Article Figures & Data
- Figure 1
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of the literature screening process. RCT, randomised controlled trials.
- Figure 2
Trial sequential analysis on the effect of vitamin E compared with control on total stroke prevention.
- Figure 3
Trial sequential analysis on the effect of vitamin E compared with control on fatal stroke prevention.
- Figure 4
Trial sequential analysis on the effect of vitamin E compared with control on non-fatal stroke prevention.
- Figure 5
Trial sequential analysis on the effect of vitamin E compared with control on haemorrhagic stroke prevention.
- Figure 6
Trial sequential analysis on the effect of vitamin E compared with control on ischaemic stroke prevention.
- Table 1
Characteristics of trials
First author (Trial) Area Study design Age, mean (SD) Gender, n (%) Comorbidity Baseline BMI, mean (SD) Current smoker, n (%) Type of prevention Vitamin E dose (source) Trial duration Stroke outcomes Intervention Control Intervention Control Intervention Control Intervention Control Belch et al 47 (POPADAD) Scotland Double blind randomised controlled trial 60.5 (10.2) 60.1 (9.9) Male, 290 (45.3);
Female, 350 (54.7)Male, 273 (42.9);
Female, 363 (57.1)Diabetes with asymptomatic peripheral arterial disease 29.7 (2.1) 29.2 (2.2) 211 (33.0) 186 (29.2) Primary 200 mg daily (n/a) Median 6.7 years (4.5–8.6 years) Total, fatal, non-fatal, ischaemic, haemorrhagic Boaz et al 49 (SPACE) Israel Double blind randomised controlled trial 64.9 (8.3) 64.4 (8.8) Male, 67 (69.1);
Female, 30 (30.9)Male, 68 (68.7);
Female, 31 (31.3)Cardiovascular disease with end stage renal disease Not stated Not stated 24 (24.7) 14 (14.1) Secondary 800 IU daily (natural) Median of 519 days (range 10–763) Ischaemic Brown et al 41 (HATS) Canada and USA Double blind randomised controlled trial 53 Male, 139 (87);
Female, 21 (13)Coronary disease and low HDL cholesterol levels 29 38 (24) Primary 800 IU daily (natural) 3 weeks Ischaemic Catalano et al 39 (CLIPS) Europe Double blind randomised controlled trial 67.1 (8.0) 64.9 (9.2) Male, 141 (76.2);
Female, 44 (23.8)Male, 141 (77.9);
Female, 40 (22.1)Peripheral arterial disease Not stated Not stated 51 (27.6) 44 (24.4) Primary 600 mg daily (synthetic) Mean 20.7±6.4 months Total, fatal, non-fatal Collaborative Group of the Primary Prevention Project48 (PPP) Italy Open label randomised controlled trial 64.4 (7.6) 64.4 (7.7) Male, 937 (42.0);
Female, 1294 (58.0)Male, 975 (43.0);
Female, 1289 (57.0)Hypertension, hypercholesterolaemia, diabetes mellitus or obesity 27.5 (4.6) 27.8 (4.7) 342 (15) 325 (14) Primary 300 mg daily (synthetic) Mean 3.6 years Total, fatal, non-fatal Cook et al 52 (WACS) USA Double blind randomised controlled trial 60.6 (8.9) 60.6 (8.8) Female, 4083 (100.0) Female, 4088 (100.0) History of cardiovascular event or three or more cardiovascular risk factors 30.3 (6.6) 30.3 (6.7) 632 (15.5) 637 (15.6) Secondary 600 IU alternate days (natural) Mean 9.4 years (8.3–10.1 years) Total, fatal, non-fatal, ischaemic, haemorrhagic GISSI-Prevenzione Investigators40 (GISSI) Italy Open label randomised controlled trial 59.3 (10.5) 59.4 (10.6) Male, 4849 (85.7);
Female, 811 (14.3)Male, 4810 (84.9);
Female, 854 (15.1)Recent (≤3 months) myocardial infarction 26.6 (3.6) 26.5 (3.7) 2384 (42.4) 2423 (43.1) Primary 300 mg daily (synthetic) 3.5 years Total stroke Heart Protection Study Collaborative Group43 (HPS) UK Double blind randomised controlled trial 40–70 Male, 7727 (75.2);
Female, 2542 (24.8)Male, 7727 (75.3);
Female, 2540 (24.7)Substantial 5-year risk of death from coronary heart disease because of a medical history of coronary heart disease, of other occlusive arterial disease, of diabetes mellitus, or of treated hypertension alone Not stated Not stated 1448 (14.1) 1465 (14.3) Secondary 600 mg daily (synthetic) 18 weeks Total, fatal, non-fatal, ischaemic, haemorrhagic Hodis et al 51 (VEAPS) USA Double blind randomised controlled trial 55.7 (9.2) 56.7 (8.6) Male, 77 (48);
Female 85 (52)Male, 83 (49); Female 87 (51) Healthy individuals Not stated Not stated 6 (4) 5 (3) Primary 400 IU daily (synthetic) Mean 3 years Total stroke Lamas et al 50 (TACT) USA and Canada Double blind randomised controlled trial 65.3 (3.8) 65.5 (3.5) Male, 706 (83.0);
Female, 147 (17.0)Male, 703 (82.0);
Female, 152 (18.0)Myocardial infarction, cardiovascular disease, cardiovascular disease risk factors 29.3 (2.0) 30.3 (2.0) Not stated Not stated Secondary 400 IU daily (natural) Median 55 months (IQR, 26 to 60 months) Fatal stroke Lee et al 53 (WHS) USA Double blind randomised controlled trial 54.6 (7.0) 54.6 (7.0) Female, 19 937 (100.0) Female, 19 939 (100.0) None 26.0 (5.1) 26.0 (5.1) 2590 (13.0) 2645 (13.3) Primary 600 IU on alternate days (natural) Mean 10.1 years (8.2–10.9 years) Total, fatal, non-fatal, ischaemic, haemorrhagic Leppala et al 15 (ATBC) Finland Double blind randomised controlled trial 57.7 57.7 Male 14 238 (100.0) Male 14 281 (100.0) No history of cancer or serious illness 26.3 26.3 14 238 (100.0) 14 281 (100.0) Primary 50 mg daily (synthetic) Median 6 years Total, fatal, non-fatal, ischaemic, haemorrhagic Li et al 45 (Linxian) China Double blind randomised controlled trial Median 54 Male, 730 (44);
Female, 927 (56)Male, 731 (44);
Female, 930 (56)Cytological evidence of oesophageal dysplasia Not stated Not stated 477 (29) 477 (29) Primary 60 IU daily (synthetic) 6 weeks Fatal stroke Milman et al 44 (ICARE) Israel Double blind randomised controlled trial 68.7 (8.1) 69.5 (8.1) Male, 344 (47.4);
Female, 382 (52.6)Male, 339 (47.9);
Female, 369 (52.1)Type 2 diabetes with Hp 2–2 genotype Not stated Not stated 82 (11.3) 89 (12.6) Secondary 400 IU daily (natural) Not stated Non-fatal stroke Sesso et al 46 (PHS II) USA Double blind randomised controlled trial 64.2 (9.1) 64.3 (9.2) Male, 7315 (100.0) Male, 7326 (100.0) Cardiovascular disease (myocadiac infarction, stroke) or cancer 26.0 (3.6) 26.0 (3.7) 239 (3.3) 285 (3.9) Secondary 400 IU alternate day (synthetic) Mean 8 years Total, fatal, non-fatal, ischaemic, haemorrhagic Steiner et al 54 USA Double blind randomised controlled trial 70.7 (11.6) 71.4 (10.1) Male, 22 (42.3);
Female, 30 (57.7)Male, 20 (41.7);
Female, 28 (58.3)Minor stroke or reversible ischaemic neurological deficit, retinal ischaemic event, transient ischaemic attack Not stated Not stated Not stated Not stated Secondary 400 IU daily (n/a) 2 years Total stroke, ischaemic, haemorrhagic Stephens et al 38 (CHAOS) UK Double blind randomised controlled trial 61.8 (9.3) 61.8 (8.9) Male, 848 (81.9);
Female, 187 (18.1)Male, 842 (87.1);
Female, 125 (12.9)Coronary atherosclerosis 26.5 (3.5) 26.4 (3.4) 149 (14.4) 121 (12.5) Primary 800 IU daily for first 546 patients; 400 IU daily for remainder 489 patients (natural) Median of 510 days (range 3–981) Fatal stroke Yusuf et al 42 (HOPE) USA, Canada, Europe, South America Double blind randomised controlled trial 66 (7) 66 (7) Male, 3498 (73.5);
Female, 1263 (26.5)Male, 3498 (73.2);
Female, 1282 (26.8)Cardiovascular disease (coronary artery disease, stroke, or peripheral vascular disease) or diabetes with at least one other cardiovascular risk factor (dyslipidaemia, hypertension, microalbuminuria, or current smoking) 28 (4) 28 (4) 665 (14.0) 679 (14.2) Secondary 400 IU daily (natural) 4–6 years (mean 4.5 years) Total stroke, haemorrhagic ATBC, Alpha-Tocopherol, Beta-Carotene Cancer ; BMI, body mass index; CHAOS, Cambridge Heart Antioxidant Study; CLIPS, Critical Leg Ischaemia Prevention Study; GISSI, Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico; HATS, HDL-Atherosclerosis Treatment Study; HDL, High-Density Lipoprotein; HOPE, Heart Outcomes Prevention Evaluation; HPS, Heart Protection Study; ICARE, Israel Cardiovascular Atherosclerosis Risk and Vitamin E; PHS II, Physicians’ Health Study II; POPADAD, Prevention of Progression of Arterial Disease and Diabetes; PPP, Primary Prevention Project; SPACE, Secondary Prevention with Antioxidants of Cardiovascular Disease in End Stage Renal Disease; TACT, Trial to Assess Chelation Therapy; VEAPS, Vitamin E Atherosclerosis Prevention Study; WACS, Women’s Antioxidant Cardiovascular Study; WHS, Women’s Health Study.
- Table 2
Relative risks of the effects of vitamin E on stroke for the pooled population and its subgroup analysis
Variables N Risk ratio 95% CI I2 (%) P value Forest plot Total stroke 12 0.98 0.92–1.04 0 0.57 Online supplemental figure S1 Type of prevention Primary 7 0.96 0.87–1.05 0 0.33 Online supplemental figure S2 Secondary 5 1.00 0.90–1.12 32 0.93 Source of vit E Synthetic 7 0.97 0.90–1.04 0 0.41 Online supplemental figure S3 Natural 3 1.00 0.84–1.18 54 0.97 Dosage of vit E High 9 0.99 0.91–1.07 1 0.72 Online supplemental figure S4 Low 3 0.99 0.88–1.10 14 0.80 Total stroke (vitamin E alone) 4 1.04 0.91–1.19 0 0.56 Online supplemental figure S5 Fatal stroke 11 0.96 0.77–1.20 32 0.73 Online supplemental figure S6 Type of prevention Primary 7 1.03 0.68–1.55 45 0.90 Online supplemental figure S7 Secondary 4 0.93 0.76–1.14 2 0.48 Source of vit E Synthetic 6 0.94 0.72–1.24 47 0.67 Online supplemental figure S8 Natural 4 0.88 0.59–1.29 0 0.51 Dosage of vit E High 7 0.96 0.77–1.19 0 0.72 Online supplemental figure S9 Low 4 1.01 0.66–1.55 68 0.97 Non-fatal stroke 9 0.96 0.88–1.05 20 0.35 Online supplemental figure S10 Type of prevention Primary 5 0.93 0.84–1.03 0 0.16 Online supplemental figure S11 Secondary 4 0.96 0.82–1.13 46 0.65 Source of vit E Synthetic 5 0.99 0.87–1.12 39 0.83 Online supplemental figure S12 Natural 3 0.89 0.74–1.08 27 0.25 Dosage of vit E High 6 0.95 0.85–1.07 14 0.42 Online supplemental figure S13 Low 3 0.99 0.82–1.19 53 0.88 Haemorraghic stroke Total haemorrhagic stroke 7 1.17 0.98–1.39 0 0.08 Online supplemental figure S14 Ischaemic stroke Total ischaemic stroke 7 0.92 0.85–0.99 5 0.04 Online supplemental figure S15
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