Reactive Oxygen Species and the Cardiovascular System

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.