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PCSK9 inhibition cuts events in very-high-risk groups

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PCSK9 benefit clear in high-risk patients

These two secondary analyses of the ODYSSEY OUTCOMES trial are very important studies that reinforce the usefulness of PCSK9 inhibition in extremely high risk populations.

Although each study has limitations as acknowledged, it provides further evidence that should lead us to strongly consider the use of PCSK9 inhibitors in patients with a previous coronary artery bypass grafting (CABG) or a history of polyvascular disease.

The studies confirm that aggressive lipid-lowering therapy will benefit patients in those high-risk subsets. The significant reductions in mortality associated with lowering LDL cholesterol using alirocumab can no longer be ignored.

Economic analyses would be interesting, as the substantial reductions in major adverse cardiovascular events and all-cause deaths attributed to alirocumab would likely impact health care costs and society at large.

However, it is concerning that patients with prior CABG and those with a high atherosclerosis burden in multiple arterial territories were seemingly less well treated than acute coronary syndrome patients.

An LDL cholesterol level of at least 100 mg/dL was seen in upward of 40% of the high-risk participants at randomization, while 87% had high BP, 40% had diabetes, and 16% were current smokers.

A reasonable first step 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 to strive to eliminate smoking and to enforce lifestyle modifications with known benefits in atherosclerotic cardiovascular disease.

Jacques Genest, MD, and Alexandre M. Bélanger, MD, of McGill University, Montreal, and Mandeep S. Sidhu, MD, of Albany (N.Y.) Medical College made these comments in an accompanying editorial ( J Am Coll Cardiol. 2019 Aug 26. doi: 10.1016/j.jacc.2019.07.016 ). The authors reported disclosures related to Sanofi, Amgen, Pfizer, Aegerion Pharmaceuticals, Valeant Pharmaceuticals, and others.



Patients at very high risk of adverse cardiovascular outcomes derive substantial benefit from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, according to results of two analyses from the ODYSSEY OUTCOMES trial.

In one prespecified analysis, the PCSK9 inhibitor alirocumab was linked to improved cardiovascular outcomes in patients with prior coronary artery bypass grafting (CABG), while in the other, researchers wrote that alirocumab showed a “large absolute benefit” in patients with polyvascular disease, which they defined as the presence of concomitant peripheral artery disease, cerebrovascular disease, or both.

These reports on alirocumab outcomes in patients with prior CABG and polyvascular disease appear in the Journal of the American College of Cardiology.

Prior CABG and polyvascular disease were both associated with markedly elevated risks of major adverse coronary events (MACE) and death, investigators wrote in the reports.

The ODYSSEY OUTCOMES trial included 18,924 patients with recent acute coronary syndrome (ACS) and high atherogenic lipoproteins despite intensive statin treatment. The primary outcome was MACE, comprising a composite of coronary heart disease death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization. During a median 2.8 years of follow-up, this outcome occurred in 9.5% of the overall population randomized to alirocumab and 11.1% of those on placebo, for a statistically significant and clinically meaningful 15% relative risk reduction.

Polyvascular disease

In the trial population, 1,405 patients had polyvascular disease in at least two beds, including a coronary artery, plus either peripheral artery or cerebrovascular, while 149 had polyvascular disease in all three beds. The remainder, including 17,370 patients, were classified as having monovascular disease.

The incidences of MACE for placebo-treated patients with monovascular disease, two-bed polyvascular disease, and three-bed polyvascular disease were 10.0%, 22.2%, and 39.7%, respectively. Alirocumab treatment resulted in an absolute risk reduction for MACE of 1.4%, 1.9%, and 13.0%, for those respective groups (P = .0006).

Similarly, the incidence of the secondary endpoint of death for placebo-treated patients was 3.5%, 10.0%, and 21.8%, and the ARR with alirocumab was 0.4%, 1.3%, and 16.2% (P = .002), according to their reported data.

These results suggest that patients with polyvascular disease are an “easily identifiable subgroup” of ACS patients with a high absolute risk of MACE and death, according to the investigators, led by J. Wouter Jukema, MD, PhD, of Leiden (the Netherlands) University Medical Center.

“The large absolute benefit of PCSK9 inhibition with alirocumab, when added to high-intensity statin therapy, is a potential benefit for this group of patients,” Dr. Jukema and coauthors wrote.

Prior CABG

Of the ODYSSEY OUTCOMES patients, 1,025 had an index CABG after ACS, 1,003 had CABG before ACS, and the remaining 16,896 had no such procedure.

Hazard ratios for both MACE and death in all CABG categories were consistent with the overall results of ODYSSEY OUTCOMES, the investigators wrote. Specifically, alirocumab reduced MACE and death in the overall study, with HRs of 0.85 for both endpoints.

The ARRs in MACE with alirocumab were 1.3% for no CABG, 0.9% for index CABG, and 6.4% for prior CABG (P = .0007), while ARRs in death with the treatment were 0.4%, 0.5%, and 3.6% (P = .03) for those categories, respectively. In this analysis, the investigators calculated the number needed to treat to prevent one primary or secondary endpoint over the median 2.8 years of follow-up. The numbers needed to treat were 16 for prior CABG, 111 for index, and 77 for no prior CABG.

“Although the relative benefit of alirocumab versus placebo is consistent regardless of prior CABG status, those with prior CABG achieve substantially greater absolute risk reduction and consequently lower number needed to treat,” wrote the authors of the analysis, led by Shaun G. Goodman, MD, MSc, of St. Michael’s Hospital, Toronto.

Funding for the ODYSSEY OUTCOMES trial and its subanalyses was provided by Sanofi and Regeneron. Authors of the analyses reported disclosures related to Sanofi, Regeneron, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and others.

SOURCES: Goodman SG et al. J Am Coll Cardiol. 2019 Aug 26. doi: 10.1016/j.jacc.2019.07.015; Jukema JW et al. J Am Coll Cardiol. 2019 Aug 26. doi: 10.1016/j.jacc.2019.03.013.

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