ACS: What happens after the acute phase? Frans Van de Werf, MD, PhD Leuven, Belgium

Transcription

1 ACS: What happens after the acute phase? Frans Van de Werf, MD, PhD Leuven, Belgium

2 4/14/2011

3 Cumulative death rates in 3721 ACS patients from UK and Belgium at ± 5 year (GRACE) % TOTAL 14% % CV 22% TOTAL 16% CV 17% TOTAL 13% CV 10 65% after discharge 83% after discharge 95% after discharge 5 0 n=1403 n=1107 n=850 STEMI Non-STEMI UA Fox K et al. Eur Heart J 2010

4 Death, MI, or Stroke (%) Dual Antiplatelet Therapy in NSTE ACS: CURE Death, MI, or Stroke ASA + Placebo ASA + Clopidogrel Months of follow-up 11.4% P< % 80% Residual Risk CURE. N Engl J Med. 2001;345:494.

5 Cumulative Hazard Rates Death / MI PCI Cure: Death / MI at One Year PCI < 48 hrs after rand PCI 48 hrs from rand and during initial hosp PCI after hospital discharge 0.20 Denotes median Time to PCI ASA 0.15 ASA 0.15 ASA ASA + Clopidogrel 0.05 ASA + Clopidogrel 0.05 ASA + Clopidogrel 0.0 RR:0.53 ( ) 0.0 RR:0.72 ( ) 0.0 RR:0.70 ( ) Days of Follow-up Days of Follow-up Days of Follow-up Lewis BS, et al. Am Heart J. 2005;150:

6 Percentage With Endpoint (%) Dual Antiplatelet Therapy in STEMI: CLARITY CV Death, MI, RI Urg Revasc ASA +Placebo 14.1% ASA + Clopidogrel P= % 80% Residual Risk Days Sabatine et al. N Engl J Med. 2005;352:1179.

7 Event (%) Dual Antiplatelet Therapy in STEMI : COMMIT Effects of CLOPIDOGRELon Death, Re-MI or Stroke Placebo + ASA: 2311 events (10.1%) Clopidogrel + ASA: 2125 events (9.3%) 9% (SE3) relative risk reduction (2P=0.002) 92 % Residual Risk Days since randomisation (up to 28 days)

8 Combined Endpoint Occurrence (%) Dual Antiplatelet Therapy in PCI: CREDO Death, MI, or Stroke ASA + Placebo ASA + Clopidogrel 11.5% 8.5% P= % Residual Risk Months From Randomization Steinhubl et al. JAMA. 2002;288:2411.

9 Primary Endpoint (%) Dual Antiplatelet Therapy in ACS with PCI: TRITON 15 CV Death, MI, or Stroke 10 ASA + Clopidogrel ASA + Prasugrel 12.1% P= % 5 81% Residual Risk Days Wiviott et al. N Engl J Med. 2007;357:

10 Cumulative incidence (%) PLATO K-M Estimate of Time to first primary Efficacy Event (CV death, MI or stroke) No. at risk Ticagrelor Clopidogrel Days after randomisation 9,333 8,628 8,460 8,219 6,743 5,161 9,291 8,521 8,362 8,124 6,743 5,096 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Clopidogrel Ticagrelor % Residual Risk HR 0.84 (95% CI ), p= ,147 4,047

11 Why is there a high late event rate after ACS? Discontinuation of antithrombotic therapy prescribed at discharge Suboptimal secondary prevention (diet, physical exercise, BP, lipids and glucose control...) Insufficient platelet inhibition and/or absence of anticoagulant therapy

12 Flow diagram: Study sample and cumulative incidence of ATD during follow-up after DES Ferreira-Gonzalez, I. et al. Circulation 2010;122: Copyright 2010 American Heart Association

13 Cumulative rate of double AT during the study period Ferreira-Gonzalez, I. et al. Circulation 2010;122: Copyright 2010 American Heart Association

14 Rate of first detected ATD according to the number of readmissions Ferreira-Gonzalez, I. et al. Circulation 2010;122: Copyright 2010 American Heart Association

15 Better antithrombotic treatment after the ACS? 4/14/2011

16 Longer and better antithrombotic treatment after the acute phase Prolonged anticoagulation (eg oral anti-xa agents) Prolonged dual platelet inhibition with aspirin and a P2Y12 inhibitor (eg ticagrelor in PEGASUS study) Adding a third antiplatelet agent inhibiting yet another pathway of platelet aggregation (eg thrombin receptor inhibitors)

17 FRAXIS Study Design Non-ST-Segment Elevation Acute Coronary Syndrome (UA or NSTE MI) N+3,468 Randomize 1:1:1 Double blind Aspirin in all patients (up to 325 mg/d) Fraxiparine (IV + SQ) 86 Anti-Xa IU/kg for 14 days Fraxiparine (IV + SQ) 86 Anti-Xa IU/kg for 6 days IV Unfractionated heparin for 6 days Primary outcome: Cardiac death, MI, refractory/recurrent angina at day 14 Secondary outcome: Primary outcome at 6 days and 3 months The FRAXIS Study Group. Eur Heart J. 1999;20:

18 Death or MI (%) FRAXIS: Death or MI 10 8 IV UFH 6 days Fraxiparine 6 days Fraxiparine 14 days Days 14 Days 3 Months The FRAXIS Study Group. Eur Heart J. 1999;20:

19 Major Hemorrhage (%) FRAXIS: Major Hemorrhage 4 IV UFH 6 days Fraxiparine 6 days Fraxiparine 14 days Days 14 Days The FRAXIS Study Group. Eur Heart J. 1999;20:

20 % ESTEEM: Oral Ximelagatran on top of Aspirin (alone) in ACS Primary endpoint: Death, MI, severe recurrent ischaemia Wallentin et al., Lancet, % p=0.036 n=638 n= % p=ns Major bleeding

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22 % Clinical endpoint composite of CV death, non fatal MI, stroke ITT OT ITT OT ITT OT ITT OT ITT OT Placebo DE 50 DE 75 DE 110 DE 150 ITT = Intention to treat; OT = On treatment 22 (within 3 days before the event) Stroke Non-fatal MI CV death N=

23 APPRAISE Ischemic Events -2.7% -1.1% -2.1% 0.2% Alexander J et al. ESC 2008

24 APPRAISE Bleeding Complicationsby Clopidogrel Status 6.0% 3.9% 1.4% -0.3% N Alexander J et al. ESC 2008

25 Death / MI / Stroke (%) SECONDARY EFFICACY ENDPOINT: Incidence of Death / MI / Stroke 6 4 All Placebo (n = 1160) P = % 3.9% Days After Randomization All Rivaroxaban (n = 2331) HR 0.69 ( ) P=0.028 ARR = 1.6% NNT = 63 Mega et al. Lancet. 2009;374: Gibson CM, AHA 2008

26 Clinically Significant Bleeding (%) Total Daily Dose: Rivaroxaban 20 mg ---- Rivaroxaban 15 mg ---- Rivaroxaban 10 mg ---- Rivaroxaban 5 mg ---- Placebo --- PRIMARY SAFETY ENDPOINT: CLINICALLY SIGNIFICANT BLEEDING (= TIMI Major, TIMI Minor, Bleed Req. Med. Attn.) 15.3% 12.7% 10.9% HR 5.1 ( ) 3.6 ( ) 3.4 ( ) Days After Start of Treatment Kaplan-Meier estimates for cumulative events, HR(CI), for bleeding rates during the 180 day period ; HR=Hazard Ratio; CI=Confidence Interval Mega et al. Lancet. 2009;374: % 3.3% 2.2 ( ) *p<0.01 for placebo Vs Riva 5mg. p<0.001 for Riva 10,15,20mg vs placebo Gibson CM, AHA 2008

27 Longer and better antithrombotic treatment after the acute phase Prolonged anticoagulation (eg oral anti-xa agents) Prolonged dual platelet inhibition with aspirin and a P2Y12 inhibitor (eg ticagrelor in PEGASUS study) Adding a third antiplatelet agent inhibiting yet another pathway of platelet aggregation (eg thrombin receptor inhibitors)

28 PEGASUS: Design N ~ 21,000 History of MI 1-3 yrs prior + 1 additional atherothrombosis risk factor* RANDOMIZED DOUBLE BLIND * Age >65 yrs, diabetes, 2 nd prior MI, multivessel CAD, or chronic non-end stage renal dysfunction Planned treatment with ASA mg & Standard background care Ticagrelor 90 mg bid Ticagrelor 60 mg bid Placebo Follow-up Visits Q4 mos for 1 st yr, then Q6 mos Min 14 mos and average 26 mos follow-up Event-driven trial Primary Efficacy Endpoint: CV Death, MI, or Stroke Primary Safety Endpoint: TIMI Major Bleeding

29 Longer and better antithrombotic treatment after the acute phase Prolonged anticoagulation (eg oral anti-xa agents) Prolonged dual platelet inhibition with aspirin and a P2Y12inhibitor (eg ticagrelor in PEGASUS study) Adding a third antiplatelet agent inhibiting yet another pathway of platelet aggregation (eg. thrombin receptor inhibitors)

30 The Phase 2 Studies TRA-PCI (Lancet 2009;373:919-28)

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36 Vorapaxar Phase 3 program vorapaxar placebo vorapaxar placebo F/U: 30 Days, 4, 8, 12 months and 6 months thereafter F/U 1 yr minimum Primary EP: Composite of CV Death, MI, Stroke, Recurrent Ischemia with Rehosp, Urgent Coronary Revascularization Primary EP: Composite of CV Death, MI, Stroke and Urgent Revascularization

37 DSMB Communications TRA2P "The DSMB has communicated to us that based on all of the data (safety and efficacy) available to them from both trials, they recommend that subjects with a history of stroke not receive vorapaxar. They have observed an increase in intracranial hemorrhage in patients with a history of stroke that is not outweighed by their considerations of potential benefit." TRACER : The DSMB informed us that the trial reached enough endpoints to answer the primary question.

38 Conclusions High event rate after hospital discharge for ACS Little is known why and more studies are needed in this regard... eg EPICOR Suboptimal antiplatelet therapy could play a role as well as premature discontinuation of antiplatelet therapy and other guidelines recommended treatments Natural history... 4/14/2011

39 EPICOR : Patient flow chart Index event Inclusion (see Figure 2) ACS event management Follow-up Pre-hospital In-hospital Post-discharge Day 0 Admission Discharge Phone calls follow-up at: 6w and quarterly 24 months (after index event) Baseline data Short-term medical management from symptoms onset: antithrombotics (dose and timing), invasive procedure Early clinical outcomes Economic evaluation Lon-term medical management Post-discharge clinical outcomes Quality of life assessment Persistence on antithrombotic treatment: planed and unplanned interruptions Economic evaluation

40 Conclusions High event rate after hospital discharge for ACS Little is known why and more studies are needed in this regard... eg EPICOR Suboptimal antiplatelet therapy could play a role as well as premature discontinuation of antiplatelet therapy and other guidelines recommended treatments Natural history... 4/14/2011

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42 Targets of Antithrombotic Agents direct Xa inhib: rivaroxaban apixaban TK-442 YM-150 fondaparinux LMWH heparin bivalirudin hirudin dabigatran AT Fibrinogen Factor Xa AT Tissue factor Coagulation cascade Prothrombin Thrombin aspirin vorapaxar atopaxar Collagen, vwf etc. TxA 2 ADP activation of GPIIb/IIa Platelet aggregation Fibrin clopidogrel prasugrel cangrelor ticagrelor elinogrel GPIIb/IIa inhibitors Van de Werf F Eur Heart J 2009;30: Thrombus