ODYSSEY Outcomes: Alirocumab Cuts CV Events, All-Cause Death Post-ACS

Patrice Wendling

March 10, 2018

ORLANDO, FL — A second large randomized trial has shown that a PCSK9 inhibitor reduces LDL-cholesterol and cardiovascular events but also provides the first evidence of a survival advantage for the pricy drugs, at least when given to patients after an acute coronary syndrome (ACS) who have high cholesterol despite maximal statin therapy.

After a median follow-up of 2.8 years of nearly 19,000 participants in the ODYSSEY Outcomes trial, patients who received biweekly injections of alirocumab (Praluent, Sanofi/Regeneron) 75 or 150 mg every other week had a 15% reduction in the primary outcome of time to first coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina compared with those given placebo.

The absolute event rate for all-cause death was 3.5% in the alirocumab group and 4.1% in the control group, a difference that translated into a relative reduction of 15% (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.3 - 0.98; nominal P value = .026 based on hierarchal testing).

There was a nonsignificant trend in cardiovascular (CV) death rates favoring the alirocumab group (2.5% vs 2.9%; HR, 0.88; 95% CI, 0.74 - 1.05, log-rank P =.15), study cochair Gabriel Steg, MD, chief of cardiology at Hôpital Bichat, Paris, France, reported during a late-breaking session here at the American College of Cardiology (ACC) 2018 Annual Scientific Session.

Post hoc analyses suggest the greatest benefit was among patients with ACS with a baseline low-density lipoprotein cholesterol (LDL-C) of at least 100 mg/dL, in which the relative risk reductions reached 24% for CV events (3.4% absolute risk) and 29% for all-cause death (1.7% absolute risk).

Although these are the patients who would benefit most from treatment, it's the effect on all-cause mortality that "I assume will sway most patients, physicians, and hopefully payers and regulators to give greater access to these drugs, because this is not a minimal improvement in the care of these patients," Steg told theheart.org | Medscape Cardiology.

He noted that a 15% reduction in major adverse cardiovascular events (MACE) is in the range of what, for instance, aspirin achieves, and that even statins have not shown a mortality reduction in the post-ACS setting. Roughly, the number needed to treat for alirocumab over the duration of the trial was 64 for MACE and 163 for all-cause mortality, and 29 and 60, respectively, among the subgroup with an LDL above 100 mg/dL.

At last year's ACC meeting, the FOURIER trial reported a 15% reduction in CV-event risk, using a softer MACE definition with no mortality benefit at 2.2 years in patients with stable atherosclerotic CV disease (CVD) treated with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen). The number needed to treat was 50 for 3 years of treatment.

"I consider this very reassuring that for individuals who questioned whether PCSK9 inhibition for some reason was different than statins and wouldn't have a benefit for fatal events, now with a trial that's gone a bit longer, we start to see that signal emerging," FOURIER lead investigator Marc S Sabatine, MD, Brigham and Women's Hospital, Boston, Massachusetts, told theheart.org | Medscape Cardiology.

"Ultimately, we'll need longer trials like what we're planning to do in ORION-4 that last 4 to 5 years, and in that setting, I think we'll have definitive evidence for CV mortality. But I think this is a wonderful piece for the puzzle and should buoy people to think that this class should function just like statins in terms of clinical benefits."

Sabatine said if these drugs were pennies a day, they would be widely used, but that patients are being undertreated in today's cost-conscious environment, and he called for payers to provide an easy-access pathway for high-risk patients.

"We may argue about certain groups, but for people who are at very high risk, whose LDL cholesterol is above 100, have multivessel disease, have multiple MI, surely we can all agree that those patients need to be treated now," he said.

Asked by theheart.org | Medscape Cardiology how the two drugs would be used in daily practice, he said that, based on the evidence to date, evolocumab should used in stable atherosclerotic patients with CVD and alirocumab in the ACS setting until a class effect can be confirmed.

ACC president Mary Norine Walsh, MD, from St Vincent Medical Group, Indianapolis, Indiana, said in an interview that for patients with ACS who don't have effective lipid lowering on high-intensity statins, "this is paradigm-shifting," but agreed that the issue for patients and physicians alike remains one of access to these expensive drugs.

"One of the most important takeaways is that more data like this will help when cardiologists and lipid experts feel that this is the drug that's needed; we should have more traction in getting insurance companies to pay for it," she said.

LDL Reduction Drift

ODYSSEY Outcomes investigators in 57 countries randomly assigned 18,924 individuals 4 weeks to 1 year after an ACS on maximal-intensity statins and optimal medical therapy to alirocumab 75 mg every 2 weeks or placebo. The alirocumab dose was escalated in blinded fashion to 150 mg every 2 weeks in patients who did not reach the target LDL-C goal between 25 and 50 mg/dL. An additional 7.7% of patients were switched to placebo because they achieved LDL-C below 15 mg/dL on two measurements.

Their median age was 58 years, median LDL-C was 87 mg/dL in both groups, and non-LDL-C was 115. In all, 1955 patients experienced a primary end point and 726 patients died.

In the on-treatment analysis, LDL-C values at 4, 12, and 48 months were 93.3, 96.4, and 101.4 mg/dL in the placebo group and 37.6, 42.3, and 53.3 mg/dL in the alirocumab group, a difference that translated into declines of 62.7%, 61.0%, and 54.7%, respectively.

Panelist Pamela Bowe Morris, MD, from the Medical University of South Carolina, Charleston, observed that there was a very sustained reduction in LDL-C over the course of FOURIER and questioned whether differences in the protocols, the 8% alirocumab treatment discontinuation rate, or 5% incidence of neutralizing antibodies with alirocumab might explain why "we're noticing in ODYSSEY a drift over time, and a pretty substantial drift" downward in LDL-C reduction.

Steg said down-titration and premature discontinuation of alirocumab played a role, although the incidence of neutralizing antibodies was extremely low in the trial. The absolute number was 42 in one group and 9 in the other, and as shown in prior studies, the presence of neutralizing antibodies had no effect on LDL efficacy.

Among the components of the primary efficacy end point, alirocumab was associated with significantly lower rates of nonfatal MI (6.6% vs 7.6%; HR, 0.86; 95% CI, 0.77 - 0.96), ischemic stroke (1.2% vs 1.6%; HR, 0.73; 95% CI, 0.57 - 0.93), and unstable angina (0.4% vs 0.6%; HR, 0.61; 95% CI, 0.41 - 0.92).

The overall MACE rate was 9.5% with alirocumab vs 11.1% with placebo (HR, 0.85; 95% CI, 0.78 - 0.93); log rank P = .0003).

Commenting for theheart.org | Medscape Cardiology, Dmitriy Feldman, MD, from New York Presbyterian Hospital Weill Cornell Medical Center in New York City, said "The magnitude of reduction in the primary and secondary end points gives reassurance that this class of drugs is efficacious for ACS patients."

He noted that the percentage of patients who don't achieve satisfactory lipid reduction within a few months after ACS is large, and that for these patients, "it [would] be very reasonable to consider alirocumab."

Over the duration of the trial, the only signal of safety was more local injection site reactions in the alirocumab vs placebo group (3.8% vs 2.1%). If anything, Steg said event rates trended lower in the alirocumab group for hemorrhagic stroke (9 vs 16 events), new-onset diabetes (648 vs 676 events), and neurocognitive disorders (143 vs 167 events). Neurocognitive issues were an issue raised by the US Food and Drug Administration in March 2014 when the agency asked Regeneron and Sanofi to monitor for this potential concern in its clinical trials.

Session cochair Valentin Fuster, MD, from Mount Sinai School of Medicine, New York City, said during a media briefing that "This study is going to change practice. It was a hypothesis that has been fulfilled."

He said that the reductions in CV events and all-cause mortality were not trivial, and that given the LDL-C levels achieved in the trial, "The message is maybe what we consider a normal LDL-C level is too high today, and that we have to go lower and lower."

The study was sponsored by Sanofi and Regeneron Pharmaceuticals. Steg disclosed receiving research grants from Bayer, Merck, Sanofi, and Servier, and speaking or consulting fees from Amarin, Amgen, AstraZeneca, Bayer/Janssen, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, Merck, Novartis, Novo-Nordisk, Pfizer, Regeneron, Sanofi, and Servier. Walsh reported being a trialist for DECIDE-LVAD PCORI. Morris reported consulting fees/honoraria from Amgen, AstraZeneca, and Sanofi Regeneron, and research grants from Amgen. Feldman and Fuster have disclosed no relevant financial relationships.

American College of Cardiology (ACC) 2018 Annual Scientific Session: Presentation 401-08. Presented March 10, 2018.

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