DECLARATION OF CONFLICT OF INTEREST. Lecture fees: AstraZeneca, Ely Lilly, Merck.

Transcription

1 DECLARATION OF CONFLICT OF INTEREST Lecture fees: AstraZeneca, Ely Lilly, Merck.

2 Risk of stopping dual therapy. S D Kristensen, FESC Aarhus Denmark

3 Acute coronary syndrome: coronary thrombus Platelets E Falk 1983 and 1985

4 Antithrombotic therapy in ACS Risk factors ischemic events Risk factors for bleeding

5 Dual antiplatelet therapy How long should we treat? ACS and stenting. Prolonged treatment to anybody? Risk of stopping according to schedule? Bleeding and surgery stop, continue or substitute with other drugs?

6 Dual antiplatelet therapy Aspirin P2Y12-inhibitor ACS and stenting

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8 Long-term Efficacy of ASA in Reducing Death or MI in Patients with Unstable Angina Probability of death or MI Placebo Risk ratio after 1 year % Cl (p=0.0001) ASA 75 mg Months Wallentin LC et al JACC 1991;18:

9 Cumulative no. of vascular deaths STEMI: ISIS-2 Randomized, placebo-controlled trial in 17,187 STEMI patients comparing streptokinase vs. 1-month aspirin vs. both active treatments vs. neither 600 Placebo infusion and tablets: 588/4300 (13.2%) Aspirin: 461/4295 (10.7%) Streptokinase: 448/4300 (10.4%) Streptokinase and aspirin: 343/4292 (8.0%) Days from randomization ISIS-2 Collaborative Group. Lancet 1988;2:349-60

10 Cumulative event rate (%) 20 Primary end point within 30 Days 1,572 patients DANAMI-2 Fibrinolysis (front loaded tpa) NNT= % 10 Log rank: p= PCI 8.0% Days Primary end point: Death or reinfarction or stroke

11 Cumulative Hazard Rate CURE Study (ACS): Primary End Point: MI/Stroke/CV Death Placebo + Aspirin (n=6303) 20% Relative Risk Reduction Clopidogrel + Aspirin (n=6259) P <.001 N=12, Months of Follow-up Yusuf S, et al. N Engl J Med. 2001;345:

12 Primary endpoint Cardiovascular death, myocardial infarction or stroke 14% % RRR p= n= Standard-therapy Clopidogrel + standard-therapy Months of follow-up

13 PCI-CURE Overall results Composite of cardiovascular death or MI from 0.15 randomization to end of follow-up Cumulative hazard rates 12.6% % Standard therapy Clopidogrel + standard therapy % RRR p=0.002 n= a b Days of follow-up a = median time from randomization to PCI (10 days) b = 30 days after median time of PCI up to 12 months including ASA The CURE Investigators. Lancet August 2001

14 Duration of therapy: months? 3 months? 6 months? 9 month? 12 months?

15 Primary endpoint (stroke, MI or cardiovascular death) CURE : Clopidogrel in the early phase and later 8% 7% RR: 0.79 ( ) p=0.003 p < ,3% RR: 0.82 ( ) p=0.009 p < % 5% 5,4% 4,3% 5,2% 4% 3% 2% 1% 0% 0 to 30 days >30 days to 1 year Placebo* Clopidogrel* Yusuf S. Circulation 2003; 107: RR = Relative risk MI = Myocardial infarction * On top of standard therapy including acetylsalicylic acid

16 COMBINED ENDPOINT OCCURRENCE (%) CREDO: Long-term Benefits of Clopidogrel in PCI Patients 15 1 year results (MI, Stroke, or Death) % 8.5% 27% RRR p = Placebo* # Clopidogrel* MONTHS FROM RANDOMIZATION * On top of standard therapy including ASA # All patients received clopidogrel post PCI up to day 28 Steinhubl S, et al. JAMA, November 20, 2002 Vol 288, No 19:

17 Clopidogrel in STEMI

18 Patients with endpoint (%) CLARITY: CV death, MI or recurrent ischaemia leading to urgent revascularisation within 30 days Placebo Clopidogrel 20% odds reduction 5 0 Odds ratio 0.80 (95% CI ) p= Days Sabatine MS et al. N Engl J Med. 2005;352:

19 Mortality (%) COMMIT: death in hospital 7 Placebo + ASA: 1845 deaths (8.1%) Clopidogrel + ASA: 1726 deaths (7.5%) Days since randomisation (up to 28 days) 7% (SE3) relative risk reduction (2p=0.03) COMMIT Collaborative Group. Lancet. 2005;366:

20 ESC Guidelines: PCI for acute CAD Recommendations PPCI for STEMI (within 2 hours) Class LOE I A Rescue PCI for failed fibrinolysis (within 12 hours) IIa A PCI for STEMI with shock and contraindications to fibrinolytic therapy irrespective of time delay I B Angiography and PCI after successful fibrinolysis (within 24 hours) IIa A Urgent PCI for hemodynamically unstable NSTE- ACS (within 2 hours) I C Early PCI for high-risk NSTE-ACS (within 72 hours) I A

21 ACS: dual antiplatelet therapy ESC Guidelines: NSTEMI, STEMI, Myocardial Revascularization. 12 months of dual antiplatelet therapy aspirin clopidogrel ticagrelor prasugrel

22 COMBINED ENDPOINT OCCURRENCE (%) CREDO: Long-term Benefits of Clopidogrel in PCI Patients 15 1 year results (MI, Stroke, or Death) % 8.5% 27% RRR p = Placebo* # Clopidogrel* MONTHS FROM RANDOMIZATION * On top of standard therapy including ASA # All patients received clopidogrel post PCI up to day 28 Steinhubl S, et al. JAMA, November 20, 2002 Vol 288, No 19:

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26 Stents...and drug-eluting stents Platelets aggregating on DES strut

27 Aspirin and ticlopidine

28 Bare metal stents

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31 Dual antiplatelet therapy How long should we treat? ACS and stenting. Prolonged treatment to anybody? Risk of stopping according to schedule? Bleeding and surgery stop, continue or substitute with other drugs?

32 Duration of clopidogrel after DES: longer than 12 months Late stent thrombosis Only registry data No randomized trials

33 Late stent thrombosis

34 Dual antiplatelet therapy Prolonged treatment to anybody?

35 Dual antiplatelet therapy Prolonged treatment to anybody?

36 Dual antiplatelet therapy: prolonged treatment to anybody? Recurrent stent thrombosis Extensive DES stenting? Left main stenting? Extensive vascular disease?

37 Dual antiplatelet therapy How long should we treat? ACS and stenting. Prolonged treatment to anybody? Risk of stopping according to schedule? Bleeding and surgery stop, continue or substitution with other drugs?

38 Western Denmark: Definite Stent Thrombosis at months after PCI Adjusted RR = 10.9 (1.27 to 93.76) p=0.029 DES 0.09% BMS 0.009% LO Jensen et al JACC 2007

39 Risk of stopping DAPT Platelet rebound?

40 Risk of stopping DAPT Platelet rebound? Probably no

41 Duration of dual antiplatelet therapy After implantation of DES: 12 months After implantation of BMS: 1-12 month (stable patients) After ACS: 12 months No evidence for benefit after 12 months Trials to investigate the duration of dual therapy after DES implantation are warranted

42 Steg et al Eur Heart J 2011

43 Dual antiplatelet therapy How long should we treat? ACS and stenting. Prolonged treatment to anybody? Risk of stopping according to schedule? Bleeding and surgery stop, continue or substitute with other drugs?

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45 P2Y12 Reaction Units (PRU) 450 VerifyNow P2Y12 Assay Ticagrelor (n=54) Loading Dose Last Maintenance Dose Clopidogrel (n=50) Placebo (n=12) * * * * * * weeks Onset Maintenance Offset Time (hours)

46 Stopping dual antiplatelets 5 days of interruption of P2Y12 inhibitors to restore ADP-induced platelet function.

47 ACS and stenting: scenarios

48 Interruption of dual antiplatelet Bleeding /surgery. therapy Risk for thrombotic events is a lot higher in the first weeks.

49 Interruption of dual antiplatelet Bleeding /surgery. therapy Risk for thrombotic events is higher after stenting than after ACS?

50 Risk for thrombotic events is higher after stenting than after ACS?

51 Interruption of dual antiplatelet Bleeding /surgery. therapy Continue dual antiplatelet therapy if possible.

52 Interruption of dual antiplatelet Bleeding /surgery. therapy When do we have to stop dual antiplatelet therapy?

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54 Interruption of dual antiplatelet Bleeding /surgery. therapy When do we have to stop dual antiplatelet therapy? Severe life threatening bleeding

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56 Interruption of dual antiplatelet therapy When do we have to stop dual antiplatelet therapy? Major surgery

57 Interruption of dual antiplatelet Bleeding /surgery. therapy When do we have to stop dual antiplatelet therapy? Major surgery?

58 Interruption of dual antiplatelet Surgery therapy

59 Urgent surgery / maladies urgente No time to waste! speaker

60 ESC recommendations on perioperative aspirin use Recommendation Continuation of aspirin in patients previously treated with aspirin should be considered in the perioperative period IIa B Discontinuation of aspirin therapy in patients previous e.g. treated with aspirin should be considered only in those in which haemostasis is difficult to control during surgery IIa B speaker

61 Recommendations: non-cardiac surgery Temporary interruption of dual antiplatelet therapy (aspirin and clopidogrel) within 12 months after an acute coronary syndrome or after implantation of a drug eluting stent is discouraged (IC) Temporary interruption of dual antiplatelet therapy (aspirin and clopidogrel) within one month after implantation of a bare metal stent is discouraged (IC) Temporary interruption of dual antiplatelet therapy is recommended in patients undergoing surgery (brain or spinal), where even minor bleedings may result in severe consequences (IIa-C)

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64 Steg et al Eur Heart J 2011

65 Stopping dual antiplatelet therapy Bridging therapy with tirofiban/eptifibatide.

66 Platelet testing: the future? Light transmission aggregometry Multiplate aggregometry Flow cytometry Point-of-Care Assay

67 Scenarios: bleeding/surgery

68 Risk of stopping dual therapy? Individualized decision Experienced cardiologists are needed

69 Risk of stopping dual therapy? Individualized decision Experienced cardiologists are needed