The article published by van Bruggen and colleagues contains multiple errors and uses erroneous data to reach incorrect conclusions[Citation1]. It must be remembered that in clinical trials, prespecified study endpoints are typically treated separately from other serious adverse events (SAEs) and are adjudicated by blinded clinical events committees using standard FDA definitions [Citation2,Citation3], as was the case both in FOURIER and ODYSSEY OUTCOMES. Thus, van Bruggen and colleagues did not extract data on, for example, MI or stroke, but rather on small numbers of subjects who reported cardiac or neurologic adverse events that did not meet the FDA criteria for MI or stroke. To that end, they found only 408 subjects who experienced an adverse event nominally listed as an MI and 376 listed as a stroke or TIA. Their flawed methods resulted in implausibly low calculated annual rates of MI and stroke in these high-risk populations of only 0.3%/year. In fact, in the four PCSK9 inhibitor outcomes trials there were >3000 subjects who had a confirmed MI and >800 with a confirmed stroke [Citation4–6].
The FOURIER, ODYSSEY OUTCOMES, and SPIRE trials provide randomized, double-blind, placebo-controlled data from a total of more than 73,000 patients with cardiovascular disease or at high cardiovascular risk. Upon review of the data from the FOURIER and ODYSSEY OUTCOMES trials, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) concluded that both evolocumab and alirocumab significantly reduce the risk of MI and of stroke, with the FDA validating the efficacy and safety data presented and published for FOURIER and ODYSSEY OUTCOMES [Citation7,Citation8]. The trials, separately and in aggregate, provided convincing evidence of cardiovascular benefit of PCSK9 inhibitors leading to a Class I, Level A recommendation for their use in secondary prevention in the most recent ESC/EAS Guidelines for Management of Dyslipidaemias.[Citation9].
The data van Bruggen and colleagues present on all-cause mortality are also incorrect. They present odds ratios, which is inappropriate in time-to-event analyses, and even their odds ratios are based on incorrect numbers of events. The correct hazard ratios, as previously reported and validated by the FDA, are 1.04 (95% CI 0.91–1.19) for evolocumab and 0.85 (95% CI, 0.73–0.98) for alirocumab. There are no data to suggest an increase in mortality with either drug.
The paper by van Bruggen and colleagues is flawed and, in our opinion, a disservice to the medical literature, cardiovascular health-care providers, patients who participated in the clinical trials, and those who would benefit from PCSK9 inhibitors in the future.
Declaration of interest
M.S. Sabatine reports research grant support through Brigham and Women’s Hospital from: Amgen; Anthos Therapeutics; AstraZeneca; Bayer; Daiichi-Sankyo; Eisai; Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis; Pfizer; Quark Pharmaceuticals; Takeda and consulting for: Althera; Amgen; Anthos Therapeutics; AstraZeneca; Bristol-Myers Squibb; CVS Caremark; DalCor; Dr. Reddy’s Laboratories; Dyrnamix; Esperion; IFM Therapeutics; Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Merck; Novartis. R.P. Giugliano has received grants from Amgen and Anthos Therapeutics, honoraria for CME lectures from Amgen, Daiichi Sankyo and Servier and consultant fees from Amgen, American College of Cardiology, Amgen, Astra Zeneca, CryoLife, CVS Caremark, Daiichi Sankyo, Esperion, Gilead, GlaxoSmithKline, SAJA Pharmaceuticals, Samsung and Servier. G.G. Schwartz reports research support to the University of Colorado from AstraZeneca, Resverlogix, Roche, Sanofi, and The Medicines Company. He is coinventor of US patent 62/806,313 (‘Methods for Reducing Cardiovascular Risk’) assigned in full to the University of Colorado. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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References
- van Bruggen FH, Nijhuis GBJ, Zuidema SU, et al. Serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review. Expert Rev Clin Pharmacol. 2020;13(7):787–796.
- Hicks KA, Tcheng JE, Bozkurt B, et al. 2014 ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials: a report of the American College of Cardiology/American Heart Association task force on clinical data standards (writing committee to develop cardiovascular endpoints data standards). J Am Coll Cardiol. 2015;66(4):403–469. .
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- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–188.