Cardiovascular efficacy and safety of bococizumab in high-risk patients

P. M. Ridker, J. Revkin, P. Amarenco, R. Brunell, M. Curto, F. Civeira, M. Flather, R. J. Glynn, J. Gregoire, J. W. Jukema, Y. Karpov, J. J.P. Kastelein, W. Koenig, A. Lorenzatti, P. Manga, U. Masiukiewicz, M. Miller, A. Mosterd, J. Murin, J. C. NicolauS. Nissen, P. Ponikowski, R. D. Santos, P. F. Schwartz, H. Soran, H. White, R. Scott Wright, M. Vrablik, C. Yunis, C. L. Shear, J. C. Tardif

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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.

Original languageEnglish (US)
Pages (from-to)1527-1539
Number of pages13
JournalNew England Journal of Medicine
Volume376
Issue number16
DOIs
StatePublished - Apr 20 2017

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Safety
LDL Cholesterol
Placebos
Confidence Intervals
bococizumab
Antibodies, Monoclonal, Humanized
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Unstable Angina
Hospitalization
Stroke
Myocardial Infarction
Injections
Antibodies

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ridker, P. M., Revkin, J., Amarenco, P., Brunell, R., Curto, M., Civeira, F., ... Tardif, J. C. (2017). Cardiovascular efficacy and safety of bococizumab in high-risk patients. New England Journal of Medicine, 376(16), 1527-1539. https://doi.org/10.1056/NEJMoa1701488

Cardiovascular efficacy and safety of bococizumab in high-risk patients. / Ridker, P. M.; Revkin, J.; Amarenco, P.; Brunell, R.; Curto, M.; Civeira, F.; Flather, M.; Glynn, R. J.; Gregoire, J.; Jukema, J. W.; Karpov, Y.; Kastelein, J. J.P.; Koenig, W.; Lorenzatti, A.; Manga, P.; Masiukiewicz, U.; Miller, M.; Mosterd, A.; Murin, J.; Nicolau, J. C.; Nissen, S.; Ponikowski, P.; Santos, R. D.; Schwartz, P. F.; Soran, H.; White, H.; Wright, R. Scott; Vrablik, M.; Yunis, C.; Shear, C. L.; Tardif, J. C.

In: New England Journal of Medicine, Vol. 376, No. 16, 20.04.2017, p. 1527-1539.

Research output: Contribution to journalArticle

Ridker, PM, Revkin, J, Amarenco, P, Brunell, R, Curto, M, Civeira, F, Flather, M, Glynn, RJ, Gregoire, J, Jukema, JW, Karpov, Y, Kastelein, JJP, Koenig, W, Lorenzatti, A, Manga, P, Masiukiewicz, U, Miller, M, Mosterd, A, Murin, J, Nicolau, JC, Nissen, S, Ponikowski, P, Santos, RD, Schwartz, PF, Soran, H, White, H, Wright, RS, Vrablik, M, Yunis, C, Shear, CL & Tardif, JC 2017, 'Cardiovascular efficacy and safety of bococizumab in high-risk patients', New England Journal of Medicine, vol. 376, no. 16, pp. 1527-1539. https://doi.org/10.1056/NEJMoa1701488
Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. New England Journal of Medicine. 2017 Apr 20;376(16):1527-1539. https://doi.org/10.1056/NEJMoa1701488
Ridker, P. M. ; Revkin, J. ; Amarenco, P. ; Brunell, R. ; Curto, M. ; Civeira, F. ; Flather, M. ; Glynn, R. J. ; Gregoire, J. ; Jukema, J. W. ; Karpov, Y. ; Kastelein, J. J.P. ; Koenig, W. ; Lorenzatti, A. ; Manga, P. ; Masiukiewicz, U. ; Miller, M. ; Mosterd, A. ; Murin, J. ; Nicolau, J. C. ; Nissen, S. ; Ponikowski, P. ; Santos, R. D. ; Schwartz, P. F. ; Soran, H. ; White, H. ; Wright, R. Scott ; Vrablik, M. ; Yunis, C. ; Shear, C. L. ; Tardif, J. C. / Cardiovascular efficacy and safety of bococizumab in high-risk patients. In: New England Journal of Medicine. 2017 ; Vol. 376, No. 16. pp. 1527-1539.
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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.",
author = "Ridker, {P. M.} and J. Revkin and P. Amarenco and R. Brunell and M. Curto and F. Civeira and M. Flather and Glynn, {R. J.} and J. Gregoire and Jukema, {J. W.} and Y. Karpov and Kastelein, {J. J.P.} and W. Koenig and A. Lorenzatti and P. Manga and U. Masiukiewicz and M. Miller and A. Mosterd and J. Murin and Nicolau, {J. C.} and S. Nissen and P. Ponikowski and Santos, {R. D.} and Schwartz, {P. F.} and H. Soran and H. White and Wright, {R. Scott} and M. Vrablik and C. Yunis and Shear, {C. L.} and Tardif, {J. C.}",
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TY - JOUR

T1 - Cardiovascular efficacy and safety of bococizumab in high-risk patients

AU - Ridker, P. M.

AU - Revkin, J.

AU - Amarenco, P.

AU - Brunell, R.

AU - Curto, M.

AU - Civeira, F.

AU - Flather, M.

AU - Glynn, R. J.

AU - Gregoire, J.

AU - Jukema, J. W.

AU - Karpov, Y.

AU - Kastelein, J. J.P.

AU - Koenig, W.

AU - Lorenzatti, A.

AU - Manga, P.

AU - Masiukiewicz, U.

AU - Miller, M.

AU - Mosterd, A.

AU - Murin, J.

AU - Nicolau, J. C.

AU - Nissen, S.

AU - Ponikowski, P.

AU - Santos, R. D.

AU - Schwartz, P. F.

AU - Soran, H.

AU - White, H.

AU - Wright, R. Scott

AU - Vrablik, M.

AU - Yunis, C.

AU - Shear, C. L.

AU - Tardif, J. C.

PY - 2017/4/20

Y1 - 2017/4/20

N2 - 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.

AB - 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.

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