• Some Gain More Than Others from Alirocumab

    Patients at the highest risk derived the most benefit from aggressive lipid-lowering with PCSK9 inhibition, according to two analyses of the ODYSSEY OUTCOMES trial.

    Investigators previously showed that people randomized to receive alirocumab (Praluent) administered every 2 weeks instead of placebo had a lower risk of major adverse cardiovascular events (MACE) -- coronary heart disease death, non-fatal MI, ischemic stroke, or unstable angina requiring hospitalization -- and all-cause mortality over a median 2.8 years of follow-up.

    Now, it appears there are two groups that may enjoy especially large absolute reductions in risk: those with atherosclerosis in two or more vascular beds, and those who had undergone coronary artery bypass grafting (CABG) surgery prior to their qualifying acute coronary syndrome (ACS) event.

    Both pre-specified secondary analyses of ODYSSEY OUTCOMES were published in the Sept. 3 issue of the Journal of the American College of Cardiology.

    Polyvascular Disease

    Trial participants were 18,924 patients who had dyslipidemia -- low-density lipoprotein (LDL) cholesterol at least 70 mg/dl, non–high-density lipoprotein cholesterol at least 100 mg/dl, or apolipoprotein B at least 80 mg/dl -- despite intensive statin therapy. All had survived an ACS and were randomized 1-12 months later to PCSK9 inhibition or placebo.

    The 1,554 people who had atherosclerosis in two or more vascular beds (coronary and peripheral artery and/or cerebrovascular) showed greater benefit on alirocumab vs placebo. The more vascular beds with disease, the greater the absolute risk reduction in MACE (P=0.0006 for interaction):

    • One vascular bed: 10.0% with placebo, absolute risk down by 1.4% with alirocumab (95% CI 0.6% to 2.3%)
    • Two vascular beds: 22.2%, reduced by 1.9% (95% CI -2.4% to 6.2%)
    • Three vascular beds: 39.7%, reduced by 13.0% (95% CI -2.0% to 28.0%)

     

    Polyvascular disease also interacted with alirocumab's survival benefit to give patients with more diseased vascular beds greater absolute reductions in death (P=0.002 for interaction):

    • One vascular bed: 3.5% with placebo, absolute risk down by 0.4% with alirocumab (95% CI -0.1% to 1.0%)
    • Two vascular beds: 10.0%, reduced by 1.3% (95% CI -1.8% to 4.3%)
    • Three vascular beds: 21.8%, reduced by 16.2% (95% CI 5.5% to 26.8%)

     

    "The large absolute reductions in those risks with alirocumab are a potential benefit for these patients," wrote researchers led by J. Wouter Jukema, MD, PhD, of Leiden University Medical Center in the Netherlands.

    Prior CABG

    People who have had CABG surgery before their index ACS are another group that may benefit especially from PCSK9 inhibition, according to another pre-specified analysis from the same research team.

    CABG status interacted with the benefit of alirocumab over placebo in MACE reduction (P=0.0007 for interaction in absolute risk reduction), reported ODYSSEY OUTCOMES investigators led this time by Shaun Goodman, MD, MSc, of St. Michael's Hospital in Toronto, Ontario:

    • No CABG (n=16,896): 10.2% with placebo, absolute risk down by 1.3% with alirocumab (95% CI 0.5% to 2.2%)
    • Post-ACS CABG (n=1,025): 7.5%, reduced by 0.9% (95% CI -2.3% to 4.0%)
    • Pre-ACS CABG (n=1,003): 30.9%, reduced by 6.4% (95% CI 0.9% to 12.0%)

     

     

    "The current analysis reinforces the concept that the benefits from effective secondary prevention therapies in atherosclerosis are greatest among those at high residual atherothrombotic risk," the investigators noted.

    "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," wrote Goodman's team.

    Moreover, a similar interaction was observed between CABG status and alirocumab's death reduction such that those with pre-ACS bypass surgery had the biggest drop in risk (P=0.0304 for interaction):

    • No CABG: 3.7% with placebo, absolute risk down by 0.4% with alirocumab (95% CI -0.1% to 1.0%)
    • Post-ACS CABG: 4.1%, reduced by 0.5% (95% CI -1.9% to 2.9%)
    • Pre-ACS CABG: 11.2%, reduced by 3.6% (95% CI 0.0% to 7.2%)

     

    The Take-Away

    One important caveat of these ODYSSEY OUTCOMES analyses was that some of the participants deemed to have only coronary disease could have had undetected peripheral artery or cerebrovascular disease, given that they were not systematically evaluated for them at baseline, Jukema's group acknowledged.

    "However, the classification used in the present analysis is representative of daily clinical practice and decision making because patients with ACS are not routinely screened for polyvascular disease," the study authors maintained.

    As for the prior-CABG analysis, Goodman and colleagues pointed out that patients with prior CABG who went on to have another CABG after the index ACS were "arbitrarily" categorized as having received post-ACS CABG.

    These are nevertheless "important" pre-specified secondary analyses confirming two "extremely high-risk populations" that would benefit from aggressive lipid-lowering therapy, said Jacques Genest, MD, of McGill University Health Centre in Montreal, Quebec, and colleagues, writing in an accompanying editorial.

    "It is a concern that, despite a higher burden of cardiovascular risk factors and extent of atherosclerosis, patients with a prior CABG and those with a high burden of atherosclerosis in two or more arterial territories are seemingly less well treated that recent ACS patients," Genest and co-authors noted.

    They pointed out that more than 40% of such participants in ODYSSEY OUTCOMES had low-density lipoprotein cholesterol at or above 100 mg/dl at the time of randomization, 16% were currently smoking, 40% had diabetes, and 87% had high blood pressure.

    "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 enforce lifestyle modifications with known benefits in [atherosclerotic cardiovascular diseases]," the editorialists wrote.

    It would be interesting to conduct an economic analysis to see how alirocumab's clinical benefits affect health care costs and society in general, Genest et al said.

     

    The trial was funded by Sanofi and Regeneron.

    The analysis by Jukema's group also received support from Fondation Assistance Publique-Hôpitaux de Paris.

    Jukema reported receiving research grants from The Netherlands Heart Foundation, the Interuniversity Cardiology Institute of The Netherlands, and the European Community Framework KP7 Program; and other research support from Amgen, Astellas, AstraZeneca, Daiichi-Sankyo, Eli Lilly, Merck-Schering-Plough, Pfizer, Roche, and Sanofi.

    Goodman reported financial relationships with Daiichi-Sankyo, Luitpold Pharmaceuticals, Merck, Novartis, Servier, Regeneron, Sanofi, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Eli Lilly, Pfizer, Tenax Therapeutics, Fenix Group International, and Ferring Pharmaceuticals.

    Genest reported financial relationships with Sanofi, Amgen, Pfizer, Aegerion, Valeant, Novartis, Merck, and Eli Lilly.

    Source:

    Journal of the American College of Cardiology

    Source Refere

    Journal of the American College of Cardiology

    Source Reference: Goodman SG, et al "Effects of alirocumab on cardiovascular events after coronary bypass surgery" J Am Coll Cardiol 2019; DOI: 10.1016/j.jacc.2019.07.015.nce: Jukema JW, et al "Alirocumab in patients with polyvascular disease and recent acute coronary syndrome: ODYSSEY OUTCOMES trial" J Am Coll Cardiol 2019; DOI: 10.1016/j.jacc.2019.03.013.

     

    Journal of the American College of Cardiology

    Source Reference: Genest J, et al "How the cow ate the CABG: Aim low, live longer?" J Am Coll Cardiol 2019; DOI: 10.1016/j.jacc.2019.07.016.

     

    Read the original article on Medpage Today: Some Gain More Than Others from Alirocumab

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