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Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease.
N Engl J Med 2017; 376(18):1713-1722NEJM

Abstract

BACKGROUND

Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.

METHODS

We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years.

RESULTS

At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).

CONCLUSIONS

In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633 .).

Authors+Show Affiliations

From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.S.S., R.P.G., S.D.W., S.A.M., J.F.K.); Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney (A.C.K.); Amgen, Thousand Oaks, CA (N.H., H.W., T.L., S.M.W.); International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.); and Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo (T.R.P.).No affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Comment

Language

eng

PubMed ID

28304224

Citation

Sabatine, Marc S., et al. "Evolocumab and Clinical Outcomes in Patients With Cardiovascular Disease." The New England Journal of Medicine, vol. 376, no. 18, 2017, pp. 1713-1722.
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722.
Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., ... Pedersen, T. R. (2017). Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. The New England Journal of Medicine, 376(18), pp. 1713-1722. doi:10.1056/NEJMoa1615664.
Sabatine MS, et al. Evolocumab and Clinical Outcomes in Patients With Cardiovascular Disease. N Engl J Med. 2017 05 4;376(18):1713-1722. PubMed PMID: 28304224.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. AU - Sabatine,Marc S, AU - Giugliano,Robert P, AU - Keech,Anthony C, AU - Honarpour,Narimon, AU - Wiviott,Stephen D, AU - Murphy,Sabina A, AU - Kuder,Julia F, AU - Wang,Huei, AU - Liu,Thomas, AU - Wasserman,Scott M, AU - Sever,Peter S, AU - Pedersen,Terje R, AU - ,, Y1 - 2017/03/17/ PY - 2017/3/18/pubmed PY - 2017/5/13/medline PY - 2017/3/18/entrez SP - 1713 EP - 1722 JF - The New England journal of medicine JO - N. Engl. J. Med. VL - 376 IS - 18 N2 - BACKGROUND: Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS: At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS: In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633 .). SN - 1533-4406 UR - https://www.unboundmedicine.com/medline/citation/28304224/full_citation L2 - http://www.nejm.org/doi/full/10.1056/NEJMoa1615664?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -