Antiplatelet in diabetics: strong but incomplete umbrella

Transcription

1 Antiplatelet in diabetics: strong but incomplete umbrella Seung-Whan Lee, MD. Heart Institute, University of Ulsan College of Medicine Asan Medical Center, Seoul, Korea

2 Global Projections for the Number of People wit h Diabetes (20-79 age group), 2007 and 2025 (millions) from International Diabetes Federation

3 Incidence During 7-Year Follow-up (%) Diabetes = Risk Equivalent of CAD Non diabetics with no prior MI Non diabetics with prior MI Diabetics with no prior MI Diabetics with prior MI P < P < Events per 100 Person-yr 3.5 n=1304 n=67 n=890 n= Haffner SM et al. N Engl J Med. 1998;339:

4 Causes of Death in Diabetic Patients Pneumonia/Influenza Others Malignant Neoplasm 13% 4% 5% Diabetes 13% 55% 10% Stroke Heart Disease Geiss LS et al. In: Diabetes in America. 2nd ed. 1995; ch 11.

5 World #1 Killer Heart Attack and Brain Attack Axis of Evil Arterial wall side - LDL cholesterol (statin) - inflammation Arterial lumen side - platelet (aspirin/plavix) - coagulation

6 Platelet Activation Mechanisms

7 Prothrombotic state in DM

8 Why Secondary Prevention is aspirin so popular in the management of CV disease?

9 Cumulative Number of Vascular Deaths Placebo infusion and tablets 568/4300 (13.2%) Aspirin 461/4295 (10.7%) Streptokinase 448/4300 (10.4%) Streptokinase and Aspirin 343/4292 (8.0%) Aspiri n in AMI (ISIS-2) 100 N = 17,187 AMI Aspirin should be initiated at ER Days from Randomization Lancet 1988;2:34

10 Long-term Effects of Aspirin: ISIS-2 Long-term benefits of short-term aspirin treatment One month of aspirin treatment was associated with a highly significant absolute improvement in survival at 35 days, which still persisted after several years. BMJ 1998;316:

11 Percentage Changes Over Time in The Use of Aspirin in Patients Hospitalized with AMI (1975 to 1997) ISIS Am Heart J 2002;144:25

12 Primary end points Reduction in Sudden Death/MI Seen With the Addition of Aspirin to Sotalol in Patients With Stable Angina: SAPAT No Background Statin! Aspirin 75mg, 34% reduction of sudden death/mi Placebo + sotalol ASA + sotalol 20 0 Months Number of patients at risk in each of the two treatment arms Lancet 1992;340: 1421

13 Explaining the Decrease in US Deaths from Coronary Disease, The age-adjusted death rate for CHD fell from to deaths per 100,000 population among men (50% ) & from to deaths per 100,000 population among women. Changes in medical treatments accounted for approximately 47% and risk-factor changes accounted for approximately 44% of the decrease in deaths. Anti-platelet therapy A cornerstone of cardiovascular pharmacologic strategies for prevention of cardiovascular events Aspirin: 15% risk reduction of total mortality in AMI, unstable angina and post-mi. Post-MI: aspirin1 15%, blocker 23%, ACI 20%, statin 22%, rehabilitation 26% N Engl J Med 2007;356:2388

14 Primary Aspirin Prevention

15 Aspirin Antithrombotic Trialists Collaboration (ATTC) in Primary Prevention 6 major trials Serious bleeding 0.8%/year ICH 32% ( ) Major extracranial bleeding 54% ( ) Lancet 2009;373:1849

16 Aspirin The Japanese Primary Prevention Project in Primary Prevention 14,464 patients, aged 60 to 85 years with HTN, dyslipidemia, or DM Follow-up 5.02 yrs, early terminated based on likely futility Primary endpoint: composite (cardiovascular death, stroke, and MI) JAMA. 2014;312:

17 The Japanese Primary Prevention Project JAMA. 2014;312:

18 Aspirin Clinical trials in Primary Prevention

19 JACC 2010;55:2878 Aspirin in Diabetes Coronary Events AHA vs. ESC: The same data_ the divergent conclusions All patients with diabetes do not have high CV risk. Aspirin appears to have a modest effect on CV events (~10% RR risk reduction). In contrast with prevailing beliefs, clinical efficacy of aspirin in DM is substantially lower than in non-dm. Stroke 2007AHA/ADA: all diabetes >age 40 under the assumption that diabetes is a CHD risk equivalent AHA/ADA: IIaB (10 years risk >10%) > 50 M & > 60 W with diabetes plus 1 RFs (smoking, HT, dyslipidemia, FHx, albuminuria) Publication bias: small positive trials published, small negative trials not submitted!

20 Aspirin ad Infinitum for Prevention: Really Works? Wide Use Little Evidence FREE LUNCH & HAPPY LIFE!... FDA has not approved aspirin for use in primary prevention. Number needed to treat for 1 year to cause Aspirin 1 GI bleeding 248 International guidelines have started to recommend withdrawal of aspirin. Statin 2 Severe myositis 100,000 Fatal GI bleeding 2,066 Fatal myositis 1,000,000 1 Derry S, Loke YK Thompson PD, et al. 2003

21 International guideline in general population for primary prevention J Thromb Thrombolysis. 2015;40:

22 AMC Coronary CT screening and its outcomes according to status Lee SW et al. Int J ccardiol (in press).

23 Relationship between clinical benefit and bleeding risk according to absolute cardiovascular risk in primary prevention trials of aspirin. JACC 2014;64:319-27

24 JACC 2014;64: A Proposed Practical Stepwise Approach to Aspirin in Primary CV Prevention ADA recommendation

25 Ongoing trials: aspirin primary prevention. The ASCEND study involves aspirin for patients 40 years and older with type 1 or 2 diabetes; ARRIVE study is testing aspirin in middle-aged and older patients who are at higher risk based on the presence of multiple CVD risk factors. ASPREE study is testing aspirin in individuals older than 70 years.

26 Secondary Aspirin Prevention

27 Risk Differences of Vascular Death, MI and Stroke in Patients with Post-MI Pooled analysis: a 3.3% reduction in the risk of MI, stroke or vascular death for 1 month

28 Risk Difference of Vascular Death, MI and Stroke in Patients with uap Pooled analysis: a 6.6% reduction in the risk of MI, stroke or vascular death for 1 year

29 Risk Difference of Vascular Death, MI and Stroke in Patients with sap Pooled analysis: a 0.7% reduction in the risk of MI, stroke or vascular death for 1 year

30 Summary Secondary prevention (CHD, TIA, Stroke, PAD) - IA recommendation Primary prevention : remain unclaer - based on 10-year risk of CHD (>10%); > 50 M & > 60 W with diabetes plus 1 RFs (smoking, HT, dyslipidemia, FHx, albuminuria)

31 Beyond Aspirin CLOPIDOGREL C ADP ADP GPllb/llla (Fibrinogen receptor) Activation Collagen thrombin TXA 2 ASA COX The constant need for better clinical efficacy beyond aspirin monotherapy lead to the production of different molecules, such as clopidogrel. TX A 2

32 Clopidogrel Risk of event Stent Acute MI Acute stroke UA/NQWMI Polyvascular TIA Stroke MI Symptomatic PAD Stable angina Diabetes Asymptomatic PAD Risk factors TIA, transient ischemic attack; PAD, peripheral arterial disease; UA, unstable angina; NQWMI, non-q-wave MI CAPRIE Disease progression CLASSICS CREODO CURE

33 Cumulative Event Rate (%) Clopidogrel monotherapy Lancet 1996;348: Cumulative Risk of Stoke, MI or Vascular Death in Patients in the CAPRIE Trial Event Rate per Year Aspirin 5.83% Aspirin Clopidogrel 8.7%* Overall Relative Risk Reduction (N=19,185) 8 4 Conclusion 5.32% Clopidogrel Clopidogrel is more effective P = than aspirin in reducing the risk of ischemic event in patients with MI, stroke & established PAD, suggesting clopidogrel as the best alternative to aspirin in pts with aspirin allergy. Months of Follow-Up

34 Event rates (% death, MI, revasc.) Superior efficacy of ADP Receptor Antagonists in Coronary Stenting 12 Coumadin + ASA ASA Ticlopidine + ASA 11 Clopidogrel + ASA Clopidogrel LD + ASA ISAR N=517 FANTASTIC N=485 STARS N=1653 MATTIS N=350 CLASSICS N=1020

35 Dual AntiPlatelet Therapy (DAPT) Effects of Clopidogrel in Addition to Aspirin in Patients with ACS without STE (CURE Trial) Patients with ACS (unstable angina or NQMI without STE) R Day 0 Clopidogrel 300 mg loading dose Placebo loading dose Day 1 Day 1 12 months 12 months Clopidogrel 75 mg od + standard therapy (n=6259) Placebo 1 tab od + standard therapy (n=6303) R=Randomization, occurred within 24 hours of symptom onset Standard therapy always included ASA, and could also include heparin, LMWH, GP IIb/IIIa inhibitors post-randomization, beta-blockers, ACE-inhibitors, lipid-lowering agents, and/or other therapies or interventions (e.g. PTCA, CABG) at physician s discretion. Primary endpoint: first occurrence of cardiovascular death, MI or stroke

36 % of patients with recurrent ischemic event* NSTE-ACS, Dual AntiPlatelet Therapy (DAPT) Primary Endpoint Benefits were seen within hours and continued to increase over the 12 months Conclusion Months of follow-up 20% RRR P<0.001 n=12,562 Standard therapy Clopidogrel + standard therapy Clopidogrel on top of standard therapy (including ASA) 0 demonstrates an early 4 5 effect 6 and 7 sustained 8 9 long-term benefit including throughout ASA the entire trial period of 12 months. *cardiovascular death, MI, or stroke N Eng J Med 2001;345:

37 Lancet 2006;366:1607 COMMIT/CCS-2: ClOpidogrel & Metoprolol in Myocardial Infarction Trial Clopidogrel 75 mg QD* Patients with acute STEMI 24 hours n=~46,000 R Double-blind treatment until hospital discharge or for a maximum of 4 weeks (n ~ 23,000) Placebo* (2 2 Factorial with metoprolol) (n ~ 23,000) Patients with Acute MI within the previous 24 h received ASA 162 mg & either placebo or clopidogrel 75 mg/d with no loading dose of clopidogrel 2 primary endpoints: 1) death, 2) the composite of death, non-fatal MI, or non-fatal stroke.

38 Mortality (%) STEMI, Dual AntiPlatelet Therapy (DAPT) Clopidogrel reduced mortality by 7% Placebo (8.1%) RRR=7% p=0.03 Clopidogrel (7.5%) Days since randomization (up to 28 days) Lancet 2006;366:1607

39 Events (%) STEMI, Dual Therapy Clopidogrel Reduced the Composite of Death, MI, or Stroke by 9% Placebo (10.1%) Clopidogrel (9.3%) RRR=9% P= Conclusion 3 Clopidogrel 2 (75 mg/day) on a background of standard therapy including ASA was beneficial for a wide range of acute STEMI 1 patients Days since randomization (up to 28 days) Lancet 2006;366:1607

40 CHARISMA Clopidogrel for High Atherothrombotic Risk & Ischemic Stabilization, Management and Avoidance Patients at high risk of atherothrombotic events (n=15,603) R Low dose ASA mg/day Double-blind treatment up to 1040 primary efficacy events* Clopidogrel 75 mg/day (n=~7800) Low dose ASA mg/day Visits every 6 months Placebo 1 tablet/day (n=~7800) Primary endpoint: first occurrence of CV death, MI or stroke Patients was followed until a fixed study end date, allowing at least 1040 primary efficacy endpoints.

41 Cumulative event rate (%) High-Risk, Dual AntiPlatelet Therapy (DAPT) Primary Outcome (MI, Stroke or CV Death) 8 6 Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% 4 2 RRR: 7.1% [95% CI: -4.5%, 17.5%] p= Months since randomization First Occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death *All patients received ASA mg/day Median follow-up was 28 months

42 Primary Outcome (MI/Stroke/CV Death) by Category of Inclusion Criteria Population N RR (95% CI) p value Atherothrombosis 12, (0.77, 0.998) Coronary 5, (0.71, 1.05) 0.13 Cerebrovascular 4, (0.69, 1.03) 0.09 PAD 2, (0.67, 1.13) 0.29 Multiple RF 3, (0.91, 1.59) 0.20 Overall Population 15, (0.83, 1.05) 0.22 Conclusion Clopidogrel + ASA Placebo + ASA Better Better High-Risk, Dual AntiPlatelet Therapy (DAPT) In patients with atherothrombotic disease or multiple risk factors * First Occurrence dual of antiplatelet MI (fatal or not), Stroke was (fatal not or beneficial not), or CV Death for prevention of CV events. RF= Risk Factors, AT= Atherothrombosis

43 Randomized trials evaluating clinical efficacy of oral antiplatelet treatment in diabetic patients with ACS or PCI clopidogrel ACS trial with double dose clopidogrel ACS trials with new antiplatelet

44 Trade-off, Dual antiplatelet Therapy (DAPT) Safety of Long-Term Clopidogrel

45 KR.PM.CLO [ ] DAPT Trial Multicenter, randomized, international, placebo-controlled (N=9,961) Purpose: To compare the safety and effectiveness of 12 vs. 30 months dual antiplatelet therapy (DAPT) in patients with drug-eluting stents (DES). Mauri L, et al. N Engl J Med 2014 Dec 4;371(23):

46 DAPT Trial: Primary co-effectiveness endpoint MACCE (Death, MI or stroke) MACCE: major adverse cardiovascular and cerebrovascular events KR.PM.CLO [ ] Mauri L, et al. N Engl J Med 2014 Dec 4;371(23):

47 KR.PM.CLO [ ] DAPT Trial co-1 EP & Components (12-30 mo.) Mauri L, et al. N Engl J Med 2014 Dec 4;371(23):

48 Cumulative Incidence (%) DAPT Trial: Moderate or Severe Bleeding 3.5% 3.0% 2.5% 2.0% 1.5% 1.0% 0.5% 0.0% % 1.6% Moderate or Severe < % < % % 1.5% 1.5% % 0.8% 0.6% % 0.1% Moderate Severe BARC Type 2 BARC Type 3 BARC Type 5 Thienopyridine (4710) Placebo (N=4649) NEJM 2014;371:

49 Duration of Dual Anti-platelet Therapy after DES Placement 2011 ACCF/AHA/SCAI Guideline - at least 12 months after DES implantation if patients are not at high risk of bleeding 2014 ESC/EACTS Guideline - 6 months after DES implantation - <6 months ( bleeding risk), >6 ( ischemic risk)

50 On My Watch Old DAPT: aspirin+clopidogrel New DAPT: aspirin+prasugrel or ticagrelor DAPT Use in CAD Stable CAD after DES Placement - High risk of bleeding: Old DAPT for 6 months - Stable without bleeding: Old DAPT indefinitely ACS without Contraindications - AMI with RFs: New DAPT (A+T) indefinitely - Other ACS Patients with DES Placement: New DAPT for 12 months DAPT indefinitely (ACS in DAPT trial: ~40%)

51 Cumulative event rate (%) Platelet Hypothesis War Against The Platelet 8 Placebo + ASA 7.3% 6 4 CHARISMA (n=15,603) Clopidogrel + ASA 6.8% 2 0 Death, MI, stroke RRR: 7.1%, p= Months since randomization Despite its proven benefits, many patients continue to suffer from acute vascular events.

52 Antiplatelet Drugs Metabolism

53 Beyond Clopidogrel P2Y12 blocker Type Action Phase Dose Platelet inhibition (Time required) Clopidogrel (oral) Thienopyridine Hepatic conversion Irreversible binding Approved mg LD 75 mg QD MD 15-20% 300mg: 8-24hr 600mg: 2-6hr 75mg QD: 5-7days Prasugrel (oral) Thienopyridine Hepatic conversion Irreversible binding 3 (TRITON) 60 mg LD 15 mg QD MD 70% < 1hr Ticagrelor (oral) Cyclopetyltriazolopyrimidine Direct inhibition Competitive binding 3 (PLATO) 90 mg bid 95% <1h, peak 2-3h Cangrelor (parenteral) ATP analogue Direct inhibition Competitive binding 3 (CHAMPION) 4 mcg/kg/min 95% Few minutes Elinogrel (iv and oral) Novel Thienopyridine Competitive binding 3 (Impending) mg 95% Few minutes

54 P2Y12 Antagonists: Drug Design Evolution Revolution N N COOCH 3 F S Cl Ticlopidine S Cl Clopidogrel HO O N N N HN N N S F O HO OH CH 3 O O N S F Prasugrel Ticagrelor (CPTP: Cyclo-Pentyl- Triazolo-Pyrimidine; orally active)

55 TRITON TIMI 38 ACS (STEMI or UA/NSTEMI) & Planned PCI ASA Double-blind N = 13,000 PRASUGREL CLOPIDOGREL Median duration of therapy 12 months 1 o endpoint: CV death, MI, Stroke 2 o endpoints: CV death, MI, Stroke, Rehosp Re-isch, CV death, MI, UTVR

56 Primary Endpoint (%) TRITON-TIMI 38 Prasugrel Lowers Events but Ups Bleeding versus Clopidogrel in ACS , 608 ACS patients scheduled for PCI EARLY ST (definite/probable) Clopidogrel 12.1 HR 0.41 [ ], P< (781) (643) Prasugrel 1.56% HR 0.81 HR ( ) P= HR 0.77 P= P= % NNT= ITT=13, % LTFU=14(0.1%) Days Early Benefits, Late Hazards! ACS, New Dual AntiPlatelet Therapy (New DAPT) Late ST (definite/probable) NEJM 2007;357:2001 Cardiovascular death/mi/stroke HR0.81 ( ), p<0.001 HR Nonfatal 0.60 [ ], MI P=0.03 HR 0.76 ( ), p<0.001 Stent CLOPIDOGREL thrombosis (1.1% vs. 2.4%) HR 0.48 ( ), p<0.001 PRASUGREL Fatal bleeding (0.4% vs 0.1%) HR 4.19 ( ), p= % TIMI major/minor bleeding HR 1.31 ( ), p=0.002 Risk groups: age>75 & lean<60kg 0.49% or history of stroke/tia % Prasugrel (more rapid, consistent, and greater inhibition of P 2 Y 12 receptor) would probably benefit patients with ACS who are undergoing PCI & who are at high risk of ischemic events and low risk for DAYS bleeding.

57 PLATO A Study of PLATelet Inhibition & Patient Outcomes ACS (STEMI/NSTEMI) (<24 h after chest pain) ASA N = 18,624 Double-blind IIbIIIa 27% Ticagrelor Clopidogrel Median duration of therapy: 6-12 months 1 o endpoint: CV death, MI, Stroke (15%RRR) 2 o endpoints: Death, CV death, MI, stroke, recurrent ischemia, arterial thrombotic events

58 More Benefits Without additional Bleeding A formidable opponent to clopidogrel & prasugrel ACS, New Dual AntiPlatelet Therapy (New DAPT) Definite ST33% P=0.009 Total death 22% P< (NNT70) 1 endpoint 0.84 ( ) <0.001 Major bleed 1.04 ( ) 0.43 In ACS patients with or without STEMI, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of CV death, MI, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non procedure-related bleeding. In invasive subgroup (72% of PLATO), impressive ticagrelor results mirror overall trial findings. the reduction in risk with ticagrelor was similar, regardless of whether the comparator group was patients treated with 300-mg or 600-mg loading doses(20%) (HR 0.85 & 0.83).

59 Randomized trials evaluating primary efficacy of intensified antiplatelet regimen vs. clopidogrel in diabetic patients with ACS

60 PEGASUS Trial: Study Design Randomized 10/2010 5/2013: 31 countries; 1161 sites; 21,162 patients Stable patients with history of MI 1-3 yrs prior + 1 additional atherothrombosis risk factor* RANDOMIZE 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 12 months of Follow Up Event-driven trial Primary Efficacy Endopoint: CV Death, MI, or Stroke Primary Safety Endpoint: TIMI Major Bleeding NEJM 2015 (online)

61 CV Death, MI, or Stroke (%) High residual risk PEGASUS Trial: Primary Endpoint 10 N = 21,162 Median follow-up, 33 months Placebo (9.0%) 8 Ticagrelor 90 (7.8% Ticagrelor 60 (7.8% Ticagrelor 90 mg HR 0.85 (95% CI ) P=0.008) Ticagrelor 60 mg HR 0.84 (95% CI ) P= NEJM 2015 (online) Months from Randomization

62 3-Year KM Event Rate (%) PEGASUS Trial: Bleeding Complications Ticag 90: HR 2.69 ( ) Ticag 60: HR 2.32 ( ) TIMI Major TIMI Minor Fatal bleeding or ICH ICH Ticagrelor 90 mg Ticagrelor 60 mg Placebo Fatal bleeding NEJM 2015 (online)

63 Reduction in ischemic events (%) Net clinical benefits: the balance of benefits & harms Evolution of Anti-platelet Therapy -22% -20% -19% PAR-1? Placebo Aspirin Aspirin+ Clopidogrel Aspirin+ Ticagrelor..+ new drugs

64 Major Bleeding (%) Trade-off, Dual Therapy Bleeding: TIMI Major, Not Fatal or ICH RR 38% P = CURE (12 m) RR 25% to 57% RR 25% P = CHARISMA (28 m) RR 57% P < ACTIVE (12 m) RR 32% P = 0.03 TRITON (15 m) Circulation J 2015;79: RR 23% P = 0.29 TRILOGY (30 m) RR 25% P = 0.03 PLATO (12 m)

65 Duration of Dual Anti-platelet Therapy in Patients With ACS 2014 AHA/ACC Guidelines - up to 12 months in all patients after ACS without contraindications (New DAPT preferred, IIa) 2014 ESC/EACTS Guidelines - 12 months in all patients after ACS unless contraindicated (New DAPT preferred, IB)

66 Old DAPT: aspirin+clopidogrel New DAPT: aspirin+prasugrel or ticagrelor On My Watch DAPT Use in CAD Stable CAD after DES Placement - High risk of bleeding: Old DAPT for 6 months - Stable without bleeding: Old DAPT indefinitely ACS without Contraindications - AMI with RFs: New DAPT (A+T) indefinitely - Other ACS Patients with DES Placement: New DAPT for 12 months Old DAPT indefinitely (ACS in DAPT trial: ~40%)

67 Primary & secondary prevention Risk of event Secondary prevention: New DAPT for ACS, old DAPT Stent for stable angina STEMI Secondary prevention: new NSTEMI DAPT > Old DAPT Unstable angina TIA Secondary Stroke prevention: clopidogrel > aspirin MI Symptomatic PAD Secondary prevention: Aspirin Stable angina Diabetes Asymptomatic PAD Risk factors TIA, transient ischemic attack; PAD, peripheral arterial disease; UA, unstable angina; NQWMI, non-q-wave MI Primary prevention: Aspirin or not Disease progression

68 Conclusions The role of aspirin in primary prevention among DM patients still remains questionable, upcoming results from ongoing aspirin trials in primary prevention and clinical evidences from other treatment strategies (e.g. statin, P2Y12 antagonist, and polypill) are warranted. For secondary prevention in high-risk DM patients (e.g. ACS), more potent or new antiplatelet therapy may control the enhanced hypercoagulable state and improve clinical outcomes.. Large-scale randomized trials specifically designed to evaluate these new antiplatelet strategies in DM patients are warranted to determine their efficacy and safety

69 Thank you for your attention