ODYSSEY Outcomes: High-risk Patients Benefit More From PCSK9s

Debra L Beck

August 27, 2019

Among ODYSSEY Outcomes participants, those with polyvascular disease or previous coronary artery bypass grafting (CABG) had a greater risk for adverse events and saw the greatest benefit from treatment with alirocumab (Praluent, Sanofi/Regeneron).

The findings are from two prespecified secondary analyses published online August 26 in the Journal of the American College of Cardiology.

"Any subgroup analyses, including ours which were prespecified, have to be taken with a grain of salt because the study, of course, wasn't powered to see these subgroup differences, but I think the findings really make the argument that in high-risk patients, those with previous CABG and polyvascular disease, as examples, we have to be as aggressive as possible in managing these patients, not just in terms of LDL lowering, but in all facets of management," said Shaun G. Goodman, MD, MSc, from St. Michael's Hospital, University of Toronto, in an interview.

The ODYSSEY Outcomes trial enrolled 18,924 patients with a recent acute coronary syndrome (ACS) and blood lipid levels that were inadequately controlled with intensive statin therapy. Alirocumab reduced the primary MACE end point — a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, and unstable angina requiring hospitalization — from 11.1% for placebo to 9.5% for alirocumab (hazard ratio [HR], 0.85; P < .001).

Polyvascular Disease Subanalysis

In the first subanalysis, conducted by J. Wouter Jukema, MD, PhD, Leiden University Medical Center, the Netherlands, and colleagues, the investigators wanted to understand not just the effect of alirocumab treatment in patients with polyvascular disease, but also how more severe vascular disease itself might influence risks for MACE and death.

To this end, they grouped ODYSSEY Outcomes participants according to their number of diseased vascular beds. Of 18,924 patients, 17,370 just had coronary artery disease (monovascular disease), 1405 had vascular disease in two territories (coronary artery disease and either peripheral artery disease or cerebrovascular disease), and 149 had vascular disease in three territories (coronary, peripheral artery, and cerebrovascular).

In the placebo group, the incidence of MACE — used as an indication of how disease severity impacts risk irrespective of treatment — in patients with one, two, or three diseased vascular beds was 10.0%, 22.2%, and 39.7%, respectively. The corresponding absolute risk reductions with alirocumab were 1.4%, 1.9%, and 13.0%, respectively (P = .0006 for interaction).

Similarly, for all-cause death, there was a gradient of absolute risk seen in the placebo group and a gradient of absolute risk reduction noted with alirocumab: all-cause death was seen in 3.5%, 10.0%, and 21.8% of those with one, two, or three disease vascular beds, respectively.

Alirocumab reduced all-cause death, in absolute terms, by 0.4%, 1.3%, and 16.2%, respectively (P = .002 for interaction).

"In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyvascular disease is associated with high risks of MACE and death," the authors write. "The large absolute reduction in those risks with alirocumab are a potential benefit for these patients," they add.

CABG Subanalysis

In a second subanalysis, Goodman and colleagues split trial participants according to their history of CABG, a subgroup of patients known to be at particularly high risk for recurrent events or death.

In ODYSSEY Outcomes, 16,896 of enrolled patients had no history of CABG, whereas 1025 had undergone an index CABG after their qualifying ACS but before randomization, and an additional 1003 underwent CABG before the qualifying ACS.

Alirocumab reduced MACE by 15% in the overall treated population (HR, 0.85), with consistent benefits seen across all CABG categories (HRs, 0.86, 0.85, and 0.77 for no CABG, index CABG, and previous CABG, respectively).

However, the absolute risk reduction for MACE for those with previous CABG was 6.4%, compared with 1.3% for no CABG and 0.9% for index CABG (= .0007 for interaction).

In an interview, Goodman explained that this is a relatively common finding, where the hazard ratios are similar for higher-risk and lower-risk subgroups in a trial but the absolute benefit is greater in the higher-risk subgroups "because those patients are at such higher risk and they have higher event rates, so when you apply about a 15% to 20% relative risk reduction to a higher-risk subgroup, the absolute risk reduction becomes that much more striking."

The number needed to treat for 2.8 years to prevent 1 MACE event was 16 for patients with previous CABG, compared with 111 for those with an index CABG and 77 for those with no CABG history.

A similar finding was seen for all-cause death, with an overall HR with alirocumab of 0.85, and similar HRs across all three CABG categories (0.88, 0.85, and 0.67, respectively). But, once again, a greater absolute risk reduction was noted in those with previous CABG (3.6%), compared with no CABG or index CABG (0.4% and 0.5%, respectively; P = .03 for interaction).

The findings were roughly the same with other secondary end points — namely CHD death, nonfatal MI, ischemic stroke, and cardiovascular death — with absolute risk reductions that were numerically greater among patients who had a history of CABG, compared with no CABG or a more recent CABG.

"In many respects, prior CABG status may be a surrogate for chronicity and severity of coronary and systemic atherosclerosis, limited options for further percutaneous or surgical coronary revascularization, or reduced left ventricular function, all of which may affect prognosis," write the study's authors.

Goodman and colleagues point out that the mortality reduction with alirocumab is considered "nominal", given its position at the end of a relatively long list of end points considered in the hierarchical analysis, some of which were not significantly reduced with alirocumab.

Jacques Genest, MD, McGill University Health Center, Montreal, who wasn't involved in either study, wrote an editorial for JACC with coauthors Alexandre M. Belanger, MD, also from McGill, and Mandeep S. Sidhu, MD, MBA, from Albany Medical College, New York.

Regarding the confirmation that post-CABG patients with polyvascular disease are "extremely high-risk populations," and some additional indications from the studies that these higher-risk individuals, in some ways, actually appeared to be less well treated than their lower-risk counterparts, Genest and colleagues were pointed in their comments:

"A reasonable first stop in the approach to patient care is for physicians to be less complacent and apply, with enthusiasm, secondary prevention guidelines in post CABG and polyvascular disease patients," write Genest et al. They also suggest that the findings reinforce the role of PCSK9 inhibitors in the treatment of post-ACS patients, particularly those at higher risk."

These new data come on the heels of an intriguing, retrospective analysis published in July that showed a greater risk for cardiovascular events in patients who did not take advantage of their PCSK9 prescription, either because they were rejected by payers or never filled.

ODYSSEY Outcomes, which reported primary findings at the 2018 American College of Cardiology Annual Scientific Session, was the second trial to show a reduction in hard events with a PCSK9 inhibitor. It followed the FOURIER trial testing evolocumab, the findings of which were first reported at the 2017 ACC meeting, and subsequently published in the New England Journal of Medicine.

ODYSSEY Outcomes and these secondary analyses were funded by Sanofi and Regeneron Pharmaceuticals, Inc. Genest reports being the cochair of FH Canada, and receiving support from Sanofi, Amgen, Pfizer, Aegerion, and Valeant for FH Canada. He has also received honoraria from Novartis, Safnofi, Amgen, and Merck, and has collaborated with Sanofi, Amgen, Novartis, and Eli Lilly on clinical trials.

J Am Coll Cardiol. 2019;74:1167-1176, 1177-1186, 1187-1189. Published online August 26, 2019. Full text, Abstract, Editorial




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