Abstract
Purpose:
Guidelines recommend high-intensity statin treatment after ischemic stroke, but evidence is sparse on the effectiveness and safety of different statin treatment intensities. We examined effectiveness and safety outcomes among patients initiating high-intensity versus moderate-intensity statins after ischemic stroke.
Methods:
In this population-based new-user active-comparator cohort study, we used the Danish Stroke Registry, covering all Danish hospitals, to identify patients with a first-time ischemic stroke during 2012–2021. Using multiple Danish registries, patients who redeemed a statin prescription within 21 days after stroke admission were classified as high-intensity statin initiators or moderate-intensity statin initiators. Propensity score inverse probability of treatment weighting was used to balance patient characteristics. We used competing risk methods to compute 5 year risk differences (RDs) and Cox proportional hazards regression to compute 5 year hazard ratios (HRs) of stroke recurrence, myocardial infarction, heart failure, venous thromboembolism, and all-cause mortality (effectiveness outcomes) and diabetes, liver disease, and kidney disease (safety outcomes).
Results:
High-intensity (n = 13,032) and moderate-intensity (n = 14,355) statin initiators were identified. Risks of most examined effectiveness outcomes were comparable between statin intensities. There was no clear association between statin intensity and stroke recurrence (RD: 0.8% [95% CI: 0.1, 1.4], HR: 1.08 [95% CI: 0.96, 1.22]). All-cause mortality was slightly reduced among high-intensity statin initiators (RD: −1.1% [95% CI: −0.1, −2.1], HR: 0.93 [95% CI: 0.85, 1.01]. Risks of most safety outcomes were comparable between statin intensities, but high-intensity statin use was associated with an increased risk of diabetes (RD: 1.2% [95% CI: 0.4, 1.9], HR: 1.10 [95% CI: 1.00, 1.21]).
Discussion and conclusion:
Compared with initiation of moderate-intensity statins, initiation of high-intensity statins after ischemic stroke was associated with similar risks of most effectiveness and safety outcomes. However, mortality risk was reduced, and diabetes risk was increased.
Keywords: Statin, stroke, cohort study, population-based, new-user active-comparator
Introduction
The number of stroke survivors is rising globally, 1 and the risk of recurrence is approximately 13% after 10 years. 2 Level of low-density-lipoprotein-cholesterol (LDL-C) is an important prognostic factor after ischemic stroke, 3 and use of statins is a key prevention component.4,5
Evidence comparing high-intensity statins with moderate-intensity statins following ischemic stroke is sparse. The SPARCL trial showed that treatment with 80 mg atorvastatin reduced stroke recurrence risk compared with placebo. 6 Correspondingly, current American guidelines recommend high-intensity statins for patients with ischemic stroke and LDL-C levels >100 mg/dL (>2.6 mmol/L). 4 European and Danish guidelines recommend which LDL-C level to target, but without mention of a particular treatment intensity.5,7 The SPARCL trial did not investigate intensity or dose-response relations. 6 Additionally, some studies found dose-related side effects of statin use, such as increased risk of hemorrhagic stroke,6,8 diabetes, impaired liver function, and proteinuria. 5 We therefore examined the effectiveness and safety of initiation of high-intensity statins compared with moderate-intensity statins in patients with ischemic stroke.
Methods
Design, setting, and data sources
Denmark has a universal state-funded healthcare system. 9 We conducted a nationwide population-based cohort study based on data from Danish registries (Supplemental Table 1). These registries record data on inpatient, outpatient, and emergency hospital contacts, diagnosis codes based on International Classification of Diseases, Tenth Revision (ICD-10), various characteristics collected at hospitalization, prescriptions redeemed at community pharmacies, laboratory test results requested by hospital departments, outpatient clinics, and general practitioners, socioeconomic information, and vital status (deaths and emigrations) (Supplemental Table 1). Data were linked using the personal identification number assigned to all Danish residents.9,10 Using the new-user study design, we excluded all patients who used statins prior to their first ischemic stroke. By using an active comparator (moderate-intensity statins), it is possible to evaluate the effects of initiating moderate- or high-intensity statins after an ischemic stroke. This study was registered with the Danish Data Protection Agency. No ethical approval is required for registry-based studies in Denmark. This study adheres to the observational routinely collected health data statement for pharmacoepidemiology (RECORD-PE reporting guideline).
Study cohort
The cohort comprised statin initiators among patients aged ⩾18 years with a first-time ischemic stroke registered in the Danish Stroke Registry 11 between 1 January 2012 and 31 December 2018. Reporting to this registry is mandatory for hospitals treating patients with acute stroke. 11 The sensitivity and positive predictive value of the stroke diagnosis in the Stroke Registry both exceed 90%. 12 Diagnoses of ischemic stroke are based on cerebral computed tomography (CT) or magnetic resonance imaging (MRI) scans during hospitalization.
We used the Danish Prescription Registry to identify patients initiating statin therapy within 21 days after admission. Cohort entry was set as day 22 after the admission date. 13 Patients who redeemed a statin prescription after hospital admission for stroke and before cohort entry were categorized as moderate-intensity or high-intensity statin users (Table 1). If patients redeemed more than one prescription before cohort entry, the most recent prescription was used. Patients were assumed to consume one pill per day. Because the initiation of low-intensity statins was infrequent (n = 86), we excluded these patients from the analyses (Supplemental Table 2 and Supplemental Figure 1). We further excluded patients who used statins in the year prior to the date of hospital admission, as well as patients who died or suffered a recurrent stroke before cohort entry (Supplemental Figure 1).
Table 1.
Baseline characteristics of new users of statins among patients with a first-time ischemic stroke, before and after propensity score weighting (IPTW), Denmark, 2012–2021.
| Overall cohort |
Propensity score-weighted cohort |
|||||
|---|---|---|---|---|---|---|
| Moderate-intensity statin users (n = 14,355) | High-intensity statin users (n = 13,032) | SD | Moderate-intensity statin users (n = 12,986.73) | High-intensity statin users (n = 14,358.86) | SD | |
| Age, median (IQR) | 69.00 (59.00, 78.00) | 69.00 (59.00, 77.00) | 0.01 | 69.00 (59.00, 78.00) | 69.00 (59.00, 77.00) | 0.00 |
| Sex, n (%) | ||||||
| Men | 7905 (55.1) | 7590 (58.2) | 0.06 | 8097.1 (56.4) | 8097.1 (56.4) | 0.01 |
| Women | 6450 (44.9) | 5442 (47.8) | ||||
| Calendar period of treatment initiation, n (%) | ||||||
| 2012–2015 | 6697 (46.7) | 704 (5.4) | 1.07 | 3878.5 (27.0) | 3464.1 (26.7) | 0.01 |
| 2016–2018 | 5033 (35.1) | 3289 (25.2) | 0.22 | 4367.0 (30.4) | 3973.1 (30.6) | 0.00 |
| 2019–2021 | 2625 (18.3) | 9039 (69.4) | 1.20 | 6113.4 (42.6) | 5549.5 (42.7) | 0.00 |
| Comorbidities, n (%) | ||||||
| Transient ischemic attack | 347 (2.4) | 322 (2.5) | 0.00 | 350.9 (2.4) | 316.0 (2.4) | 0.00 |
| Atrial fibrillation or flutter | 1890 (13.2) | 1447 (11.1) | 0.06 | 1747.3 (12.2) | 1572.9 (12.1) | 0.00 |
| Hypertension | 8100 (56.4) | 7387 (56.7) | 0.01 | 8208.6 (57.2) | 7524.2 (57.9) | 0.02 |
| Diabetes | 1147 (8.0) | 1078 (8.3) | 0.01 | 1213.8 (8.5) | 1119.2 (8.6) | 0.01 |
| Heart valve disease | 490 (3.4) | 424 (3.3) | 0.01 | 492.1 (3.4) | 440.9 (3.4) | 0.00 |
| Venous thromboembolism | 430 (3.0) | 435 (3.3) | 0.02 | 458.5 (3.2) | 403.6 (3.1) | 0.00 |
| Endocarditis | 27 (0.2) | 11 (0.1) | 0.03 | 19.8 (0.1) | 24.9 (0.2) | 0.01 |
| Myocarditis or pericarditis | 64 (0.4) | 54 (0.4) | 0.00 | 55.8 (0.4) | 50.6 (0.4) | 0.00 |
| Heart failure | 450 (3.1) | 377 (2.9) | 0.01 | 429.1 (3.0) | 390.6 (3.0) | 0.00 |
| Cardiomyopathy | 106 (0.7) | 80 (0.6) | 0.02 | 98.1 (0.7) | 82.8 (0.6) | 0.01 |
| Tachyarrhythmia | 386 (2.7) | 327 (2.5) | 0.01 | 391.2 (2.7) | 350.1 (2.7) | 0.00 |
| Rare risk factors for stroke a | 303 (2.1) | 349 (2.7) | 0.04 | 332.6 (2.3) | 315.9 (2.4) | 0.01 |
| Chronic liver disease | 172 (1.2) | 143 (1.1) | 0.01 | 167.1 (1.2) | 146.5 (1.1) | 0.00 |
| Chronic kidney disease | 235 (1.6) | 198 (1.5) | 0.01 | 237.9 (1.7) | 212.9 (1.6) | 0.00 |
| Cancer | 1964 (13.7) | 1967 (15.1) | 0.04 | 2077.9 (14.5) | 1855.3 (14.3) | 0.01 |
| Chronic obstructive pulmonary disease | 840 (5.9) | 767 (5.9) | 0.00 | 833.4 (5.8) | 767.3 (5.9) | 0.00 |
| Connective tissue disorders | 667 (4.6) | 591 (4.5) | 0.01 | 678.3 (4.7) | 635.0 (4.9) | 0.01 |
| HIV/AIDS | 16 (0.1) | 17 (0.1) | 0.01 | 15.0 (0.1) | 13.3 (0.1) | 0.00 |
| Thyroid disorder | 1033 (7.2) | 998 (7.7) | 0.02 | 1043.7 (7.3) | 948.6 (7.3) | 0.00 |
| Gout | 173 (1.2) | 203 (1.6) | 0.03 | 205.0 (1.4) | 190.8 (1.5) | 0.00 |
| Allergy | 5926 (41.3) | 5792 (44.4) | 0.06 | 6150.2 (42.8) | 5596.5 (43.1) | 0.01 |
| Ulcer/chronic gastritis | 687 (4.8) | 544 (4.2) | 0.03 | 655.0 (4.6) | 616.4 (4.7) | 0.01 |
| Inflammatory bowel disease | 194 (1.4) | 159 (1.2) | 0.01 | 181.8 (1.3) | 171.0 (1.3) | 0.00 |
| Intestinal diverticular disease | 708 (4.9) | 787 (6.0) | 0.05 | 792.0 (5.5) | 734.0 (5.7) | 0.01 |
| Prostate enlargement | 989 (6.9) | 799 (6.1) | 0.03 | 934.6 (6.5) | 845.3 (6.5) | 0.00 |
| Osteoporosis | 1185 (8.3) | 1011 (7.8) | 0.02 | 1179.0 (8.2) | 1106.1 (8.5) | 0.01 |
| Extensive analgesic drug use | 1842 (12.8) | 1785 (13.7) | 0.03 | 1946.5 (13.6) | 1740.7 (13.4) | 0.00 |
| Anemia | 559 (3.9) | 448 (3.4) | 0.02 | 533.4 (3.7) | 494.3 (3.8) | 0.00 |
| Vision impairment | 2219 (15.5) | 2111 (16.2) | 0.02 | 2306.9 (16.1) | 2057.7 (15.8) | 0.01 |
| Hearing impairment | 1862 (13.0) | 1627 (12.5) | 0.01 | 1859.5 (13.0) | 1669.8 (12.9) | 0.00 |
| Migraine | 306 (2.1) | 285 (2.2) | 0.00 | 314.4 (2.2) | 275.3 (2.1) | 0.00 |
| Epilepsy | 2114 (14.7) | 2020 (15.5) | 0.02 | 2214.0 (15.4) | 2021.3 (15.6) | 0.00 |
| Parkinson’s disease | 89 (0.6) | 75 (0.6) | 0.01 | 86.3 (0.6) | 69.6 (0.5) | 0.01 |
| Multiple sclerosis | 49 (0.3) | 36 (0.3) | 0.01 | 38.8 (0.3) | 28.8 (0.2) | 0.01 |
| Neuropathy | 1114 (7.8) | 1167 (9.0) | 0.04 | 1196.8 (8.3) | 1095.4 (8.4) | 0.00 |
| Dementia | 340 (2.4) | 209 (1.6) | 0.05 | 288.3 (2.0) | 241.8 (1.9) | 0.01 |
| Bipolar affective disorder | 100 (0.7) | 80 (0.6) | 0.01 | 93.1 (0.6) | 91.9 (0.7) | 0.01 |
| Schizophrenia or schizoaffective disorders | 82 (0.6) | 69 (0.5) | 0.01 | 76.2 (0.5) | 60.7 (0.5) | 0.01 |
| Alcohol problems | 672 (4.7) | 522 (4.0) | 0.03 | 624.0 (4.3) | 547.5 (4.2) | 0.01 |
| Substance abuse | 116 (0.8) | 104 (0.8) | 0.00 | 114.9 (0.8) | 111.8 (0.9) | 0.01 |
| Depression or anxiety | 1831 (12.8) | 1579 (12.1) | 0.02 | 1797.9 (12.5) | 1600.6 (12.3) | 0.01 |
| Hormone therapy, including oral contraceptives | 4084 (28.5) | 3610 (27.7) | 0.02 | 4055.5 (28.2) | 3632.7 (28.0) | 0.01 |
| Aspirin | 3193 (22.2) | 2679 (20.6) | 0.04 | 3146.4 (21.9) | 2900.9 (22.3) | 0.01 |
| Adenosine diphosphate receptor inhibitors | 652 (4.5) | 734 (5.6) | 0.05 | 772.0 (5.4) | 746.9 (5.8) | 0.02 |
| Anticoagulants | 1237 (8.6) | 1204 (9.2) | 0.02 | 1290.8 (9.0) | 1144.1 (8.8) | 0.01 |
| Mono antiplatelet therapy | 3393 (23.6) | 2889 (22.2) | 0.03 | 3372.0 (23.5) | 3132.3 (24.1) | 0.02 |
| Dual antiplatelet therapy | 452 (3.1) | 524 (4.0) | 0.05 | 546.4 (3.8) | 515.5 (4.0) | 0.01 |
| Triple antiplatelet therapy | 71 (0.5) | 93 (0.7) | 0.03 | 94.4 (0.7) | 92.2 (0.7) | 0.01 |
| Essens Risk Score, n (%)b,c | ||||||
| 0 | 825 (5.7) | 793 (6.1) | - | 926.3 (6.5) | 660.7 (5.1) | - |
| 1 | 2561 (17.8) | 2243 (17.2) | - | 2577.9 (18.0) | 2092.0 (16.1) | - |
| 2 | 3802 (26.5) | 3368 (25.8) | - | 3832.2 (26.7) | 3451.2 (26.6) | - |
| 3 | 3506 (24.4) | 2983 (22.9) | - | 3398.8 (23.7) | 3092.0 (23.8) | - |
| 4 | 1887 (13.1) | 1598 (12.3) | - | 1776.0 (12.4) | 1797.1 (13.8) | - |
| 5+ | 678 (4.7) | 626 (4.8) | - | 660.6 (4.6) | 704.7 (5.4) | - |
| Information not available | 1096 (7.6) | 1421 (10.9) | - | 1186.9 (8.3) | 1189.2 (9.2) | - |
| Scandinavian Stroke Scale score, median (IQR) b | 54.00 (49.00, 58.00) | 54.00 (48.00, 58.00) | - | 54.00 (49.00, 58.00) | 54.00 (48.00, 58.00) | - |
| Scandinavian Stroke Scale score, n (%) b | ||||||
| Mild (SSS score 43–58) | 12314 (85.8) | 11217 (86.1) | - | 12,447.1 (86.7) | 11,218.1 (86.4) | - |
| Moderate (SSS score 26–42) | 1431 (10.0) | 1362 (10.5) | - | 1366.5 (9.5) | 1304.5 (10.0) | - |
| Severe (SSS score 0–25) | 390 (2.7) | 337 (2.6) | - | 380.8 (2.7) | 353.7 (2.7) | - |
| Information not available | 220 (1.5) | 116 (0.9) | - | 164.4 (1.1) | 110.4 (0.8) | - |
| Smoking habit, n (%) b | ||||||
| Daily/occasional | 4688 (32.7) | 3862 (29.6) | - | 4441.4 (30.9) | 4013.7 (30.9) | - |
| Former | 3539 (24.7) | 3483 (26.7) | - | 3548.8 (24.7) | 3520.2 (27.1) | - |
| Never | 5032 (35.1) | 4266 (32.7) | - | 5181.7 (36.1) | 4263.6 (32.8) | - |
| Information not available | 1096 (7.6) | 1421 (10.9) | - | 1186.9 (8.3) | 1189.2 (9.2) | - |
| Alcohol consumption, n (%) b | ||||||
| High risk (>7/14 drinks weekly (women/men)) | 1832 (12.8) | 1632 (12.5) | - | 1778.3 (12.4) | 1645.2 (12.7) | - |
| Low risk (⩽7/14 drinks weekly (women/men)) | 11696 (81.5) | 10035 (77.0) | - | 11,646.2 (81.1) | 10,270.9 (79.1) | - |
| Information not available | 827 (5.8) | 1365 (10.5) | - | 934.3 (6.5) | 1070.7 (8.2) | - |
| Thrombolysis, n (%) b | 2472 (17.2) | 2733 (21.0) | - | 2593.2 (18.1) | 2447.7 (18.8) | - |
| Thrombectomy, n (%) b | 236 (1.6) | 408 (3.1) | - | 304.8 (2.1) | 347.5 (2.7) | - |
| Highest attained education, n (%) b | ||||||
| Low (elementary school) | 2524 (17.6) | 2402 (18.4) | - | 2608.4 (18.2) | 2238.2 (17.2) | - |
| Intermediate (upper secondary school) | 5327 (37.1) | 4612 (35.4) | - | 5215.5 (36.3) | 4844.5 (37.3) | - |
| High (tertiary education) | 6117 (42.6) | 5789 (44.4) | - | 6190.1 (43.1) | 5635.1 (43.4) | - |
| Information not available | 387 (2.7) | 229 (1.8) | - | 344.9 (2.4) | 268.9 (2.1) | - |
| LDL, (mmol/L), median (IQR) b | 3.30 (2.80, 3.90) | 3.40 (2.90, 4.00) | - | 3.30 (2.70, 3.90) | 3.50 (2.90, 4.10) | - |
| LDL, (mmol/L), n (%) b | ||||||
| < 2.0 | 2579 (18.0) | 2550 (19.6) | - | 2690.0 (18.7) | 2321.4 (17.9) | - |
| 2.0–2.9 | 3880 (27.0) | 4364 (33.5) | - | 3780.2 (26.3) | 4400.4 (33.9) | - |
| 3.0–3.9 | 304 (2.1) | 320 (2.5) | - | 319.0 (2.2) | 293.0 (2.3) | - |
| ⩾ 4 | 2034 (14.2) | 2804 (21.5) | - | 1906.6 (13.3) | 3261.3 (25.1) | - |
| Information not available | 5558 (38.7) | 2994 (23.0) | - | 5663.0 (39.4) | 2710.6 (20.9) | - |
SD: absolute standardized difference; IQR: interquartile range.
Including thrombophilia (incl. antiphospholipid syndrome), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral artery stenosis, Moyamoya disease, Ehlers-Danlos syndrome, patent foramen ovale, Marfan syndrome, Fabry disease, sickle cell anemia, and thalassemia.
Covariates not included in the propensity score model in primary analyses.
The modified Essen Risk Score was based on the following risk factors: age 65–75 years (1 point), age >75 years (2 points), smoker (1 point), hypertension (1 point), diabetes (1 point), peripheral artery disease (1 point), transient ischemic attack (1 point), myocardial infarction (1 point), other cardiovascular disease (ischemic heart disease, venous thromboembolism, or heart failure, 1 point).
Recommendations for treatment with statins after ischemic stroke have varied during the study period.4,14,15 In recent years, use of high-intensity statins has increased. 16
Effectiveness and safety outcomes
Effectiveness outcomes included stroke recurrence, myocardial infarction, heart failure, venous thromboembolism, and all-cause mortality. Stroke recurrence was defined as any stroke subtype occurring later than 21 days after onset of the first-time stroke. 13 Safety outcomes included diabetes, liver disease, and kidney disease.
In additional analyses, we varied the stroke recurrence definition and separately considered ischemic stroke recurrence and hemorrhagic stroke occurrence. We also investigated cardiovascular and non-cardiovascular mortality (information on cause-specific mortality was available until the end of 2020). All outcome definitions are provided in Supplemental Table 3.
Statistical analyses
Propensity score weighting
We applied propensity score (PS) inverse probability of treatment weighting (IPTW) to address confounding. 17 Using a multivariable logistic regression, we estimated the PS as the predicted probability of being prescribed high-intensity statins, conditional on 53 covariates measured before cohort entry (Supplemental Table 3). We weighted cohorts using IPTW, that is, initiators of high-intensity statins were assigned a weight equal to 1/PS and initiators of moderate intensity statins were assigned a weight equal to 1/(1-PS). Weights were stabilized. 18
The distribution of baseline characteristics was cross-tabulated before and after PS weighting. We calculated standardized mean differences (SDs) to assess covariate balance between cohorts, with values <0.1 interpreted as well-balanced. 19
Risk analyses
Patients were followed from cohort entry until occurrence of an outcome, death, emigration, 5 years of follow-up, or end of study (31 December 2021), whichever occurred first. We used an intention-to-treat approach in the main analysis, that is, patients continued to contribute risk time in their initial exposure group regardless of exposure switching/discontinuation during follow-up. We computed the 3 year and 5 year absolute risks (ARs) and risk differences (RDs), and 5 year cause-specific hazard ratios (HRs) before and after PS weighting. ARs and RDs for non-fatal events were computed using the Aalen-Johansen estimator, accounting for the competing risk of death, 20 and using the Kaplan-Meier estimator for all-cause mortality. HRs were computed using Cox proportional hazards regression analysis, and the proportionality assumption was deemed satisfied. Analyses were performed using R, version 3.6.1.
Subgroup analyses
Statin treatment is presumably more effective in preventing recurrence after ischemic strokes of an atherosclerotic rather than non-atherosclerotic cause.4,5,7 As the distribution of different underlying causes vary substantially in different patient subgroups, 21 we investigated possible effect modification according to age (18–49 years, ⩾50 years), sex, modified Essen risk score (<3, ⩾3), history of atherosclerotic disease (yes, no), and LDL-C level (<3.0 mmol/L, ⩾3.0 mmol/L) (Supplemental Table 4). Subgroup analyses were performed for stroke recurrence, myocardial infarction, all-cause mortality, and diabetes only. PS weights were re-estimated within each examined strata.
Sensitivity analyses
We repeated the analyses in four sensitivity analyses:
(1) We used an as-treated approach. Assuming a prescription duration of 90 days (derived from a data-driven approach), we created a supply diary for each patient, aggregating consecutive prescription redemptions, while allowing a 30 day grace period. We then identified the date of discontinuation or exposure switching, whichever came first. Patients were censored upon discontinuation or exposure switching.
(2) We additionally included the following variables in the PS model: Essens Risk Score, stroke severity at admission according to the Scandinavian Stroke Scale, 22 smoking habit, alcohol consumption, treatment with intravenous thrombolysis, treatment with endovascular thrombectomy, highest attained education, and LDL-C level. Data for these additional variables were missing in varying degrees (Table 1). For this analysis, we handled missing data on these additional variables using missing data indicator variables in the PS estimation. 23
(3) We restricted the cohorts to patients without a prior diagnosis of each examined outcome. This analysis was performed to rule out potential error of disease occurring prior to cohort entry being re-registered in the medical record after cohort entry, thus wrongly being counted as occurrence of a study outcome.
(4) We redefined the cohort entry date as day 45 after the ischemic stroke hospital admission date.
Data availability
No additional data available.
Standard protocol approvals, registrations, and patient consent
According to Danish legislation, informed consent and approval from an ethics committee are not required for registry-based studies. The study was approved by the Danish Data Protection Agency and the Danish Clinical Quality Program.
Results
Cohort characteristics
The analysis comprised 27,387 statin initiators (48% high-intensity and 52% moderate intensity) following ischemic stroke (Supplemental Figure 1). The median time from admission for stroke to first redemption of a statin prescription was 6 days for moderate-intensity initiators and 5 days for high-intensity initiators. Across all outcome analyses, median follow-up time ranged from 5.3 to 5.8 years for moderate-intensity initiators and from 2.2 to 2.5 years for high-intensity initiators. Before IPTW, the distributions of age (median 69 years) and sex (55.5% and 57.0% men respectively) were similar in the two cohorts, while the calendar period distribution was imbalanced (Table 1). After weighting, all covariates had standardized differences below 0.1.
Effectiveness outcomes
Comparing initiators of high-intensity statins with initiators of moderate-intensity statins, weighted 5-year risks were 9.1% versus 8.3% for stroke recurrence (RD: 0.8% [95% CI: 0.1, 1.4], HR: 1.08 [95% CI: 0.96, 1.22]); 1.7% versus 1.6% for myocardial infarction (RD: −0.1% [95% CI: −0.2, 0.4], HR: 1.03 [95% CI: 0.77, 1.38]); 3.7% versus 3.6% for heart failure (RD: 0.1% [95% CI: −0.3, 0.5], HR: 1.04 [95% CI: 0.87, 1.25]), 0.8% versus 1.1% for venous thromboembolism (RD: −0.3% [95% CI: −0.5, −0.1], HR: 0.78 [95% CI: 0.53, 1.14]); and 17.2% versus 18.3% for all-cause mortality (RD: −1.1% [95% CI: −0.1, −2.1], HR: 0.93 [95% CI: 0.85, 1.01]) (Figure 1 and Table 2).
Figure 1.
Absolute risks for effectiveness outcomes according to statin treatment intensity after a first-time ischemic stroke, following propensity score weighting (IPTW), Denmark, 2012–2021.
Table 2.
Three- and 5-year absolute risks, risk differences, and hazard ratios for effectiveness and safety outcomes according to statin treatment intensity after a first-time ischemic stroke (Denmark, 2012–2018).
| Outcome | Follow-up | Statin treatment intensity | Events a | Adjusted absolute risk (95% CI) a | Adjusted risk difference (95% CI) a | Unadjusted hazard ratio (95% CI) | Adjusted hazard ratio (95% CI) a |
|---|---|---|---|---|---|---|---|
| Stroke recurrence | 3 years | Moderate | 472 | 6.2 (5.8, 6.5) | 0.4 (–0.2, 0.9) | 1.00 (0.91, 1.09) | 1.08 (0.96, 1.22) |
| High | 535 | 6.5 (6.1, 6.9) | |||||
| 5 years | Moderate | 515 | 8.3 (8.0, 8.7) | 0.8 (0.1, 1.4) | |||
| High | 682 | 9.1 (8.6, 9.6) | |||||
| Ischemic stroke recurrence | 3 years | Moderate | 423 | 5.6 (5.3, 5.9) | 0.4 (–0.1, 1.0) | 1.01 (0.91, 1.11) | 1.10 (0.96, 1.25) |
| High | 499 | 6.0 (5.7, 6.4) | |||||
| 5 years | Moderate | 452 | 7.5 (7.2, 7.8) | 0.8 (0.2, 1.4) | |||
| High | 627 | 8.3 (7.8, 8.8) | |||||
| Hemorrhagic stroke recurrence | 3 years | Moderate | 21 | 0.6 (0.5, 0.7) | –0.1 (–0.2, 0.1) | 0.92 (0.69, 1.24) | 0.92 (0.63, 1.36) |
| High | 31 | 0.5 (0.4, 0.6) | |||||
| 5 years | Moderate | - | 0.9 (0.9, 1.0) | –0.1 (–0.3, 0.1) | |||
| High | 52 | 0.9 (0.7, 1.0) | |||||
| Myocardial infarction | 3 years | Moderate | 53 | 1.1 (1.0, 1.2) | –0.1 (–0.3, 0.1) | 0.94 (0.75, 1.17) | 1.03 (0.77, 1.38) |
| High | 70 | 1.0 (0.9, 1.2) | |||||
| 5 years | Moderate | - | 1.6 (1.5, 1.7) | 0.1 (–0.2, 0.4) | |||
| High | 111 | 1.7 (1.5, 1.9) | |||||
| Heart failure | 3 years | Moderate | 157 | 2.6 (2.4, 2.8) | 0.2 (–0.2, 0.5) | 1.04 (0.90, 1.19) | 1.04 (0.87, 1.25) |
| High | 219 | 2.8 (2.5, 3.0) | |||||
| 5 years | Moderate | 171 | 3.6 (3.4, 3.8) | 0.1 (–0.3, 0.5) | |||
| High | 272 | 3.7 (3.4, 4.0) | |||||
| Venous thromboembolism | 3 years | Moderate | 23 | 0.7 (0.7, 0.8) | –0.1 (–0.3, 0.0) | 0.75 (0.56, 1.00) | 0.78 (0.53, 1.14) |
| High | 40 | 0.6 (0.5, 0.7) | |||||
| 5 years | Moderate | - | 1.1 (1.0, 1.2) | –0.3 (–0.5, –0.1) | |||
| High | 51 | 0.8 (0.7, 0.9) | |||||
| Diabetes | 3 years | Moderate | 1126 | 9.9 (9.5, 10.4) | 1.0 (0.3, 1.7) | 1.18 (1.10, 1.28) | 1.10 (1.00, 1.21) |
| High | 1142 | 10.9 (10.4, 11.4) | |||||
| 5 years | Moderate | 1158 | 11.6 (11.2, 12.1) | 1.2 (0.4, 1.9) | |||
| High | 1258 | 12.8 (12.2, 13.4) | |||||
| Liver disease | 3 years | Moderate | 34 | 0.6 (0.5, 0.7) | –0.2 (–0.3, –0.0) | 1.06 (0.79, 1.43) | 0.72 (0.51, 1.04) |
| High | 22 | 0.5 (0.4, 0.6) | |||||
| 5 years | Moderate | - | 1.0 (0.9, 1.1) | –0.3 (–0.5, –0.2) | |||
| High | 35 | 0.7 (0.6, 0.8) | |||||
| Kidney disease | 3 years | Moderate | 108 | 2.0 (1.8, 2.1) | –0.0 (–0.3, 0.3) | 1.04 (0.89, 1.23) | 0.99 (0.81, 1.22) |
| High | 126 | 2.0 (1.8, 2.2) | |||||
| 5 years | Moderate | 117 | 2.9 (2.7, 3.0) | –0.1 (–0.4, 0.2) | |||
| High | 177 | 2.8 (2.5, 3.1) | |||||
| All-cause mortality | 3 years | Moderate | 931 | 11.1 (10.5, 11.6) | –0.8 (0.0, –1.6) | 0.88 (0.82, 0.95) | 0.93 (0.85, 1.01) |
| High | 800 | 10.3 (9.7, 10.9) | |||||
| 5 years | Moderate | 1251 | 18.3 (17.6, 19.1) | –1.1 (–0.1, –2.1) | |||
| High | 1194 | 17.2 (16.4, 18.0) | |||||
| Cardiovascular mortality | 3 years | Moderate | 202 | 3.7 (3.5, 3.9) | –0.1 (–0.5, 0.3) | 0.65 (0.57, 0.74) | 1.00 (0.85, 1.18) |
| High | 282 | 3.6 (3.3, 3.9) | |||||
| 5 years | Moderate | 244 | 5.7 (5.5, 6.0) | 0.1 (–0.4, 0.6) | |||
| High | 418 | 5.8 (5.4, 6.3) | |||||
| Non-cardiovascular mortality | 3 years | Moderate | 352 | 5.8 (5.5, 6.0) | –0.5 (–1.0, 0.0) | 0.65 (0.59, 0.72) | 0.80 (0.70, 0.92) |
| High | 386 | 5.3 (4.9, 5.6) | |||||
| 5 years | Moderate | 473 | 9.8 (9.4, 10.2) | –2.0 (–2.6, –1.4) | |||
| High | 536 | 7.8 (7.3, 8.3) |
Adjusted through propensity score weighting (IPTW) of possible confounders and prognostic factors: age, sex, calendar period, transient ischemic attack, atrial fibrillation, hypertension, ischemic heart disease, diabetes mellitus, heart valve disease, peripheral artery disease, venous thromboembolism, endocarditis, myocarditis or pericarditis, heart failure, cardiomyopathy, tachyarrhythmia, rare risk factors for stroke (thrombophilia incl. antiphospholipid syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral artery stenosis, Moyamoya disease, Ehlers-Danlos syndrome, patent foramen ovale, Marfan syndrome, Fabry disease, sickle cell anemia, and thalassemia), chronic liver disease, chronic kidney disease, cancer, chronic pulmonary disease, connective tissue disorders, HIV/AIDS, thyroid disorder, gout, allergy, ulcer/chronic gastritis, inflammatory bowel disease, diverticular disease of intestine, prostate enlargement, osteoporosis, extensive analgesic drug use, anemia, vision impairment, hearing impairment, migraine, epilepsy, Parkinson’s disease, multiple sclerosis, neuropathy, bipolar affective disorder, schizophrenia or schizoaffective disorders, dementia, alcohol problems, substance abuse, depression or anxiety, hormone therapy incl. oral contraceptives, aspirin, adenosine diphosphate receptor inhibitors, anticoagulants (mono therapy, dual therapy, and triple therapy).
Weighted 5 year risks when comparing initiators of high-intensity statins with initiators of moderate-intensity statins were 8.2% versus 7.5% for ischemic stroke recurrence (RD: 0.8% [95% CI: 0.2, 1.4], HR: 1.10 [95% CI: 0.96, 1.25]), and 0.9%versus 0.9% for hemorrhagic stroke (RD: −0.1% [95% CI: −0.3, 0.1], HR: 0.92 [95% CI: 0.63, 1.36]). The observed association between high-intensity statin use and reduced risk of death was pronounced regarding non-cardiovascular mortality (RD: −2.0 [95% CI: −2.6, −1.4], HR: 0.80 [95% CI: 0.70, 0.92]), but not for cardiovascular mortality (RD: 0.1 [95% CI: −0.4, 0.6], HR: 1.00 [95% CI: 0.85, 1.18]) (Figure 2 and Table 2).
Figure 2.
Absolute risks for ischemic stroke recurrence, hemorrhagic stroke and cause-specific mortality according to statin treatment intensity after a first-time ischemic stroke, following propensity score weighting (IPTW), Denmark, 2012–2021. Information on cause-specific mortality was available until the end of 2020.
Safety outcomes
Comparing initiators of high-intensity statins with initiators of moderate-intensity statins, weighted 5-year risks were 12.8% versus 11.6% for diabetes (RD: 1.2% [95% CI: 0.4, 1.9], HR: 1.10 [95% CI: 1.00, 1.21]); 0.7% versus 1.0% for liver disease (RD: −0.3% [95% CI: −0.5, −0.2], HR: 0.72 [95% CI: 0.51, 1.04]), and 2.8% versus 2.9% for kidney disease (RD: −0.1% [95% CI: −0.4, 0.2], HR: 0.99 [95% CI: 0.81, 1.22]) (Figure 3 and Table 2).
Figure 3.
Absolute risks for safety outcomes according to statin treatment intensity after a first-time ischemic stroke, following propensity score weighting (IPTW), Denmark, 2012–2021.
Subgroup analyses
All estimates are presented in Supplemental Table 5. No clear effect modification was observed in subgroups of age, sex, and Essen Risk Score, although there was some indication that high-intensity statins were associated with increased stroke recurrence risk in women (and not in men) and in those with an Essen Risk Score of less than 3 (and not in those with a score of 3 or more). Initiation of high-intensity statins was associated with a similar risk of diabetes and a reduced risk of death in patients with atherosclerotic comorbidity, but not in those without. Lastly, there was an indication that high-intensity statins were associated with a slightly higher stroke recurrence risks in those with a high baseline LDL-C level (⩾3.0 mmol/L) and not in those with a low baseline LDL-C level (<3.0 mmol/L). In general, however, subgroup estimates lacked precision.
Sensitivity analyses
Among moderate-intensity initiators, 1958 (13.6%) switched to a high-intensity statin during follow-up, while 1195 (9.0%) of high-intensity initiators switched to a moderate-intensity statin. The median time to discontinuation/exposure switching was 327 days (IQR: 195, 612) among moderate-intensity initiators and 396 days (IQR: 229, 690) among high-intensity initiators. Across all outcome analyses, median follow-up time ranged from 0.81 to 0.86 years for moderate-intensity initiators and from 0.81 to 0.88 years for high-intensity initiators. Results of the as-treated analysis, which were broadly similar to the main analysis, are shown in Table 3. Similarly, results were broadly consistent with the main analysis in all three additional sensitivity analyses (Supplemental Tables 6–8).
Table 3.
Sensitivity analysis: 3- and 5-year absolute risks, risk differences, and hazard ratios for effectiveness and safety outcomes according to statin treatment intensity after a first-time ischemic stroke (Denmark, 2012–2021), using the as-treated approach.
| Outcome | Follow-up | Statin treatment intensity | Events,* | Adjusted absolute risk (95% CI),* | Adjusted risk difference (95% CI),* | Unadjusted hazard ratio (95% CI) | Adjusted hazard ratio (95% CI),* |
|---|---|---|---|---|---|---|---|
| Stroke recurrence | 3 years | Moderate | 275 | 6.0 (5.6, 6.4) | –0.3 (–1.0, 0.4) | 0.96 (0.84, 1.09) | 1.07 (0.90, 1.26) |
| High | 339 | 5.8 (5.3, 6.2) | |||||
| 5 years | Moderate | - | 7.5 (7.1, 8.0) | –0.0 (–0.9, 0.9) | |||
| High | 360 | 7.5 (6.8, 8.3) | |||||
| Myocardial infarction | 3 years | Moderate | 25 | 1.1 (0.9, 1.4) | –0.4 (–0.6, –0.1) | 0.81 (0.58, 1.13) | 0.91 (0.61, 1.36) |
| High | 31 | 0.8 (0.6, 0.9) | |||||
| 5 years | Moderate | - | 1.3 (1.1, 1.6) | 0.4 (–0.1, 1.0) | |||
| High | 41 | 1.8 (1.2, 2.3) | |||||
| Heart failure | 3 years | Moderate | 109 | 2.5 (2.3, 2.8) | 0.2 (–0.3, 0.6) | 0.91 (0.61, 1.36) | 1.16 (0.91, 1.47) |
| High | 162 | 2.7 (2.4, 3.0) | |||||
| 5 years | Moderate | - | 3.3 (3.0, 3.6) | –0.3 (–0.8, 0.2) | |||
| High | - | 3.0 (2.5, 3.4) | |||||
| Venous thromboembolism | 3 years | Moderate | 12 | 0.8 (0.7, 0.9) | –0.4 (–0.6, –0.2) | 0.67 (0.44, 1.00) | 0.68 (0.39, 1.18) |
| High | 19 | 0.5 (0.3, 0.6) | |||||
| 5 years | Moderate | - | 1.1 (0.9, 1.2) | –0.6 (–0.8, –0.4) | |||
| High | - | 0.5 (0.3, 0.6) | |||||
| Diabetes | 3 years | Moderate | 1006 | 9.6 (9.1, 10.1) | 1.1 (0.3, 1.9) | 1.16 (1.06, 1.26) | 1.08 (0.97, 1.21) |
| High | 1028 | 10.8 (10.2, 11.3) | |||||
| 5 years | Moderate | - | 10.9 (10.5, 11.4) | 0.5 (–0.3, 1.4) | |||
| High | 1038 | 11.5 (10.8, 12.2) | |||||
| Liver disease | 3 years | Moderate | 23 | 0.6 (0.5, 0.8) | –0.2 (–0.4, –0.0) | 1.30 (0.83, 2.02) | 1.30 (0.83, 2.02) |
| High | 9 | 0.4 (0.3, 0.5) | |||||
| 5 years | Moderate | - | 0.8 (0.7, 1.0) | –0.3 (–0.6, 0.0) | |||
| High | - | 0.5 (0.3, 0.8) | |||||
| Kidney disease | 3 years | Moderate | 66 | 1.8 (1.6, 2.0) | –0.1 (–0.5, 0.2) | 1.10 (0.88, 1.38) | 0.99 (0.75, 1.33) |
| High | 67 | 1.7 (1.4, 1.9) | |||||
| 5 years | Moderate | - | 2.2 (2.1, 2.4) | 0.2 (–0.3, 0.8) | |||
| High | 76 | 2.5 (2.0, 3.0) | |||||
| All-cause mortality | 3 years | Moderate | 414 | 11.2 (10.1, 12.4) | –1.4 (–0.1, –2.8) | 0.80 (0.72, 0.89) | 0.86 (0.75, 0.99) |
| High | 410 | 9.8 (8.9, 10.8) | |||||
| 5 years | Moderate | 420 | 19.1 (16.6, 21.6) | –3.9 (–2.0, –5.9) | |||
| High | 456 | 15.1 (13.4, 16.8) |
Adjusted through propensity score weighting (IPTW) of possible confounders and prognostic factors: age, sex, calendar period, transient ischemic attack, atrial fibrillation, hypertension, ischemic heart disease, diabetes mellitus, heart valve disease, peripheral artery disease, venous thromboembolism, endocarditis, myocarditis or pericarditis, heart failure, cardiomyopathy, tachyarrhythmia, rare risk factors for stroke (thrombophilia incl. antiphospholipid syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral artery stenosis, Moyamoya disease, Ehlers-Danlos syndrome, patent foramen ovale, Marfan syndrome, Fabry disease, sickle cell anemia, and thalassemia), chronic liver disease, chronic kidney disease, cancer, chronic pulmonary disease, connective tissue disorders, HIV/AIDS, thyroid disorder, gout, allergy, ulcer/chronic gastritis, inflammatory bowel disease, diverticular disease of intestine, prostate enlargement, osteoporosis, extensive analgesic drug use, anemia, vision impairment, hearing impairment, migraine, epilepsy, Parkinson’s disease, multiple sclerosis, neuropathy, bipolar affective disorder, schizophrenia or schizoaffective disorders, dementia, alcohol problems, substance abuse, depression or anxiety, hormone therapy incl. oral contraceptives, aspirin, adenosine diphosphate receptor inhibitors, anticoagulants (mono therapy, dual therapy and triple therapy).
Discussion
There was no clear association between statin intensity and stroke recurrence. Compared with initiation of low- or moderate-intensity statins, initiation of high-intensity statins was associated with a reduced mortality risk (driven by a reduced risk of non-cardiovascular mortality), but a similar risk of myocardial infarction, heart failure, venous thromboembolism, liver disease, and kidney disease. At the same time, initiation of high-intensity statins was associated with an increased risk of diabetes.
Effectiveness of high-intensity statins
Previous cohort studies reported a dose-dependent effect of statins in reducing risk of composite endpoints comprising cardiovascular events and mortality.24,25 One study found a reduced risk of major adverse cardiovascular events (MACE) associated with high-intensity statins compared with low- or moderate-intensity statins (HR: 0.76 [95% CI: 0.59–0.96]). 24 Another study found a greater reduction of MACE when comparing with low-intensity statin initiation only (HR: 0.48 [95% CI: 0.24–0.96]), 25 although the MACE definition differed between the two studies. Aligned with our findings, two other studies did not find such an effect.26,27 For example, one study observed similar risks of MACE (HR: 1.02 [95% CI: 0.97–1.08]), all-cause mortality (HR: 1.00 [95% CI: 0.93–1.08]), and ischemic stroke recurrence (HR: 1.02 [95% CI: 0.91–1.14]) across statin intensity cohorts. 26 These inconsistent findings might stem from different risk factor profiles across study populations. For example, the prevalence of diabetes was 8.0%–8.3% (across statin intensity groups) in our cohort and 26.6%–29.2% in another study. 24 Apart from the lipid-lowering effect, statins have also been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, endothelial improving, plaque-stabilizing, and platelet inhibiting effects, 28 but for most of the outcomes examined in this study, a higher dose did not seem to translate into a clinical benefit.
In this study, we found a reduced risk of non-cardiovascular, but not cardiovascular, mortality associated with high-intensity statin use. If true, the explanations for these findings are not clear, and it was beyond the scope of this study to further disentangle the presumed benefit of high-intensity statins in reducing non-cardiovascular mortality. Consistent with previous reports,8,25 we found no association between statin intensity and risk of hemorrhagic stroke.
Our subgroup analyses were subject to imprecision. In one study, patients aged ⩾65 years, but not patients aged <65 years, benefited from a low LDL-C target level (⩽70 mg/dL, ⩽1.8 mmol/L) compared with a higher LDL-C target (<90–110 mg/dL, <2.3–2.8 mmol/L). 29 They also found that the beneficial effect of a low LDL-C target was more pronounced in men than women. 29 These subgroup effects differ from what was observed in our study, in which no clear effect modification was observed.
Safety of high intensity statins
The increased risk of diabetes associated with high-intensity statin use observed in our study is consistent with the results from a meta-analysis which found an increased diabetes risk associated with high-intensity statin use compared with moderate-intensity statin use (odds ratio: 1.12, 95% CI: 1.04–1.22). 30
The finding of similar risk of liver disease and kidney disease across statin intensity cohorts in this study indicate that, despite previous reports of increased risk of impaired liver function and proteinuria 5 associated with use of high-intensity statins, this did not seem to manifest clinically as increased risk of kidney or liver disease.
Limitations and strengths
Our study has important limitations. First, the follow-up period, particularly in the high-intensity cohort, was relatively short. Second, the as-treated analysis indicated that patients discontinued their statin therapy or switched to another statin of different intensity (13.6% and 9.0% of cohorts, respectively) after 327 days (moderate-intensity) and 396 days (high-intensity). Thus, the relatively short time on the initial treatment could, to some extent, explain the null results observed in this study. By extension, our findings probably do not apply to long-term statin effects. Thereby we cannot rule out a high-intensity statin benefit in the long-term.
The major strength of our study was the nationwide, population-based design of large size, which reduced, to the extent possible, selection bias. This design further allowed for virtually complete follow-up of patients, and most hospital-based diagnoses captured from Danish registries are known to have high positive predictive values. 9 Another strength was our ability to balance a range of possible confounding factors in a new-user active comparator design. However, residual confounding cannot be ruled out. For example, we lacked data on baseline LDL-C level for 38.7% and 23.0% of the cohorts, respectively. Also, only 13.3% of patients in the moderate-intensity cohort had a baseline LDL-C level of ⩾4 mmol/L compared with 25.1% of patients in the high-intensity cohort (after IPTW). Assuming a true high-intensity statin benefit, this imbalance may have biased estimates toward the null.
Conclusions
Contrary to expectations, initiation of high-intensity statins was associated with similar risks of cardiovascular effectiveness outcomes when compared with initiation of moderate-intensity statins. However, considering the relatively short time on treatment, we cannot rule out a high-intensity statin benefit in the long-term.
Supplemental Material
Supplemental material, sj-docx-1-eso-10.1177_23969873231193288 for High-intensity versus moderate-intensity statin treatment for patients with ischemic stroke: Nationwide cohort study by Frederikke Bach, Nils Skajaa, Buket Öztürk Esen, Cecilia Hvitfeldt Fuglsang, Henrik Toft Sørensen and Kasper Adelborg in European Stroke Journal
Acknowledgments
None.
Footnotes
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FB, NS, HTS, BOE and EHP have nothing to declare. CHF owns stock in Novo Nordisk. KA was employed at Dept. of Clinical Epidemiology during the work with this manuscript, but he is now an employee of Novo Nordisk “A/S”. The Department of Clinical Epidemiology, Aarhus University Hospital, receives funding from private and public institutions as research grants administered by Aarhus University. None of these grants has any relation to the present study.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was internally funded by the Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital.
Ethical approval: Ethical approval is not required for registry-based studies in Denmark. The study was approved by the Danish Data Protection Agency at Aarhus University (no. 2016-051-000001-1502).
Informed consent: Informed consent is not required for registry-based studies in Denmark.
Guarantor: HTS is the guarantor.
Contributorship: All authors contributed to the design of the study and to the interpretation of results. FB, NS, KA and HTS directed the analyses, which was carried out by FB with supervision from NS and BOE. FB wrote the initial draft. All authors approved the final version for submission.
ORCID iD: Nils Skajaa 
https://orcid.org/0000-0001-8351-7133
Supplemental material: Supplemental material for this article is available online.
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Supplementary Materials
Supplemental material, sj-docx-1-eso-10.1177_23969873231193288 for High-intensity versus moderate-intensity statin treatment for patients with ischemic stroke: Nationwide cohort study by Frederikke Bach, Nils Skajaa, Buket Öztürk Esen, Cecilia Hvitfeldt Fuglsang, Henrik Toft Sørensen and Kasper Adelborg in European Stroke Journal
Data Availability Statement
No additional data available.