ACC 2018: The PCSK9 Inhibitor Alirocumab Reduces Cardiovascular Events After ACS
March 12, 2018—Orlando, Florida— Among patients with persistently high cholesterol despite high-intensity statin therapy, the proprotein convertase subtilisin-kexin 9 (PCSK9) inhibitor alirocumab reduced rates of major adverse cardiovascular events by 15% vs placebo. The effect was even greater among patients at highest risk—those with LDL cholesterol ≥100 mg/dL. These patients saw a 24% reduction in cardiovascular events, including heart attack and stroke vs placebo.
This outcome of the ODYSSEY trial was reported at the American College of Cardiology’s 67th Annual Scientific Session, from March 10 – 12.
Philippe Gabriel Steg, MD, of Hôpital Bichat, Paris, France, explained that the ODYSSEY Outcomes trial was conducted in patients who had recently suffered acute coronary syndrome. Such patients face substantial risk of further cardiovascular problems and related death, particularly if their cholesterol level is not controlled adequately.
Alirocumab is a fully human monoclonal antibody that blocks PCSK9, allowing the liver to remove more LDL from the blood. Research has shown that PCSK9 inhibitors reduce LDL levels by about half.
ODYSSEY Outcomes was only the second large, randomized trial to determine whether this LDL reduction translates into improved cardiovascular outcomes. It was the first study of a PCSK9 inhibitor to show an associated mortality benefit.
Results of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER), the first outcomes trial, were reported at the American College of Cardiology’s 66th Annual Scientific Session in 2017.
Similarly, FOURIER reported that evolocumab, a second PCSK9 inhibitor, reduced the risk of death, heart attack, stroke, hospitalization for angina or revascularization by 15%.
The ODYSSEY Outcomes trial enrolled higher-risk patients than FOURIER, had a longer duration of follow-up (2 to 5 years), involved a different dosing strategy, and had a slightly different primary endpoint.
In addition to significantly reducing the primary endpoint—a combined rate of heart attack, stroke, hospitalization for unstable angina, or death from coronary heart disease—alirocumab was also associated with a 15% reduction in death from any cause among the full patient population and a 29 % reduction in death from any cause among those who began the trial with LDL cholesterol ≥100 mg/dL.
No major safety concerns of alirocumab arose.
According to Dr. Steg, the treatment was effective and was associated with reduced mortality. He also noted that it the safety of such a potent intervention is remarkable. He believes that patients with the highest LDL cholesterol levels are the optimal candidates for therapy based on the greater treatment effect.
Dr. Steg and colleagues enrolled nearly 19,000 patients at more than 1300 centers in 57 countries. All suffered acute coronary syndrome within 1 month to 1 year before enrollment. The trial included those whose LDL cholesterol remained ≥70 mg/dL, non-HDL cholesterol ≥100 mg/dL, or apolipoprotein B ≥80 mg/dL despite treatment with a high or maximum-tolerated dose of a high-potency statin (atorvastatin or rosuvastatin).
Patients were randomized in a blinded manner to injections of either alirocumab or placebo every 2 weeks. To mimic physician adjustments, patients randomized to alirocumab underwent blinded dose adjustment in an effort to reach LDL cholesterol levels of 25 - 50 mg/dL. If LDL cholesterol levels dropped below 15 mg/dL consistently, the patient was switched to placebo, again, in a blinded fashion.
Patients were tracked for at least 2 years, and 44% were tracked for 3 years or more. Overall, the primary endpoint occurred in 9.5% of those receiving alirocumab and 11.1% of those receiving placebo, whereas 3.5% of those receiving alirocumab and 4.1% of those receiving placebo died.
When researchers looked at causes of death, no significant difference was observed between the two groups in terms of coronary heart disease or cardiovascular disease deaths. The number of events in each subcategory may have been insufficient to show a definite difference, however.
Patients beginning the trial with LDL cholesterol levels >100 mg/dL saw improvement in all assessed outcomes, including myocardial infarction, stroke, unstable angina requiring hospitalization, death due to coronary heart disease, cardiovascular death, and all-cause death.
Among these patients, the primary endpoint occurred in 11.5% of those receiving alirocumab and 14.9% of those receiving placebo, while 4.1% of those receiving alirocumab and 5.7% of those receiving placebo died.
In terms of safety and tolerability, the only significant difference between the two groups was minor reactions (mild itching, redness, or swelling) at the injection site, which occurred in 3.1% of those receiving alirocumab and 2.1% of those receiving placebo.
The data will be used to evaluate the cost-effectiveness of alirocumab. PCSK9 inhibitors cost tens of thousands of dollars per year and often are not covered by insurers.
Dr. Steg noted that two trials have demonstrated benefits of PCSK9 inhibitors, with mortality benefit reported for the first time in this trial, which may lead to important changes for these drugs that may not only prevent nonfatal heart attacks, but also preserve life.
Dr. Steg and his team will continue to track patient outcomes for up to 10 years to determine whether benefits continue after stopping the drug.
Click on any of these tags to subscribe to Topic Alerts. Once subscribed, you can get a single, daily email any time PracticeUpdate publishes content on the topics that interest you.
Visit your Preferences and Settings section to Manage All Topic Alerts