At the 64th Annual Scientific Session of the American College of Cardiology (ACC), Marc S. Sabatine, MD, MPH, Chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group and Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine at Brigham and Women’s Hospital (BWH), presented two late-breaking clinical trials. In both studies the experimental therapy significantly reduced cardiovascular events in the studied patient populations.
“Our team is focused on conducting large-scale, practice changing clinical trials in patients with cardiovascular disease or risk factors for cardiovascular disease,” said Dr. Sabatine.
In previous short-term studies, evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels. Extension studies (the OSLER program) were conducted from these parent trials in which 4,465 patients from 12 parent studies were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every two weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months.
As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61 percent, from a median of 120 mg per deciliter to 48 mg per deciliter. The rate of cardiovascular events at one year was reduced by 53 percent, from 2.18 percent in the standard-therapy group to 0.95 percent in the evolocumab group (Figure 1). The treatment appeared to be safe and well tolerated. In mid-June 2015, Dr. Sabatine spoke about evolocumab at the FDA Advisory Committee meeting, at the end of which the committee voted to recommend approval.
The first PCSK9 inhibitor was approved by the FDA at the end of July, with the second such agent being reviewed later this year. “The PCSK9 inhibitor data is remarkable and represent important findings that are helping open up a new era in lipid-lowering therapies,” said Jorge Plutzky, MD, Director of Preventive Cardiology.
Current guidelines recommend adding a P2Y12 receptor antagonist to aspirin only for the first year after an acute coronary syndrome. In the PEGASUS-TIMI 54 study, researchers theorized that the addition of ticagrelor, a potent, reversibly-binding, direct acting P2Y12 antagonist, to standard therapy would reduce the incidence of major adverse cardiovascular events during long-term follow-up in patients with a history of myocardial infarction.
The study randomized 21,162 patients who had had a myocardial infarction one to three years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All patients received low-dose aspirin and were followed for a median of 33 months. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke.
Compared with placebo, the two ticagrelor doses each reduced the rate of the primary efficacy end point at three years, with a 15 percent reduction with the 90 mg dose and a 16 percent reduction with the 60 mg dose (3-year event rate of 7.85 percent and 7.77 versus 9.04 percent) (Figure 2). Although rates of TIMI major bleeding were higher with ticagrelor than with placebo, the rates of intracranial hemorrhage or fatal bleeding did not differ between the treatment and placebo groups. (N Engl J Med. 2015 May 7;372(19):1791-800.).
Established in 1984, the TIMI Study Group at BWH is the oldest cardiovascular Academic Research Organization (ARO) in North America and was led by Founding Chairman Eugene Braunwald, MD, until 2011. The first TIMI trial compared the effects of the then-new intravenously administered tissue plasminogen activator (tPA) with streptokinase on coronary and clinical outcomes in patients presenting with an ST-elevation myocardial infarction (STEMI). The trial was a success and demonstrated the superiority of tPA, which became the preferred fibrinolytic therapy. Since that time, the TIMI Study Group has conducted more than 60 clinical trials spanning from phase I to phase IV studies. Trials have ranged from less than 30 subjects to more than 26,000 subjects and have been conducted at more than 5,000 separate sites in 50 countries.
TIMI Investigators have studied a wide range of interventions including fibrinolytic, antiplatelet, anticoagulant, anti-ischemic, lipid-modifying, anti-inflammatory, anti-diabetes, and antiobesity agents, as well as percutaneous coronary intervention. In addition, the TIMI Study Group has used its large database of clinical findings, biomarkers, and genotypes to enhance the understanding of cardiovascular disease and its risk factors.
By leading large-scale, international, randomized controlled trials of novel therapeutics and performing sophisticated analyses, the TIMI Study Group has helped shape the very practice of cardiovascular medicine for over a quarter of a century.
To learn more about TIMI Study Group trials, latest publications, and recent news, visit TIMI.org.
The preventive cardiology team in the Heart & Vascular Center at Brigham and Women’s Hospital delivers specialized approaches for complex cardiometabolic disorders and integrated care and management for patients with conditions that often exist alongside and contribute to cardiovascular disease.
Led by Jorge Plutzky, MD, the team delivers specialized cardiovascular care within dedicated clinics for patients with obesity; diabetes and pre-diabetes; rheumatologic disease; sleep disorders; lipid disorders; premature cardiovascular diseases; and women’s cardiovascular disease issues. They have introduced novel therapeutic approaches to severe hypertriglyceridemia and recurrent pancreatitis and have successfully reduced issues with statin intolerance in order to maintain statin therapy. The team’s research has also helped to inform national and international guidelines for cardiovascular risk reduction and cardiac rehabilitation and has highlighted improvements in patient safety in myocardial infarction and heart failure care.
For more information, or to refer a patient to our Cardiovascular Disease Prevention program, please call our HVC Navigation Center access line at (857) 307-4000.
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