Controversies in Cardiology: Anti-Thrombotic Therapy in PAD

Do we need more than aspirin?

Daniel I. Simon, MD

Sahil Parikh, MD

Harrington Heart & Vascular Institute Innovations - Summer 2016

Dr. Dan Simon: President, UH Case Medical Center, Herman K. Hellerstein Chair in Cardiovascular Research, UH Cleveland Medical Center and Case Western Reserve University; Professor of Medicine, Case Western Reserve University School of Medicine "I’m talking today with Dr. Sahil Parikh, one of our interventionalcardiologists specializing in vascular medicine and endovascular therapy, who treats many patients with PAD. What is research telling us about the role of anti-thrombotic therapy for these patients?

Dr. Sahil Parikh: Sadly, PAD remains underdiagnosed by primary care physicians and cardiologists because many patients are asymptomatic despite evidence of obstructive atherosclerosis.

PAD prevalence increases with age and concomitant cardiovascular risk factors.Most contemporary cardiovascular practices have a prevalence of upward of 30 percent. Moreover, the natural history of PAD can be misleading.Only a small percentage of patients with obstructive PAD will have severe enough symptoms to merit revascularization;however, up to 75 percent will go on to die from cardiovascular causes,primarily MI and stroke. An abnormal ankle brachial index (ABI) confers a 10-year risk of cardiovascular morbidity approaching 50 percent.

Because of the systemic nature of atherosclerosis, patients with PAD should be considered candidates for secondary prevention strategies that include aggressive risk factor modification and antiplatelet therapy. In fact, recently published data suggests that adherence with guideline-based medical therapy can reduce major adverse cardiac events and major adverse limb events (MACE and MALE, respectively) by over 40 percent. Unfortunately, we know that patients with PAD are undertreated with regard to the use of lipid-lowering and antiplatelet drugs, when compared with patients who have coronary artery disease. We simply have to do better.

Dr. Simon: With that in mind, tell me about the results of a new PAD subgroup analysis of the PEGASUS trial indicating that the addition of a second antiplatelet agent, the P2Y12 inhibitor ticagrelor, not only reduced major adverse cardiovascular events, but also reduced “limb-specific” events.

Dr. Parikh: As you recall, the PEGASUSTIMI 54 trial evaluated the efficacy and safety of ticagrelor in patients with prior MI. It included 21,162 patients with prior MI (one to three years), who were randomized to ticagrelor 90 mg BID,60 mg BID or placebo, all with low-dose aspirin. History of PAD was obtained at baseline. This new subgroup analysis focused on 1,143 patients with known PAD and looked at the occurrence of MACE (defined as cardiovascular death, MI or stroke) as well as MALE (defined as acute limb ischemia or peripheral revascularization for ischemia) during follow-up.

Dr. Simon: What did the subgroup analysis show?

Dr. Parikh: There are several remarkable findings. First, in the placebo or aspirin-only arm, those with PAD had higher rates of MACE at three years,compared with those without. These differences persisted after adjusting for baseline differences. Patients with known PAD randomized to aspirin only also had higher rates of acute limb ischemia (1.0% vs 0.1%) and peripheral revascularization procedures (9.15% vs 0.46%). Second, ticagrelor reduced MACE, but because of their higher absolute risk of MACE, patients with PAD had a greater absolute risk reduction of 4.1 percent, resulting in a highly favorable number needed to treat of only 25. The absolute excess of TIMI major bleeding was quite low at 0.12 percent, corresponding to a number needed to harm of NNH 834. Third, and perhaps most important, ticagrelor (doses pooled) reduced the risk of major adverse limb outcomes by 35 percent.

Dr. Simon: This is very impressive.Do you think this will change clinical practice? Are you initiating dual antiplatelet therapy in your patients with PAD?

Dr. Parikh: This adds to our knowledge that potent P2Y12 antagonists in patients with known PAD and MI may have strong grounds for prolonged therapy with ticagrelor on the basis of not just reduction of MACE but also MALE. However, I would caution against over-extrapolating these results. In the coming year, we expect results of the EUCLID study, which has randomized more than 13,000 PAD patients to either clopidogrel or ticagrelor monotherapy in secondary prevention, looking at the incidence of MACE and MALE after three years. Moreover, we’re humbled by the results of the SOCRATES trial, which was recently published in The New England Journal of Medicine. In this study, more than 13,000 patients were randomized to receiving ticagrelor or aspirin after ischemic stroke or TIA and were followed for achievement of a primary endpoint composite of stroke, MI or death at 90 days. There was no statistically significant difference between the two groups.

Dr. Simon: What about other antiplatelet agents, such as the PAR-1 thrombin receptor antagonist vorapaxar?

Dr. Parikh: This is controversial. Vorapaxar is approved for patients post-MI or with PAD. The clinical benefits of targeting the thrombin receptor were studied in TRA 2°P TIMI-50, in which patients had at least one of three atherosclerotic conditions – prior MI, prior stroke or established PAD. The primary endpoint of the trial was the time to cardiovascular death, MI, stroke or urgent coronary evascularization. There was a 13 percent reduction in the primary endpoint for patients treated with vorapaxar 2.5 mg. Although vorapaxar was approved for patients post-MI or with PAD, subgroup analysis shows that treatment with vorapaxar in the PAD subgroup did not significantly reduce the risk of cardiovascular death, MI, stroke or coronary revascularization.

Dr. Simon: Are there data about vorapaxar’s effect on MALE?

Dr. Parikh: Vorapaxar reduced acute limb ischemia events by 41 percent. These events were most commonly related to acute bypass graft thrombosis or in situ thrombosis of a diseased vessel, sometimes resulting in limb loss.

Dr. Simon: What about adding clopidogrel or prasugrel to ASA for PAD?

Dr. Parikh: That’s a great question, but we have incomplete clinical trial data to guide us here. The Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial compared clopidogrel 75 mg with aspirin 325 mg daily in approximately 19,000 patients with recent MI, recent ischemic stroke or PAD. The PAD group was large with 6,452 patients and included patients with claudication and an ankle brachial index value of 0.85 or less, history of claudication with previous peripheral bypass surgery, angioplasty or amputation. Clopidogrel was associated with an overall reduction of 8.7 percent in the primary endpoint of fatal or nonfatal ischemic stroke, fatal or nonfatal myocardial infarction or death from other vascular causes. In fact, clopidogrel appeared to be most effective in the PAD subgroup, reducing the primary endpoint by 23 percent. This result led to FDA approval of clopidogrel for secondary prevention of atherosclerotic events in patients with atherosclerosis, including those with PAD. EUCLID will evaluate ticagrelor vs. clopidogrel alone in patients with PAD. We’ll see if the results are similar to the retrospective findings in PEGASUS.