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Randomized Controlled Trial
. 2019 Jul 1;4(7):613-619.
doi: 10.1001/jamacardio.2019.0886.

Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial

Sabina A Murphy  1 , Terje R Pedersen  2 , Zbigniew A Gaciong  3 , Richard Ceska  4 , Marat V Ezhov  5 , Derek L Connolly  6 , J Wouter Jukema  7 , Kalman Toth  8 , Matti J Tikkanen  9 , Kyungah Im  1 , Stephen D Wiviott  1 , Christopher E Kurtz  10 , Narimon Honarpour  10 , Robert P Giugliano  1 , Anthony C Keech  11 , Peter S Sever  12 , Marc S Sabatine  1   13
Affiliations
Randomized Controlled Trial

Effect of the PCSK9 Inhibitor Evolocumab on Total Cardiovascular Events in Patients With Cardiovascular Disease: A Prespecified Analysis From the FOURIER Trial

Sabina A Murphy et al. JAMA Cardiol. .

Abstract

Importance: The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and first cardiovascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, but patients remain at high risk of recurrent cardiovascular events.

Objective: To evaluate the effect of evolocumab on total cardiovascular events, given the importance of total number of cardiovascular events to patients, clinicians, and health economists.

Design, setting, and participants: Secondary analysis of a randomized, double-blind clinical trial. The FOURIER trial compared evolocumab or matching placebo and followed up patients for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Data were analyzed between May 2017 and February 2019.

Main outcomes and measures: The primary end point (PEP) was time to first cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary end point was time to first cardiovascular death, myocardial infarction, or stroke. In a prespecified analysis, total cardiovascular events were evaluated between treatment arms.

Results: The mean age of patients was 63 years, 69% of patients were taking high-intensity statin therapy, and the median LDL-C at baseline was 92 mg/dL (to convert to millimoles per liter, multiply by 0.0259). There were 2907 first PEP events and 4906 total PEP events during the trial. Evolocumab reduced total PEP events by 18% (incidence rate ratio [RR], 0.82; 95% CI, 0.75-0.90; P < .001) including both first events (hazard ratio, 0.85; 95% CI, 0.79-0.92; P < .001) and subsequent events (RR, 0.74; 95% CI, 0.65-0.85). There were 2192 total primary events in the evolocumab group and 2714 total events in the placebo group. For every 1000 patients treated for 3 years, evolocumab prevented 22 first PEP events and 52 total PEP events. Reductions in total events were driven by fewer total myocardial infarctions (RR, 0.74; 95% CI, 0.65-0.84; P < .001), strokes (RR, 0.77; 95% CI, 0.64-0.93; P = .007), and coronary revascularizations (RR, 0.78; 95% CI, 0.71-0.87; P < .001).

Conclusions and relevance: The addition of the PCSK9 inhibitor evolocumab to statin therapy improved clinical outcomes, with significant reductions in total PEP events, driven by decreases in myocardial infarction, stroke, and coronary revascularization. More than double the number of events were prevented with evolocumab vs placebo as compared with the analysis of only first events. These data provide further support for the benefit of continuing aggressive lipid-lowering therapy to prevent recurrent cardiovascular events.

Trial registration: ClinicalTrials.gov identifier: NCT01764633.

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Conflict of interest statement

Conflict of Interest Disclosures: Ms Murphy reported research grants and personal fees from Amgen during the conduct of the study and research grant support through Brigham and Women's Hospital from Abbott Laboratories; AstraZeneca; Critical Diagnostics; Daiichi-Sankyo; Eisai; Genzyme; Gilead; GlaxoSmithKline; Intarcia; Janssen Research and Development; the Medicines Company; MedImmune; Merck; Novartis; Poxel; Pfizer; Roche Diagnostics; and Takeda. Dr Pedersen reported grants from Amgen during the conduct of the study and speakers bureau and personal fees from the Amgen Advisory Board outside the submitted work. Dr Gaciong reported personal fees from Amgen outside the submitted work. Dr Ezhov reported personal fees from Amgen during the conduct of the study and personal fees from AstraZeneca, Berlin Chemie, Egis, KRKA, NovoNordisk, Pfizer, Recordati, and Sanofi outside the submitted work. Dr Jukema reported research grants from and/or was speaker (with or without lecture fees) at CME-accredited meetings sponsored by Amgen, Astra-Zeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Sanofi Aventis, and The Medicine Company. Dr Toth reported personal fees from Amgen outside the submitted work. Dr Tikkanen reported grants and personal fees from Amgen and personal fees from Pfizer during the conduct of the study and personal fees from Amgen outside the submitted work. Dr Wiviott reported grants from Amgen during the conduct of the study; grants and personal fees from Arena, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, and Janssen; grants, personal fees, and other support from Merck; grants from Sanofi Aventis; and personal fees from Aegerion, Allergan, Angelmed, Boehringer-Ingelheim, Boston Clinical Research Institute, Icon Clinical, Lexicon, Servier, St Jude Medical, and Xoma outside the submitted work. Dr Kurtz reported other support from Amgen during the conduct of the study. Dr Honarpour reported support from Amgen during the conduct of the study and other support from Amgen outside the submitted work; in addition, he had a patent to related to evolocumab issued. Dr Giugliano reported grants from Amgen during the conduct of the study and personal fees from Akcea, Amgen, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, Pfizer, Merck, and Amarin outside the submitted work. Dr Keech reported personal fees from Amgen, Mylan, Novartis, Pfizer, Sanofi, Bayer, and AstraZeneca outside the submitted work. Dr Sever reported grants and personal fees from Amgen and Pfizer Inc during the conduct of the study and outside the submitted work. Dr Sabatine reported grants from Amgen during the conduct of the study; grants from Abbott Laboratories, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Roche Diagnostics, and Takeda; and other support from Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Dyrnamix, Esperion, Intarcia, Ionis, Janssen Research and Development, Medicines Company, MedImmune, Merck, MyoKardia, and Novartis outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. First, Additional, and Total Primary End Point Events During Follow-up by Randomization Group
The first occurrence of the primary end point was significantly reduced in the evolocumab group compared with the placebo group (hazard ratio [HR], 0.85; 95% CI, 0.79-0.92; P < .001), as were additional events (incidence rate ratio [RR], 0.74; 95% CI, 0.65-0.85) and total events (RR, 0.82; 95% CI, 0.75-0.90; P < .001).
Figure 2.
Figure 2.. Risk Differences for 1000 Patients Treated for 3 Years With Evolocumab for the First and Total Number of the Primary End Point
For every 1000 patients treated for 3 years, 22 first primary end point events and 52 total primary end point events were prevented with evolocumab.
Figure 3.
Figure 3.. Total Events During Follow-up by Randomization Group for Components of the Primary End Point
Total events were significantly reduced with evolocumab vs placebo for the component of myocardial infarction (incidence rate ratio [RR], 0.74; 95% CI, 0.65-0.84; P < .001) and stroke (RR, 0.77; 95% CI, 0.64-0.93; P = .007) and coronary revascularizations (RR, 0.78; 95% CI, 0.71-0.87; P < .001). There was no difference between treatment groups in total hospitalization for unstable angina events or in cardiovascular deaths.
Figure 4.
Figure 4.. Total Events During Follow-up by Randomization Group for Key Secondary End Point of Cardiovascular Death, Myocardial Infarction, or Stroke
Total events were reduced with evolocumab (incidence rate ratio [RR], 0.81; 95% CI, 0.73-0.90; P < .001). HR indicates hazard ratio.
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References

    1. Murphy SA, Cannon CP, Wiviott SD, McCabe CH, Braunwald E. Reduction in recurrent cardiovascular events with intensive lipid-lowering statin therapy compared with moderate lipid-lowering statin therapy after acute coronary syndromes from the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial. J Am Coll Cardiol. 2009;54(25):2358-2362. doi:10.1016/j.jacc.2009.10.005 - DOI - PubMed
    1. Tikkanen MJ, Szarek M, Fayyad R, et al. ; IDEAL Investigators . Total cardiovascular disease burden: comparing intensive with moderate statin therapy insights from the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial. J Am Coll Cardiol. 2009;54(25):2353-2357. doi:10.1016/j.jacc.2009.08.035 - DOI - PubMed
    1. Murphy SA, Cannon CP, Blazing MA, et al. . Reduction in total cardiovascular events with ezetimibe/simvastatin post-acute coronary syndrome: the IMPROVE-IT trial. J Am Coll Cardiol. 2016;67(4):353-361. doi:10.1016/j.jacc.2015.10.077 - DOI - PubMed
    1. Sabatine MS, Giugliano RP, Keech AC, et al. ; FOURIER Steering Committee and Investigators . Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664 - DOI - PubMed
    1. Sabatine MS, Giugliano RP, Keech A, et al. . Rationale and design of the further cardiovascular outcomes research with PCSK9 Inhibition in subjects with elevated risk trial. Am Heart J. 2016;173:94-101. doi:10.1016/j.ahj.2015.11.015 - DOI - PubMed

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