PracticeUpdate: Cardiology

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Ticagrelor no more effective than clopidogrel in patients with prior lower extremity revascularisation for peripheral artery disease In the Examining Use of tiCagreLor In paD (EUCLID) trial, ticagrelor did not reduce the primary composite endpoint of cardiovascular mortality, myocardial infarction, or ischaemic stroke versus clopidogrel in patients with peripheral artery disease and a history of lower extremity revascularisation. S chuyler Jones, MD, of the Duke University School of Medicine, Durham, North Carolina, The findings not only add context to knowledge of antiplatelet monotherapy after revascularisation for peripheral artery disease, but they also highlight the need for more trials of antithrombotic agents after revascularisation.

EXPERT OPINION Dr Peter Libby on the GLAGOV study Written by Peter Libby MD T he introduction of antibodies that inhibit proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors promises to revolutionise the treatment of hypercholesterolaemia due to elevations in low-density lipoprotein (LDL). Numerous studies have shown the ability of these new agents to lower LDL profoundly even in patients well treated with statins. Preliminary compilations of data from smaller studies provide encouraging evidence regarding clinical benefit. Two large-scale outcome trials in progress will inform us within the next few years regarding the ability of these monoclonal antibody therapies that target PCSK9 to lower cardiovascular events in patients at risk. The Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) study furnishes insight into how treatment with anti-PCSK9 agents might alter atherosclerotic plaques and the mechanisms by which they might provide clinical benefit. In this clinical trial, 968 patients with coronary disease, almost all treated with statins, received the anti-PCSK9 monoclonal antibody evolocumab or placebo for 76 weeks and underwent serial intravascular ul- trasound (IVUS) study to quantify coronary atheroma volume. The evolocumab-treated group had reduced LDL concentra- tions compared to those receiving placebo (36.6 vs 93.0mg/dL). Those receiving placebo slightly increased the mean percent atheroma volume over the approximately 18-month observation period (+0.05%) while the evolocumab-treated group showed a reduction in this measure of plaque volume (−0.95%, P < 0.02 vs placebo). GLAGOV shows that beyond statin treatment, the additional LDL lowering altered plaque volume about 1%, on the same order of reduction of statin treatment versus placebo in prior ultrasound studies. Statin treatment confers a disproportionate reduction in clinical events (~20–45%) compared to the small percent- age improvement in mean plaque volume (~1%). This finding indicates that changes in qualitative features of plaques invisible to ultrasound, not just quantity of plaque, may influence the ability of LDL-lowering agents to prevent cardiovascular events. Experimental studies have shown that lipid lowering can re- duce plaque inflammation and reinforce the plaque’s extracellular matrix, thus altering functional characteristics of plaques related to their liability to cause clinical complications. Indeed, some of the clinical benefit of statins likely derives from direct anti- inflammatory actions independent of LDL lowering. In contrast to statins, this and other studies show that anti-PCSK9 agents do not lower the marker of inflammation, C-reactive protein (CRP). We must await analysis of the ongoing large-scale clinical endpoints studies to ascertain whether the decrement in LDL conferred by adding anti-PCSK9 agents to statins will yield a further reduction in clinical events out of proportion to the relatively modest decrease in plaque volume, as in the case of statin treatment. In GLAGOV, about half of the statin-treated patients showed atheroma regression by the ultrasound metrics evaluated. With the addition of the biologic agent, about two-thirds of patients showed regression over the 18-month study duration. While longer treatment with the stringent lipid-combination would likely produce further regression of lesion volume, the authors point out that shrinking atherosclerotic plaques by targeting LDL alone may reach diminishing returns. With the remarkable lipid lowering enabled by the combination of statin and anti-PCSK9 antibodies, we may be wringing as much “milk out of the stone” as we can by lessening lipid accumulation in the atheroma. This consideration indicates that we may be plumbing the limits of clinically beneficial LDL lowering with the remarkable therapies we have at hand today. In an era of striving for “precision” medi- cine, we should prepare to address a residual burden of events in patients despite extreme LDL lowering by targeting other potential drivers of cardiovascular risk including inflammation or other lipid risk factors such as triglyceride-rich glycoproteins.

explained that peripheral artery disease is considered a systemic manifestation of atherosclerosis. It affects the arteries of the lower extremities, and is often thought to constitute a coronary heart disease risk equivalent due to associated high cardiovascular morbidity and mortality. He said, “Considering the uncertainty about long-term risk reduction after vascular intervention and dramatic variation in antiplatelet use after vascular intervention, we were interested in ascertaining patient risk after pulmonary vein isolation and whether we could demonstrate (in the largest subgroup of EUCLID patients) ticagrelor’s effectiveness in reducing cardiovascular risk. Symptomatic patients most commonly present with either intermittent claudication or critical limb ischaemia. These symptoms are often the focus of treatment strategies to revascularise the limb. Unlike patients with coronary artery disease, how to reduce cardiovascular risk in patients with symptomatic peripheral artery disease (whether treated with revascularisation or medical therapy) is not well understood. Clinicians often rely on data from subgroup analyses of patients with peripheral artery disease in antiplatelet and statin studies to guide cardiovascular risk reduction strategies. With limited proven medical therapies to reduce symptoms in patients with peripheral artery disease, peripheral endovascular and surgical revascularisation for the symptomatic management of patients with peripheral artery disease has increased dramatically over the past two decades. Compared with revascularisation for coronary artery disease, little evidence guides clinicians on the choice and use of antiplatelet medications in patients who have undergone a peripheral revascularisation procedure. The optimal antithrombotic regimen for long-term management of patients with peripheral artery disease after revascularisation is poorly defined and often extrapolated from trials of patients undergoing a percutaneous coronary intervention. Two critical questions surround long-term prognosis and management of patients who have undergone prior lower extremity revascularisation: 1. Are patients who have been revascularised at heightened risk for cardiovascular and limb events vs those who have not undergone prior revascularisation? 2. Are more intensive antiplatelet medications more effective yet safe in this population?

ratio 1.03, 95% CI 0.78–1.36); or major bleeding (1.9% vs 1.8%; hazard ratio 1.15, 95% CI 0.83–1.59). The median duration of follow-up was approximately 30 months. Dr Jones said that after adjustment for baseline characteristics, patients enrolled based on prior revascularisation for peripheral artery disease experienced higher rates of myocardial infarction and acute limb ischaemia with similar composite rates of cardiovascular death, myocardial infarction, and stroke versus patients enrolled based on the ankle-brachial index criterion. No significant differences between ticagrelor and clopidogrel were observed in reduction of cardiovascular or acute limb events. The findings suggest that patients with prior revascularisation have a substantial residual rate of cardiovascular and acute limb events, despite high adherence to antiplatelet and statin medications, and require further study. The findings not only add context to knowledge of antiplatelet monotherapy after revascularisation for peripheral artery disease, but they also highlight the need for more trials of antithrombotic agents after revascularisation. Specifically, whether patients should be treated with one or two antiplatelet agents, which agents should be used, the duration of antiplatelet monotherapy or dual therapy, and whether antithrombotics that utilise different mechanistic pathways (for example, P2Y12 receptor antagonists, factor Xa inhibitors) should be used in isolation or in combination for these complex patients to reduce their long- term rates of cardiovascular events and acute limb ischaemia have not been determined. Finally, while the optimal anti- platelet medication regimen is being studied and developed, the impact of disease presentation, anatomic burden of disease, and type of revascularisa- tion procedures need to be understood. “While ticagrelor was no more effec- tive in reducing risk than clopidogrel,” Dr Schuyler Jones said, “we learned valuable information about this popu- lation, specifically, that patients with a history of lower extremity revasculari- sation are at higher risk of acute limb events and cardiovascular events.”

Ticagrelor is a potent P2Y12 receptor antagonist with evidence of benefit in patients with acute coronary syndromes and those with prior myocardial infarction. The EUCLID trial was designed to evaluate treatment, specifically in patients with peripheral artery disease. EUCLID tested the hypothesis that monotherapy with ticagrelor would be superior to clopidogrel in preventing cardiovascular endpoints in patients with peripheral artery disease. Dr Jones described findings in the subgroup of patients who were enrolled based on their history of a prior lower extremity revascularisation. EUCLID randomised 13,885 patients with peripheral artery disease to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle- brachial index ≤ 0.80 or a prior lower extremity revascularisation. The analysis focused on the 7875 (57%) patients enrolled based on prior lower extremity revascularisation. Patients could not be enrolled within 30 days of their most recent revascularisation, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, or ischaemic stroke. The primary safety endpoint was major bleeding. Patients who had undergone prior revascularisation were a mean age of 66 years, 73% were male, and median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on prior revascularisation experienced similar rates of the primary composite endpoint (hazard ratio 1.10, 95% CI 0.98–1.23) and statistically significantly higher rates of myocardial infarction (hazard ratio 1.29, 95% CI 1.08–1.55, P = 0.005) and acute limb ischaemia (hazard ratio 4.23, 95% CI 2.86–6.25, P < 0.001) than patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor- versus clopidogrel-treated patients were observed for the primary efficacy endpoint (11.4% vs 11.3%, hazard ratio 1.01, 95% CI 0.88–1.15); all- cause mortality (9.2% vs 9.2%, hazard ratio 0.99, 95% CI 0.86–1.15); acute limb ischaemia (2.5% vs 2.5%; hazard

Dr Libby is Chief of Cardiovascular Medicine, Brigham and Women’s Hospital and Mallinckrodt Professor of Medicine, Harvard Medical School in Boston, Massachusetts.

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