Table 2.
Major studies with no beneficial effects of AOs on cardiovascular outcomes.
| Author/study | Journal | Design/FU | Population∗ | Agents (dosage/day) | Results |
|---|---|---|---|---|---|
| Hennekens et al./physician health [57] |
The New England Journal of Medicine | DB, PC, 2 × 2 12 y ( βC) |
N = 22.071; all M, 40–84 y; former or current smokers | βC (50 mg) on alt days | No effect on CV death, AMI, or all-cause mortality |
| Rapola et al. [58] |
The Lancet | DB, PC 5.3 y |
N = 1862; all M; 50–69 y; smokers with previous MI | E (50 mg) + βC (20 mg) | No ↓ of MCE, ↑ risk FCHD |
| Virtamo et al. [59] |
Archives of Internal Medicine | DB, PC 6.1 y |
N = 27.271; all M; 50–69 y; smokers, no MI history; primary prevention | E (50 mg) + βC (20 mg) | E: ±↓ I fatal CHD, no ↓ I nonfatal CHD; βC no effect |
| Italiano/GISSI Prevenzione Investigators [60] |
The Lancet | OL, PC, 2 × 2 3.5 y |
N = 11.234, M and F; stratified for all age groups; AMI within 3 months; secondary prevention | E (600 mg) + fish oil (10 mg) | E: no effect AMI + death + stroke, fish oil: ↓ AMI + death + stroke |
| Yusuf/HOPE [61] |
The New England Journal of Medicine | DB, PC, 2 × 2 4.5 y |
N = 9451; M and F; ≥55 y; high risk CD patients; primary and secondary prevention | E (800 mg or 400 IU) Ramipril |
E: no effect AMI + CV death + stroke; Ramipril: ↓ AMI + CV death + stroke |
| De Gaetano/PPP [62] |
The Lancet | OL, PC, 2 × 2 3.6 y |
N = 4495; M and F; mean 64.4 y; high risk CD patients; primary prevention | E (300 mg) Aspirin(100 mg) |
E: no effect Aspirin: ↓ AMI + CV death + stroke |
| Collins et al./HPSCG [63] |
The Lancet | DB, PC 5 y |
N = 20.563; M and F; 40–80 y; CD, other OAD, DM patients | C (250 mg) + E (600 mg) + βC (20 mg) | No ↓ 5 y mortality |
| Törnwall et al. [64] |
European Heart Journal |
DB, PC 5–8 y |
N = 29.133; all M; 50–69 y; smokers with risk on MCE or MI history | E (50 mg) or βC (20 mg) or both | βC: ↑ risk nonfatal MI; E: no effect |
| Armitage et al./HPS [65] |
BMC Medicine | DB, PC, 2 × 2 5.5 y |
N = 20.536; M and F; 40–80 y; high risk CD patients; primary and secondary prevention | Simvastatin (40 mg) C (250 mg) + E (600 mg) + βC (20 mg) |
AO: no effect |
| Cook et al./WACS [66] |
Archives of Internal Medicine | DB,PC, 2 × 2 9.4 y |
N = 8171; all F; ≥1 CVE in history, secondary prevention | C (500 mg) + E(600 IU) on alt days + βC (50 mg) on alt days | No effect AMI + CV death + stroke + morbidity |
| Lee et al. [67] |
Journal of The American Medical Association | DB, PC, 2 × 2 10.1 y |
N = 39.876; all F; >45 y, healthy. | E (600 IU) Asiprin (100 mg) |
No benefit for major CV events. No effect on total mortality |
| Lonn/HOPE II [68] |
Journal of The American Medical Association | DB, PC 7.0 y |
N = 3994, >55 y with vascular disease or DM; extension of HOPE I trial. | E (400 IU) | No prevention of major CV events. No prevention of cancer. Risk of HF may be ↑. |
| Kataja-Tuomola et al. [69] |
Annals Medicine | DB, PC, 2 × 2 6.1 y |
N = 29.133, all M smokers, some with DM. | E (50 mg/d) βC (20 mg/d) |
No protective effect on macrovascular outcomes or total mortality. |
Large multicenter studies all presented the same result that oral AOs had no beneficial effect on cardiovascular outcomes. Some studies even showed an increased risk of coronary heart disease. Population*: N: number of patients; M: male; F: female; y: age in years; 2 × 2: 2 × 2 factorial design comparing placebo, agent A, agent B, and combination of agent A and B; DB: double blind; PC: placebo controlled; E: vitamin E; C: vitamin C; βC: beta-carotene; FCHD: fatal coronary heart disease; MCE: myocardial event; CHD: coronary heart disease; AMI: acute myocardial infarction; CV: cardiovascular; OS: oxidative stress; IU: international units; HF: heart failure.