlled adjusted dose warfarin (INR 2,0-2,5; TTR>70%) or NOACUse BMS*, thus minimizing the duration of triple therapyUse the radial approach thus minimizing the risk of bleeding at the access siteThe 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.
46Recommendation on the Management of patients on Oral Anticoagulation With ACS and/or Undergoing PCI Risk Stratification and Balance (CHA2DS2-Vasc risk scores) for assessing the risk of stroke, and HAS-BLED to assess bleeding risk in pts with AF)