Ticagrelor

Addition of P2Y12 inhibitor fails to benefit noncritically ill patients with COVID-19

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In a cohort of noncritically ill patients with COVID-19, the addition of a P2Y12 inhibitor to anticoagulation did not extend survival or lessen disease severity, according to results of the ACTIV-4a trial.

Thrombosis and inflammation contribute to the risk for death and complications in patients with COVID-19.

COVID_19_3

Jeffrey S. Berger

“Data from the [multiplatform randomized controlled trial] demonstrated that therapeutic-dose heparin increased days alive and free of organ support in noncritically ill (moderate) patients with COVID-19,” Jeffrey S. Berger, MD, MS, associate professor of medicine and surgery with appointments in cardiology, hematology and vascular surgery at NYU Grossman School of Medicine and director of the Center for the Prevention of Cardiovascular Disease at NYU Langone Health, said during a presentation at the American Heart Association Scientific Sessions. “Nonetheless, nearly one out of four patients receiving therapeutic-dose heparin still died or received intensive care level support, highlighting the need for additional therapies in this cohort.”

This led Berger and colleagues to conduct the open-label ACTIV-4a trial, in which they randomly assigned patients 1:1 to a P2Y12 inhibitor plus standard care anticoagulation of therapeutic-dose heparin or standard care anticoagulation and no P2Y12 inhibitor (usual care).

The preferred recommended P2Y12 inhibitor was ticagrelor (60 mg twice daily without a loading dose; Brilinta, AstraZeneca). Clopidogrel (300 mg loading dose followed by 75 mg daily) and prasugrel (30 mg loading dose and 10 mg daily; Effient, Daiichi Sankyo/Eli Lilly) were also allowed. Patients received P2Y12 inhibitor treatment for 14 days or until hospital discharge, whichever came first.

The researchers defined the primary endpoint as 21-day organ support-free days; key secondary endpoint as the composite of major thrombotic events or death; and primary safety endpoint as major bleeding according to the International Society on Thrombosis and Haemostasis definition.

The study continued until a conclusion of superiority (> 99% posterior probability proportional OR > 1) or futility (> 95% posterior probability proportional OR < 1.2) with P2Y12 inhibitor treatment was reached.

In all, researchers enrolled 562 noncritically ill patients with laboratory-confirmed SARS-CoV-2 infection at the time of enrollment discontinuation. Among them, 293 patients received a P2Y12 inhibitor and 269 received usual care.

Primary endpoint data indicated an adjusted OR of 0.83 (95% credible interval, 0.55-1.25), with a futility probability of 96.2%.

In addition, there was no benefit with P2Y12 inhibition on the composite of death or organ support (aHR = 1.19; 95% CI, 0.84-1.68; P = .34); the key secondary outcome (aOR = 1.42; 95% CI, 0.64-3.13); or the primary safety endpoint (aOR = 3.31; 95% CI, 0.64-17.2).

“In noncritically ill hospitalized patients with COVID-19, use of P2Y12 inhibitors did not result in a greater number of days alive and free of cardiovascular or respiratory organ support,” Berger concluded, noting the low rate of major bleeding with the therapy, which increased the absolute risk by approximately 1%. “Testing P2Y12 inhibitors in critically ill patients is ongoing.”

Ticagrelor for Prevention of Ischemic Events After Myocardial Infarction in Patients With Peripheral Artery Disease

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Abstract

Background  Peripheral artery disease (PAD) is associated with heightened ischemic and bleeding risk in patients with prior myocardial infarction (MI).

Objectives  This study evaluated the efficacy and safety of ticagrelor on major cardiovascular (CV) events and major adverse limb events in patients with PAD and a prior MI.

Methods  PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin—Thrombolysis In Myocardial Infarction 54) randomized 21,162 patients with prior MI (1 to 3 years) to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin. History of PAD was obtained at baseline. Occurrences of major adverse cardiovascular events (MACE) (defined as CV death, MI, or stroke) and major adverse limb events (MALE) (defined as acute limb ischemia or peripheral revascularization for ischemia) were recorded in follow-up.

Results  A total of 1,143 patients (5%) had known PAD. In the placebo arm, those with PAD (n = 404) had higher rates of MACE at 3 years than those without (n = 6,663; 19.3% vs. 8.4%; p < 0.001), which persisted after adjusting for baseline differences (adjusted hazard ratio: 1.60; 95% confidence interval: 1.20 to 2.13; p = 0.0013), and higher rates of acute limb ischemia (1.0% vs. 0.1%) and peripheral revascularization procedures (9.15% vs. 0.46%). Whereas the relative risk reduction in MACE with ticagrelor was consistent, regardless of PAD, patients with PAD had a greater absolute risk reduction of 4.1% (number needed to treat: 25) due to their higher absolute risk. The absolute excess of TIMI major bleeding was 0.12% (number needed to harm: 834). The 60-mg dose had particularly favorable outcomes for CV and all-cause mortality. Ticagrelor (pooled doses) reduced the risk of MALE (hazard ratio: 0.65; 95% confidence interval: 0.44 to 0.95; p = 0.026).

Conclusions  Among stable patients with prior MI, those with concomitant PAD have heightened ischemic risk. In these patients, ticagrelor reduced MACE, with a large absolute risk reduction, and MALE. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS-TIMI 54]; NCT01225562)

Perspectives

COMPETENCY IN PATIENT CARE: Prolonged therapy with ticagrelor reduced ischemic risk and increased bleeding in patients with prior MI, and in a subgroup analysis, those with concomitant PAD appeared to derive greater absolute benefit than those without PAD.

TRANSLATIONAL OUTLOOK: An ongoing prospective trial of ticagrelor as antiplatelet monotherapy should provide more insight into the efficacy and safety of ticagrelor monotherapy versus clopidogrel monotherapy in a broad population of patients with PAD, including those without concomitant coronary disease.

Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack.

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Ticagrelor may be a more effective antiplatelet therapy than aspirin for the prevention of recurrent stroke and cardiovascular events in patients with acute cerebral ischemia. Methods We conducted an international double-blind, controlled trial in 674 centers in 33 countries, in which 13,199 patients with a nonsevere ischemic stroke or high-risk transient ischemic attack who had not received intravenous or intraarterial thrombolysis and were not considered to have had a cardioembolic stroke were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive either ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2 through 90). The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days. Results During the 90 days of treatment, a primary end-point event occurred in 442 of the 6589 patients (6.7%) treated with ticagrelor, versus 497 of the 6610 patients (7.5%) treated with aspirin (hazard ratio, 0.89; 95% confidence interval [CI], 0.78 to 1.01; P=0.07). Ischemic stroke occurred in 385 patients (5.8%) treated with ticagrelor and in 441 patients (6.7%) treated with aspirin (hazard ratio, 0.87; 95% CI, 0.76 to 1.00). Major bleeding occurred in 0.5% of patients treated with ticagrelor and in 0.6% of patients treated with aspirin, intracranial hemorrhage in 0.2% and 0.3%, respectively, and fatal bleeding in 0.1% and 0.1%. Conclusions In our trial involving patients with acute ischemic stroke or transient ischemic attack, ticagrelor was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days.

Preventing Coronary Stent Thrombosis and Post-Stent Complications.

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A structured review supports long-term low-dose aspirin plus a P2Y12-receptor inhibitor for 1 year.
More than 90% of percutaneous coronary interventions also involve stent placement. Stent thrombosis is a major complication of stent placement, and preventing it is the main goal of post-stent management. To determine the optimal approach to post-stent management, researchers conducted a structured literature review of 91 randomized trials, systematic reviews, and meta-analyses.

Dual antiplatelet therapy with long-term, low-dose aspirin (75–100 mg daily) plus a P2Y12-receptor inhibitor (usually clopidogrel) for 1 year after stent placement is the standard recommendation. Although this recommendation applies to both drug-eluting and bare-metal stents, a shorter duration of clopidogrel therapy (minimum of 1 month) is considered to be permissible for patients who have received bare-metal stents for nonacute coronary syndrome indications. Higher doses of aspirin (>200 mg daily) are associated with a twofold higher risk for bleeding, with no additional benefit. Risk for stent thrombosis continues beyond 1 year; however, studies of P2Y12-receptor inhibitor use beyond 1 year show no benefit in the face of elevated bleeding risk. Large clinical trials of shorter and longer durations of P2Y12-receptor inhibition are under way.

COMMENT

Three P2Y12-receptor inhibitors are available. However, adverse events have limited use of prasugrel (Effient) and ticagrelor (Brilinta). Studies of optimal clopidogrel dosing suggest that bleeding risk rises with higher doses; thus, the current recommendation is for a 300-mg loading dose followed by 75 mg daily. Because adding warfarin (i.e., for patients with atrial fibrillation or mechanical heart valves) is associated with two- to threefold higher risk for major bleeding complications, aspirin should be discontinued while patients receive warfarin. If at all possible, noncardiac elective surgery should be delayed until 1 full year of dual antiplatelet therapy with aspirin and clopidogrel is completed. Patients at high risk for bleeding should take proton-pump inhibitors while receiving dual antiplatelet therapy. Based on anticipated studies, clinicians soon might have more guidance for tailoring dual antiplatelet therapy duration to a patient’s specific clinical profile and type of stent.

Source: NEJM