Stroke Prevention With the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients With Stable Atherosclerosis
Open accessAbstract
Background and Purpose—: The PCSK9 (proprotein convertase subtilisin-kexin type 9) monoclonal antibody evolocumab lowered LDL (low-density lipoprotein) cholesterol by 59% to 0.8 (0.5–1.2) mmol/L and significantly reduced major vascular events in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk). Herein, we report the results of a prespecified analysis of cerebrovascular events in the overall trial population and in patients stratified by prior stroke. Methods—: FOURIER was a randomized, double-blind trial comparing evolocumab versus placebo in patients with established atherosclerosis, additional risk factors, and LDL cholesterol levels ≥1.8 (or non-HDL [high-density lipoprotein] ≥2.6 mmol/L) on statin therapy. The median follow-up was 2.2 years. We analyzed the efficacy of evolocumab to reduce overall stroke and stroke subtypes, as well as the primary cardiovascular composite end point by subgroups according to a history of stroke. Results—: Among the 27 564 patients, 469 (1.7%) experienced a total of 503 strokes of which 421 (84%) were ischemic. Prior ischemic stroke, diabetes mellitus, elevated CRP (C-reactive protein), history of heart failure, older age, nonwhite race, peripheral arterial disease, and renal insufficiency were independent predictors of stroke. Evolocumab significantly reduced all stroke (1.5% versus 1.9%; hazard ratio, 0.79 [95% CI, 0.66–0.95]; P =0.01) and ischemic stroke (1.2% versus 1.6%; hazard ratio, 0.75 [95% CI, 0.62–0.92]; P =0.005), with no difference in hemorrhagic stroke (0.21% versus 0.18%; hazard ratio, 1.16 [95% CI, 0.68–1.98]; P =0.59). These findings were consistent across subgroups, including among the 5337 patients (19%) with prior ischemic stroke in whom the hazard ratios (95% CIs) were 0.85 (0.72–1.00) for the cardiovascular composite, 0.90 (0.68–1.19) for all stroke, and 0.92 (0.68–1.25) for ischemic stroke ( P interactions, 0.91, 0.22, and 0.09, respectively, compared with patients without a prior ischemic stroke). Conclusions—: Inhibition of PCSK9 with evolocumab added to statin in patients with established atherosclerosis reduced ischemic stroke and cardiovascular events in the total population and in key subgroups, including those with prior ischemic stroke. Registration—: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
When added to a maximally tolerated statin, PCSK9 monoclonal antibodies significantly reduced the risk of major adverse cardiovascular events by 15-20% in the FOURIER and ODYSSEY OUTCOMES trials.
“When added to a maximally tolerated statin, these agents reduced LDL cholesterol by ∼60% (115) and significantly reduced the risk of major adverse cardiovascular events by 15–20% in the FOURIER (evolocumab) and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trials (115,117,122).”
From 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [122]
The Discussion (page unavailable in our copy) reports that evolocumab added to statin therapy reduced FOURIER’s primary cardiovascular composite by 15% and a narrower composite by 20%. The Study Population and Procedures section specifies moderate- or high-intensity statin therapy, not necessarily a maximally tolerated dose. This paper does not report the claimed 15–20% result for ODYSSEY OUTCOMES. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPCSK9 inhibition with evolocumab reduced ischemic strokes and major cardiovascular events in the total population of the FOURIER trial as well as in the key subgroup of patients with prior ischemic strokes.
“In line with these observations, PCSK9 inhibition with evolocumab reduced ischemic strokes and major cardiovascular events in the total population of the FOURIER trial as well as in the key subgroup of patients with prior ischemic strokes (71).”
From PCSK9 and the nervous system: a no-brainer? (2023) · cites this paper as [71]
In FOURIER, evolocumab significantly reduced all strokes and ischemic stroke, with findings consistent in individuals with or without a history of ischemic stroke at baseline.
“Evolocumab therapy also signi fi cantly reduced all strokes (1.5% vs. 1.9%; HR 0.79 [95% CI 0.66 -0.95]; P = 0.01) and ischemic stroke (1.2% vs. 1.6%; HR 0.75 [95% CI 0.62 -0.92]; P = 0.005) in the total population, with fi ndings being consistent in individuals with or without a history of ischemic stroke at baseline (115).”
From 10. Cardiovascular Disease and Risk Management: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [115]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
No citation lists for this paper
No citation lists for this paper yet — checked again daily.
References 28 · Cited by 184
Research works printed but not linked: 19
- Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. 2020;141:e139-e596. doi: 10.1161/CIR.0000000000000757 · DOI · Paper page
- Steg PG, Bhatt DL, Wilson PW, D'Agostino R Sr, Ohman EM, Röther J, et al; REACH Registry Investigators. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA. 2007;297:1197-1206. doi: 10.1001/jama.297.11.1197 · DOI · Paper page
- Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681. doi: 10.1016/S0140-6736(10)61350-5 · DOI · Paper page
- Giugliano RP, Sabatine MS. Are PCSK9 inhibitors the next break- through in the cardiovascular field? J Am Coll Cardiol. 2015;65:2638- 2651. doi: 10.1016/j.jacc.2015.05.001 · DOI
- Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce ather- osclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 suppl 2):S1-45. doi: 10.1161/01.cir.0000437738.63853.7a · DOI · Paper page
- Sabatine MS, Giugliano RP, Keech A, Honarpour N, Wang H, Liu T, 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 · Paper page
- Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk). Circulation. 2018;137:338- 350. doi: 10.1161/CIRCULATIONAHA.117.032235 · DOI · Paper page
- Giugliano RP, Pedersen TR, Park JG, De Ferrari GM, Gaciong ZA, Ceska R, et al; FOURIER Investigators. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390:1962-1971. doi: 10.1016/S0140- 6736(17)32290-0 · DOI · Paper page
- Wang X, Dong Y, Qi X, Huang C, Hou L. Cholesterol levels and risk of hemorrhagic stroke: a systematic review and meta-analysis. Stroke. 2013;44:1833-1839. doi: 10.1161/STROKEAHA.113.001326 · DOI
- Pandit AK, Kumar P, Kumar A, Chakravarty K, Misra S, Prasad K. High- dose statin therapy and risk of intracerebral hemorrhage: a meta-analysis. Acta Neurol Scand. 2016;134:22-28. doi: 10.1111/ane.12540 · DOI
- Amarenco P, Labreuche J. Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol. 2009;8:453-463. doi: 10.1016/S1474-4422(09)70058-4 · DOI · Paper page
- Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al; SPIRE Cardiovascular Outcome Investigators. Cardiovascular effi- cacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376:1527-1539. doi: 10.1056/NEJMoa1701488 · DOI · Paper page
- Pesaro AE, Serrano CV Jr, Fernandes JL, Cavalcanti AB, Campos AH, Martins HS, et al. Pleiotropic effects of ezetimibe/simv- astatin vs. high dose simvastatin. Int J Cardiol. 2012;158:400-404. doi: 10.1016/j.ijcard.2011.01.062 · DOI
- Collins R, Armitage J, Parish S, Sleight P, Peto R; Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovas- cular disease or other high-risk conditions. Lancet. 2004;363:757-767. doi: 10.1016/S0140-6736(04)15690-0 · DOI
- Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357. doi: 10.1056/NEJM199811053391902 · DOI · Paper page
- Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. cholesterol and re- current events trial investigators. N Engl J Med. 1996;335:1001-1009. doi: 10.1056/NEJM199610033351401 · DOI · Paper page
- Chan DC, Pang J, McQuillan BM, Hung J, Beilby JP, Barrett PH, et al. Plasma proprotein convertase subtilisin kexin type 9 as a predictor of carotid atherosclerosis in asymptomatic adults. Heart Lung Circ. 2016;25:520-525. doi: 10.1016/j.hlc.2015.10.017 · DOI
- Norata GD, Garlaschelli K, Grigore L, Raselli S, Tramontana S, Meneghetti F, et al. Effects of PCSK9 variants on common carotid ar- tery intima media thickness and relation to ApoE alleles. Atherosclerosis. 2010;208:177-182. doi: 10.1016/j.atherosclerosis.2009.06.023 · DOI
- Xie W, Liu J, Wang W, Wang M, Qi Y, Zhao F, et al. Association between plasma PCSK9 levels and 10-year progression of carotid atherosclerosis beyond LDL-C: a cohort study. Int J Cardiol. 2016;215:293-298. doi: 10.1016/j.ijcard.2016.04.103 · DOI
- Authors
- Giugliano, R. P., Pedersen, T. R., Saver, J. L., Sever, P. S., Keech, A. C., Bohula, E. A., Murphy, S. A., Wasserman, S. M., Honarpour, N., Wang, H., Lira Pineda, A., Sabatine, M. S., & on behalf of the FOURIER Investigators
- Affiliations
- Brigham and Women's Hospital (US)
- Oslo University Hospital (NO)
- University of California, Los Angeles (US)
- Imperial College London (GB)
- National Health and Medical Research Council (AU)
- Amgen (United States) (US)
- Amgen, Inc, Global Development, Thousand Oaks, CA (S.M.W., N.H., H.W., A.L.P.).
- ORCID
- Venue
- Stroke
- Published
- 2020-05
- Volume
- 51
- Issue
- 5
- Pages
- 1546-1554
- ISSN
- 0039-2499 (ISSN-L)
- 1524-4628
- OpenAlex
- W3017084496
- Cited by
- 184
- References
- 28
- Citations by year
- 2026: 14 · 2025: 34 · 2024: 32 · 2023: 36 · 2022: 27 · 2021: 31 · 2020: 10
- FWCI
- 23.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Stroke (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
- Keywords
- evolocumab, PCSK9 inhibitors, stroke prevention, ischemic stroke, hemorrhagic stroke, FOURIER trial, LDL cholesterol lowering, statin therapy, stroke history, cardiovascular risk factors, stroke risk prediction, monoclonal antibodies, C-reactive protein, diabetes mellitus, renal failure, peripheral arterial disease
- MeSH terms
- Aged, Anticholesteremic Agents, Double-Blind Method, Female, Humans, Hypercholesterolemia, Cholesterol, LDL, Male, Middle Aged, Myocardial Infarction, Risk Factors, Proportional Hazards Models, Stroke, Atherosclerosis, Peripheral Arterial Disease, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
