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Randomized Controlled Trial
. 2017 Dec 1;2(12):1385-1391.
doi: 10.1001/jamacardio.2017.3944.

Clinical Efficacy and Safety of Evolocumab in High-Risk Patients Receiving a Statin: Secondary Analysis of Patients With Low LDL Cholesterol Levels and in Those Already Receiving a Maximal-Potency Statin in a Randomized Clinical Trial

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Free PMC article
Randomized Controlled Trial

Clinical Efficacy and Safety of Evolocumab in High-Risk Patients Receiving a Statin: Secondary Analysis of Patients With Low LDL Cholesterol Levels and in Those Already Receiving a Maximal-Potency Statin in a Randomized Clinical Trial

Robert P Giugliano et al. JAMA Cardiol. .
Free PMC article

Abstract

Importance: Current guidelines for atherosclerotic cardiovascular disease focus on high-intensity statins and targeting or using a threshold low-density lipoprotein cholesterol (LDL-C) level of less than 70 mg/dL for the highest-risk patients. Whether further reduction of LDL-C beyond these boundaries would be beneficial is unknown.

Objective: To compare outcomes of evolocumab vs placebo in patients with stable atherosclerotic cardiovascular disease and a baseline LDL-C of less than 70 mg/dL and in those receiving background treatment with a maximal-potency statin.

Design, setting, and participants: This secondary ad hoc analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial compared randomized treatments in 2 subgroups of patients with stable atherosclerotic cardiovascular disease currently receiving statin. Patients were classified by a baseline LDL-C of less than 70 or at least 70 mg/dL and by statin intensity (maximal: atorvastatin calcium, 80 mg/d, or rosuvastatin, 40 mg/d; submaximal: all other dosages). Patients with baseline LDL of less than 70 mg/dL either had a final screening LDL-C of at least 70 mg/dL or a final screening non-high-density lipoprotein cholesterol level of at least 100 mg/dL. Data were retrieved from 2013 to 2016 and analyzed in 2017 based on intention to treat.

Main outcomes and measures: The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The secondary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. Safety outcomes included adverse events and events of interest identified in the FOURIER trial. Interaction testing was used to assess the consistency of results in patients who did vs did not satisfy the above criteria.

Results: A total of 27 564 patients (75.4% men and 24.6% women; mean [SD] age, 62.5 [9.0] years) were included in the analysis. Of 2034 patients (7.4%) who had a baseline LDL-C of less than 70 mg/dL, evolocumab reduced the risk for the primary endpoint (hazard ratio [HR], 0.80; 95% CI, 0.60-1.07) to a similar degree as in the 25 529 patients who had baseline LDL-C of at least 70 mg/dL (HR 0.86; 95% CI, 0.79-0.92; P = .65 for interaction; 1 patient was missing baseline LDL-C data). Of 7533 patients (27.3%) receiving maximal-potency statins, evolocumab significantly reduced the primary endpoint (HR, 0.86; 95% CI, 0.75-0.98) to a similar degree as in the 20 031 patients not receiving a maximal-potency statin (HR, 0.85; 95% CI, 0.78-0.93; P = .88 for interaction). The key secondary endpoint was reduced to a similar degree in both analyses. No major safety concerns were identified.

Conclusions and relevance: Evolocumab was equally effective in reducing cardiovascular events in patients with stable atherosclerotic cardiovascular disease regardless of whether the baseline LDL-C was less than 70 or at least 70 mg/dL and whether the background statin was of maximal or submaximal potency.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Giugliano reports receiving grants from Amgen during the conduct of the study; grants and personal fees from Merck; and personal fees from American College of Cardiology, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Pfizer, and Sanofi outside the submitted work. Dr Keech reports receiving grants and personal fees from Abbott and Mylan and personal fees from Amgen, Inc, AstraZeneca, and Pfizer outside the submitted work. Ms Murphy reports receiving grants from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia Therapeutics, Merck & Co, Roche Diagnostics, Takeda, Gilead, Poxel, Novartis, MedImmune, Janssen Research Development, and Genzyme outside the submitted work. Dr Tokgozoglu reports receiving honoraria for lectures and advisory board positions from Amgen, AstraZeneca, Pfizer, Sanofi, and MSD. Dr Lewis reports receiving grants from Amgen, during the conduct of the study and personal fees from Amgen outside the submitted work. Dr Ferreira reports receiving personal fees and other institutional funds from Amgen outside the submitted work. Dr Pineda reports reveiving other funds from Amgen during the conduct of the study. Dr Pedersen reports receiving grants and personal fees from Amgen during the conduct of the study and personal fees from Sanofi, Regeneron, and Merck & Co outside the submitted work. Dr Somaratne reports being an employee and stockholder of Amgen. Dr Sever reports receiving grants and personal fees from Amgen and Pfizer during the conduct of the study and outside the submitted work. Dr Sabatine reports receiving grants from Amgen during the conduct of the study; grants from Abbott Laboratories, Clinical Diagnostics, Daiichi Sankyo, Gilead, GlaxoSmithKline, Roche Diagnostics, Takeda, Novartis, Poxel, Eisai, Genzyme, and Pfizer outside the submitted work; grants and personal fees from Amgen, AstraZeneca, Intarcia Therapeutics, Merck & Co, Janssen Research Development, MedImmune, and Medicines Company outside the submitted work; and personal fees from Alnylam, CVS Caremark, Ionis, Cubist, Esperion, and MyoKardia outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Efficacy Outcomes Stratified by Baseline Low-Density Lipoprotein Cholesterol (LDL-C) Levels and Intensity of Background Statin Treatment
Hazard ratios (HRs) and 95% CIs are shown for the primary (composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization) and the key secondary (composite of cardiovascular death, myocardial infarction, and stroke) efficacy composite endpoints in the total population and (A) in patients with baseline LDL-C levels of less than 70 mg/dL vs those with LDL-C levels of at least 70 mg/dL and (B) in patients treated with maximal (atorvastatin calcium, 80 mg/d, or rosuvastatin, 40 mg/d) and submaximal background statin therapy.
Figure 2.
Figure 2.. Cumulative Event Rate of the Key Secondary Endpoint With Evolocumab vs Placebo
Cumulative event rate of the key secondary endpoint with evolocumab compared with placebo in (A) patients with a baseline LDL-C level of less than 70 mg/dL (evolocumab vs placebo, 5.2% vs 7.7%) and (B) in patients treated with a maximal-potency statin (evolocumab vs placebo, 6.8% vs 8.9%). To convert cholesterol levels to to millimoles per liter, multiply by 0.0259.

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