Is there enough evidence for DAPT after endovascular intervention for PAOD? Prof. I. Baumgartner Head Clinical & Interventional Angiology University Hospital Bern
Disclosure Speaker name:...i. Baumgartner... I have the following potential conflicts of interest to report: Consulting Employment in industry Stockholder of a healthcare company Owner of a healthcare company X X Other(s) - Member of Executive Committee: EUCLID trial I do not have any potential conflict of interest
Cumulative event rate (%) CAPRIE Efficacy of Clopidogrel vs. Aspirin for MI, Ischemic Stroke, or Vascular Death 16 12 8 ASA 5.83% 5.32% Clopidogrel 0 3 6 9 12 15 18 21 24 27 30 33 36 Months of follow-up 8.7%* P=0.043 Overall relative risk reduction Clopidogrel is superior Aspirin favored Clopidogrel to favored Stroke aspirin 4 in PAD and indicated MI N=19,185 PAD 0 All patients -30-20 -10 0 10 20 30 40 Clopidogrel effect in patients with PAD drive results ASA=aspirin. Mean follow-up=1.91 years. *ITT analysis. CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.
Probability of CV death / MI / stroke PLATO Subgroup with PAD at baseline RCT to determine whether BRILINTA is superior to clopidogrel for prevention of vascular events and death in ACS 0.25 0.20 Ticagrelor Clopidogrel 20.6% 18.0% Positive signal for ticagrelor 0.15 MACE endpoint vs clopidogrel in PAD 2.65% ARR!!! 0.10 0.05 0.00 HR ticagrelor vs clopidogrel: 0.846 (0.644, 1.111) 0 3 6 9 12 Time since randomization (months) Patel MR et al. Eur J Prev Cardiol 2015;22:734 742
EUCLID Study Design Patients with symptomatic PAD Key exclusion criteria: Poor metabolizer for CYP2C19 Patients requiring dual anti-platelet therapy Ticagrelor 90 mg bid Double-blind Double-dummy 1:1 N=13,885 Clopidogrel 75 mg od Inclusion criteria: Symptomatic PAD AND one of the following: A. ABI 0.80 at Visit 1 0.85 at Visit 2 OR B. Prior lower extremity revascularization > 30 days Duration: Event Driven Trial Approximately 14-month recruitment and 26- month follow-up Primary Endpoint: cardiovascular death, myocardial infarction, or ischemic stroke Primary Safety Endpoint: TIMI major bleeding
Primary Efficacy Endpoint (CV Death, MI, or Ischemic Stroke) Caution extrapolating evidence from CAD to PAD individual studies in PAD patients are needed
EUCLID Prior Lower Limb Revascularization (> 30 d) Subgroup Analysis Is more intensive antiplatelet therapy more effective and safe over time after revascularization
Efficacy Outcomes Patients with Prior Revascularization According to Treatment Group Ticagrelor (N=3923) Clopidogrel (N=3952) HR (95% CI) P Value Primary outcome: CV death, MI, or ischemic stroke, no. (%) 447 (11.4) 447 (11.3) 1.01 (0.88 1.15) 0.898 CV death, no. (%) 190 (4.8) 182 (4.6) 1.05 (0.86 1.29) 0.634 MI, no. (%) 237 (6.0) 229 (5.8) 1.05 (0.87 1.25) 0.629 Ischemic stroke, no. (%) 76 (1.9) 100 (2.5) 0.76 (0.57 1.03) 0.078 Key secondary efficacy outcome: CV death, MI, ischemic stroke plus ALI requiring hospitalization, no. (%) 522 (13.3) 529 (13.4) 1.00 (0.88 1.12) 0.947 ALI indicates acute limb ischemia; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Median f-u approximally 30 months
Efficacy Outcomes Patients with Prior Revascularization According to Treatment Group Ticagrelor (N=3923) Clopidogrel (N=3952) HR (95% CI) P Value Composite of CV death, MI, all-cause stroke (ischemic or hemorrhagic), no. (%) 456 (11.6) 461 (11.7) 1.00 (0.88 1.14) 0.970 Hospitalization for ALI, no. (%) 99 (2.5) 97 (2.5) 1.03 (0.78 1.36) 0.835 Lower extremity revascularization, no. (%) 654 (16.7) 680 (17.2) 0.97 (0.87 1.07) 0.519 Composite of all revascularizations (coronary and peripheral [limb, mesenteric, renal, carotid, or other]), no. (%) 906 (23.1) 914 (23.1) 1.00 (0.91 1.09) 0.929 ALI indicates acute limb ischemia; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Median f-u approximally 30 months
CHARISMA Effect of clopidogrel/asa vs ASA on MI, stroke or CV death First occurrence of MI (fatal / non-fatal),stroke (fatal / non-fatal) or CV death Cumulative event rate* (%) 8 Placebo + ASA 7.3% 6 Clopidogrel + ASA 6.8% 4 2 0 0 6 12 18 24 30 Months since randomization RRR 7.1% (95% CI -4.5, 17.5) P=0.22 Bhatt DL et al. N Engl J Med 2006;354:1706
CHARISMA Primary efficacy results (MI/stroke/CV death) by category of inclusion Population N RR (95% CI) P value Documented AT 12,153 0.88 (0.77, 0.998) 0.046 Dual anti-platelet therapy with Coronary 5835 0.86 (0.71, 1.05) 0.13 Cerebrovascular 4320 0.84 (0.69, 1.03) 0.09 Clopidogrel/ASA not better than PAD 2838 0.87 (0.67, 1.13) 0.29 Placebo/ASA Multiple risk factors 3284 1.20 (0.91, 1.59) 0.20 Overall population 15,603 0.93 (0.83, 1.05) 0.22 0.4 0.6 0.8 1.2 1.4 Clopidogrel better 1.6 Placebo better AT, atherothrombosis *First occurrence of MI, stroke (of any cause) or CV death Bhatt DL. Presented at ACC 2006
ACCF/AHA Guidelines ESC guidelines LOE Recommendation Symptomatic patients IA IB IB IIbB Antiplatelet therapy is recommended to reduce the risk of MI, stroke and vascular death in individuals with symptomatic atherosclerotic lower extremity PAD* ASA (75 325 mg) is recommended in individuals with symptomatic atherosclerotic lower extremity PAD* Clopidogrel (75 mg QD) is recommended in individuals with symptomatic atherosclerotic lower extremity PAD* ASA in combination with clopidogrel may be considered in patients who are not at increased risk of bleeding and who are at high perceived CV risk Asymptomatic patients IIaC Antiplatelet therapy can be useful to reduce the risk of MI, stroke or vascular death in asymptomatic individuals with an ABI 0.90 LOE Recommendation Symptomatic patients IC Antiplatelet therapy is recommended in patients with symptomatic PAD* Antiplatelet therapy after revascularization IC IA IIbB IIbB Antiplatelet therapy with aspirin is recommended in all patients with angioplasty for LEAD to reduce the risk of systemic vascular events Dual antiplatelet therapy with aspirin and a thienopyridine for at least one month is recommended after infrainguinal bare metal-stent implantation Antiplatelet treatment with aspirin or a combination of aspirin and dipyridamole is recommended after infrainguinal bypass surgery Dual antiplatelet therapy combining aspirin and clopidogrel may be considered in the case of below-knee bypass with a prosthetic graft Antiplatelet therapy in PAD with CAD IIaB In PAD with stable CAD, clopidogrel should be considered as an alternative to aspirin for long-term antiplatelet therapy
OAP treatment variable & often associated with LER rather than CV risk Guidelines are not specific in recommendation for ASA v clopidogrel vs DAPT; do not reflect the evidence and are inconsistent between region Clopidogrel initiation is strongly correlated to endovascular intervention Clopidogrel LER LER Clopidogrel DAPT LER Clopidogrel use in PAD patients undergoing LER (RW data)
Benefit (MACE) - harm (bleeding) profil Efficacy & Safety of AP for Prevention of MACE and Leg Amputations in PAD Systematic Review and Network Meta- Analysis (49 RCT) Surgical endovascular revascularization 3 RCT (of 49 RCT analysed) 3.527 patients > 8.000 person-years of follow up short-term DAPT reduces major amputations after revascularization PLOS ONE 10 (8),1-19,2015
Efficacy of Different Antiplatelet Agents for Prevention Leg Amputations 3 RCTs with 3,527 patients including surgical and endovascular revascularizations number of major amputations avoided greater than number of severe bleedings 32% reduction of event rates compared to aspirin monotherapy; NNT = 94 PLOS ONE DOI:10.1371/journal.pone.0135692 August 14, 2015
Conclusion Clopidogrel should be the indicated antiplatelet agent in PAD DAPT with aspirin & clopidogrel can reduce rate of major leg amputations following revascularization, but carries a slightly higher risk of severe bleeding
Is there enough evidence for DAPT after endovascular intervention for PAOD? Prof. I. Baumgartner Head Clinical & Interventional Angiology University Hospital Bern