Alirocumab PCSK9 Inhibitor Studied in ODYSSEY Outcomes Trial of ACS Patients
March 10, 2018—Findings from the ODYSSEY Outcomes trial investigating cardiovascular outcomes with alirocumab after acute coronary syndrome were presented by Philippe Gabriel Steg, MD, at the American College of Cardiology's (ACC) 67th annual scientific session held March 10–12 in Orlando, Florida.
Alirocumad (Praluent, Regeneron Pharmaceuticals, Inc. and Sanofi), a proprotein convertase subtilisin-kexin 9 (PCSK9) inhibitor, was shown to reduce rates of major adverse cardiovascular events (MACEs) by 15% compared with placebo in patients with persistently high cholesterol despite high-intensity statin therapy.
In patients at highest risk—those who started the study with low-density lipoprotein (LDL) cholesterol ≥ 100 mg/dL—experienced a 24% reduction in cardiovascular events, including heart attack and stroke, compared with placebo.
As noted in the ACC announcement, previous research has shown that PCSK9 inhibitors reduce LDL levels by approximately 50%, but ODYSSEY Outcomes is only the second large randomized trial to investigate whether this LDL reduction translates into improved cardiovascular outcomes. The ODYSSEY Outcomes investigators stated that it is the first study with a PCSK9 inhibitor to show an associated mortality benefit.
The first outcomes trial—FOURIER, presented at ACC.17—similarly reported that the PCSK9 inhibitor evolocumab reduced the risk of death, heart attack, stroke, hospitalization for angina or revascularization procedures by 15%. Compared with FOURIER, the ODYSSEY Outcomes trial enrolled a higher-risk group of patients, had a longer duration of follow-up (range, 2–5 years), involved a different dosing strategy, and had a slightly different primary endpoint.
In addition to significantly reducing the primary endpoint of MACEs—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 started the trial with LDL cholesterol > 100 mg/dL. The study did not raise any major safety concerns for alirocumab.
Dr. Steg, who serves as the study's co-chair, commented in the ACC press release, "We were really pleased to see the treatment was effective and associated with a reduction in mortality. It is remarkable that such a potent intervention is also so safe. Because the treatment effect was so much more marked in the patients with the highest LDL cholesterol, we believe that these patients are the optimal candidates for therapy."
He added, "Now that we have two trials that consistently show benefits from PCSK9 inhibitors, and given the mortality benefit that we are reporting here for the first time, I think these results may change the equation for these drugs. We're not just talking about preventing nonfatal events such as heart attacks but actually preserving life." Dr. Steg is Chief of Cardiology at Hôpital Bichat in Paris, France.
As summarized in the ACC announcement, the ODYSSEY Outcomes trial was composed of approximately 19,000 patients enrolled at more than 1,300 centers in 57 countries. All patients had ACS within 1 month to 1 year before enrolling in the study. The trial included those patients whose LDL cholesterol remained ≥ 70 mg/dL, non-high-density lipoprotein 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).
Using double-blind randomization, investigators assigned patients to receive injections of either alirocumab or placebo every 2 weeks. To mimic the adjustments a doctor might make when using the drug, those patients randomized to receive alirocumab had their doses adjusted in a blinded fashion in an effort to reach LDL cholesterol levels of 25 to 50 mg/dL. If LDL cholesterol levels dropped consistently below 15 mg/dL, the patient was switched to placebo in a blinded fashion.
Patients were tracked for at least 2 years, with 44% tracked for ≥ 3 years.
Dr. Steg reported that overall, the primary endpoint of MACEs occurred in 9.5% of those receiving alirocumab and in 11.1% of those receiving placebo, while 3.5% of those receiving alirocumab and 4.1% of those receiving placebo died. When investigators looked at causes of death separately, there was no significant difference between the two groups in terms of coronary heart disease and cardiovascular disease deaths. However, there may not have been enough events in each subcategory to show a definite difference, advised Dr. Steg.
Patients starting the trial with LDL cholesterol levels > 100 mg/dL saw improvements in all outcomes that were assessed, including rates of heart attack, stroke, unstable angina requiring hospitalization, coronary heart disease death, cardiovascular death, and death from any cause. Among these patients, the primary endpoint occurred in 11.5% of those receiving alirocumab and 14.9% of those receiving placebo; 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 study groups was minor local site 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.
Patient outcomes will be tracked for up to 10 years to determine whether the benefits continue after stopping the drug.
Going forward, investigators will use the ODYSSEY Outcomes trial data to evaluate the cost-effectiveness of alirocumab. PCSK9 inhibitors cost tens of thousands of dollars per year and are often not covered by insurers, noted the ACC announcement.