Patients with established CVD may have high oxidative stress and be at a higher risk for a clinical event. As a result, antioxidant use may be most beneficial in the secondary prevention of CVD. Randomized trials of vitamin E alone in the secondary prevention of CVD are summarized in Table 3.3.
Early small trials used surrogate endpoints to test the effects of supplemental vitamin E in patients with established atherosclerotic disease. In a trial of 100 patients over 4 months, 1,200 IU/d of vitamin E supplementation following percutaneous transluminal coronary angioplasty led to a 30% reduction in the risk of restenosis, but this did not reach statistical significance (P = 0.06).37 A study of 120 men and women with intermittent claudication randomized to antioxidants or placebo over 2 years found little improvement in lower limb function and similar rates of cardiovascular events and death,38 and the ATBC trial found that 50 mg/d of vitamin E had no preventive effect on the development of claudication (RR = 1.05; 95% CI, 0.98-1.14).39
Studies of vitamin E for the prevention of angina pectoris have had mostly negative results. A placebo-controlled trial of 3,200 IU/d of vitamin E in stable angina patients led to a nonsignificant trend toward an improved angina pain score in a 9-week placebo-controlled trial40 while a trial of large dose vitamin E (1,600 IU/d) in 48 patients with angina found no benefit on exercise capacity, left ventricular function or angina symptoms.41 These small studies of short duration may not have been adequately powered to detect small-to-moderate benefits of antioxidant therapy, but even among 1,795 smokers with angina followed over 4 years in the ATBC trial there was no evidence of a beneficial effect with low-dose vitamin E supplementation (RR = 1.06; 95% CI, 0.85-1.33).42
In the Cambridge Heart Antioxidant Study (CHAOS), vitamin E in two doses (400 or 800 IU/d) was tested vs. placebo over a median of 510 days in 2,002 patients with CHD.43 Those assigned to vitamin E had a lower risk of nonfatal MI (RR = 0.23; 95% CI, 0.11-0.47), but they also had a nonsignificant increase in CVD deaths (RR = 1.18; 95% CI, 0.62-2.27). The study's primary endpoint was combined nonfatal MI and CVD death, and vitamin E reduced this risk (RR = 0.53; 95% CI, 0.34-0.83). Because of the relatively small number of study participants, the randomization process left imbalances in the treatment groups, with the placebo u>
Table 3.3 Completed and ongoing randomized clinical trials of vitamin E supplementation in the secondary prevention of cardiovascular disease (CVD)
Effect of vitamin E supplementa tion RR (95% CI)
Cambridge Heart Antioxidant Study (CHAOS)
Beta-Carotene Cancer Prevention Trial (ATBC) substudy Gruppo Italiano per lo Studio della Soprawivenza nell'Infarto miocardico Prevenzione trial (GISSI) Heart Outcomes Prevention Evaluation trial (HOPE)
HOPE - The Ongoing Outcomes (HOPE-TOO)
2,002 men and women with atherosclerosis, mean age = 62 years; United Kingdom
I,862 male smokers aged 50-69 with prior MI; Finland
II,324 men and women with prior MI; Italy
9,541 men and women age >55 years, at high risk of CVD; N. America, S. America, Europe
3,994 men and women originally in the HOPE trial
carotene (20mg/d), or both
polyunsaturated fatty acids (1 g/d), or both; open-label design
CVD mortality + MI Nonfatal MI CVD mortality
Major coronary event Nonfatal MI CHD mortality
CVD mortality + MI + stroke CVD mortality
CVD mortality + MI + stroke CVD mortality MI
CVD mortality + MI + stroke Heart failure
Secondary Prevention with Antioxidants of Cardiovascular disease in Endstage renal disease (SPACE) Women's Antioxidant Cardiovascular Study (WACS)
196 hemodialysis patients with CVD, mean age = 65 years; Israel
8,171 female health professionals aged >45 years, with CVD or >3 coronary risk factors; United States
Vitamin E (600IU every 9.4
other day), other antioxidant", or a combination (2 x 2 x 2 x 2 factorial design)
MI + ischemic stroke + 0.46 (0.27-0.78) peripheral vascular disease + unstable angina
MI + stroke + revascularization 0.94 (0.85-1.04) + CVD mortality
All trials were placebo controlled, except for the GISSI trial which used an open-label design. Secondary 4-way analysis.
1 Beta carotene (50mg/d), vitamin C (500mg/d); or combination of folic acid (2.5mg/d), vitamin B6 (50mg/d), and vitamin B12 (1 mg/d).
group having more men, lower total cholesterol levels, lower systolic blood pressures, and fewer diabetics. There is no clear explanation for the striking difference in results for nonfatal MI and CVD death. CHAOS was the first large prospective clinical trial to produce some results in favor of the oxidation theory in atherosclerosis.
In the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico (GISSI) Prevention Trial, 11,324 patients with a history of acute MI within the last 3 months were randomized in an open-label design to vitamin E (300 mg daily), n-3 polyunsaturated fatty acids (1 g daily), both, or neither over 3.5 years.44 The primary analysis included nonfatal MI, nonfatal stroke, and CVD death, and vitamin E did not have an effect on this combined endpoint (RR = 0.98; 95% CI, 0.87-1.10). However, vitamin E supplementation did have a statistically significant effect on the secondary endpoint of CVD death (RR = 0.80; 95% CI, 0.65-0.99), in contrast to the results of the CHAOS study.
The Heart Outcomes Prevention Evaluation (HOPE) study randomized 9,541 participants with CVD or diabetes and at least one other CVD risk factor (hypertension, hypercholesterolemia, smoking, low HDL, or microalbuminuria) into a study of vitamin E (400 IU daily), the angiotensin-converting enzyme inhibitor ramipril, both agents, or neither.45 The study was stopped early after a mean follow-up of 4.5 years because of the beneficial effects of ramipril. Vitamin E had no effect on the primary combined endpoint of MI, stroke, and CVD death (RR = 1.05; 95% CI, 0.95-1.16), and secondary analysis of various CVD endpoints (e.g., unstable angina, revascularization) also failed to show any reduced risk with vitamin E supplementation. The HOPE study had high rates of compliance and used large doses of vitamin E, and an extension of the trial, HOPE-The Ongoing Outcomes (HOPE-TOO) continued to follow nearly 4,000 participants for a median duration of 7.0 years.46 In HOPE-TOO, vitamin E supplementation did not reduce major CVD events (RR = 1.04; 95% CI, 0.96-1.14), and there was an increased risk of heart failure (RR = 1.13; 95% CI, 1.01-1.26) and hospitalization for heart failure (RR = 1.21; 95% CI, 1.00-1.47) associated with long-term vitamin E supplementation.
Because antioxidants may have an earlier and more pronounced effect in patients with high oxidative stress, the Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE) trial randomized 196 hemodialysis patients with CVD to large doses of vitamin E (800 IU daily) or placebo.47 After a median follow-up of 519 days, vitamin E was associated with significant reductions in the combined endpoint of MI (fatal and nonfatal), ischemic stroke, peripheral vascular disease, and unstable angina (RR = 0.46; 95% CI, 0.270.78). Those in the vitamin E group were less likely to have an MI (RR = 0.30; 95% CI, 0.10-0.80), but there was no significant difference in other secondary endpoints including total mortality (RR = 1.09; 95% CI, 0.70-1.70). The results of this small trial with relatively short follow-up were consistent with the CHAOS trial and suggest that high doses of vitamin E may have a role in selected patients with high oxidative stress. A subsequent 9.4-year trial among 8,171 female health professionals at increased risk of CVD either because of a prior history of CVD (i.e., prior MI, angina, stroke, TIA, coronary revascularization, carotid endarterectomy, peripheral arterial disease), the Women's Antioxidant Cardiovascular Study (WACS), found no overall effect of vitamin E (600 IU every other day) on the combined endpoint of MI, stroke, revascularization, or CVD death (RR = 0.94; 95% CI, 0.85-1.04) or on the individual components of this endpoint. However, in subgroup analyses by prior CVD (vs. 3 or more risk factors), there were significant reductions in the combined endpoint (RR = 0.88; 95% CI, 0.78-0.98) and in MI (RR = 0.75; 95% CI, 0.56-0.99) among those with prior CVD.48
A 2003 meta-analysis of large randomized vitamin E trials found no benefit in total mortality (RR = 1.02; 95% CI, 0.98-1.06) or CVD death (RR = 1.00; 95% CI, 0.95-1.06) from supplementation in a wide range of doses in various study groups,49 and the authors concluded that vitamin E supplementation in primary or secondary prevention of CVD could not be routinely recommended. However, they were unable to assess particular groups with high oxidative stress and antioxidants may work best in individuals with high rates of lipid peroxidation.50 The clinical trials of vitamin E do not disprove the oxidation hypothesis in atherosclerosis, and future studies may need to be conducted in younger subjects (i.e., prior to a lifetime of lipid oxidation) or high-risk subgroups (perhaps using a marker to identify high oxidative stress) most likely to benefit from antioxidant therapy.51
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