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Cardiovascular efficacy and safety of bococizumab in high-risk patients

Ridker, Paul M.
; 
Revkin, James
; 
Amarenco, Pierre
; 
Brunell, Robert
; 
Curto, Madelyn
; 
Civeira, Fernando
; 
Flather, Marcus
; 
Glynn, Robert J.
; 
Gregoire, Jean
; 
Jukema, J. Wouter
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Author
Ridker, Paul M.
Revkin, James
Amarenco, Pierre
Brunell, Robert
Curto, Madelyn
Civeira, Fernando
Flather, Marcus
Glynn, Robert J.
Gregoire, Jean
Jukema, J. Wouter
Karpov, Yuri
Kastelein, John J. P.
Koenig, Wolfgang
Lorenzatti, Alberto
Manga, Pravin
Masiukiewicz, Urszula
Miller, Michael
Mosterd, Arend
Murin, Jan
Nicolau, Jose C.
Nissen, Steven
Ponikowski, Piotr P.
Santos, Raul D.
Schwartz, Pamela F.
Soran, Handrean
White, Harvey
Wright, R. Scott
Vrablik, Michal
Yunis, Carla
Shear, Charles L.
Tardif, Jean-Claude
Abstract
BACKGROUND Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of −56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of –59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients. (Funded by Pfizer; SPIRE-1 and SPIRE-2 ClinicalTrials.gov numbers, NCT01975376. opens in new tab and NCT01975389. opens in new tab.)
Keywords
Date
2017
Type
Journal article
Journal
New England Journal of Medicine
Book
Volume
376
Issue
16
Page Range
1527-1539
Article Number
ACU Department
Collections
Faculty of Health Sciences - General
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URI
https://hdl.handle.net/20.500.14802/33102
Relation URI
DOI
10.1056/NEJMoa1701488
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