Vitamin E Takes Center Stage in Preventive Cardiology

Vitamin E Takes Center Stage in Preventive Cardiology

David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Sep- Oct 97	Rank Last Period Jul- Aug 97
1	R.V. Considine, et al., "Serum immunoreactive-leptin concentrations in normal-weight and obese humans," New Engl. J. Med., 334(5):292-5, 1 February 1996. [Thomas Jefferson U., Philadelphia, PA; Eli Lilly Res. Labs., Indianapolis, IN] *TV695	54	1
2	J. Shepherd, et al., "Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia," New Engl. J. Med., 333(20):1301-7, 16 November 1995. [U. Glasgow, U.K.; Royal Infirm., Glasgow, U.K.; Dumfries & Galloway Dist. Gen. Hosp., Dumfries, U.K.] *TE365	35	2
3	W.P. McGuire, et al., "Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer," New Engl. J. Med., 334(1):1-6, 4 January 1996.[9 U.S. institutions] *TM482	28	†
4	J.W. Mellors, et al., "Prognosis in HIV-1 infection predicted by the quantity of virus in plasma," Science, 272(5265):1167-70, 24 May 1996. [U. Pittsburgh, PA; Chiron Corp., Emeryville, CA] *UM889	26	3
5	F.M. Sacks, et al., "The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels," New Engl. J. Med., 335(14):1001-9, 3 October 1996. [8 U.S. andCanadian institutions] *VL459	26	4
6	N.G. Stephens, et al., "Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)," The Lancet, 347(9004):781-6, 23 March 1996. [Cambridge U., U.K.; Papworth Hosp., Cambridge, U.K.; St. Thomas' Hosp., London, U.K.; Brunel U., Uxbridge, U.K] *UB153	26	†
7	C.H. Hennekens, et al., "Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease," New Engl. J. Med., 334(18):1145-9, 2 May 1996. [Brigham and Women's Hosp., Boston, MA; Harvard Sch. Publ. Hlth., Boston, MA; Harvard U. Sch. Med., Boston, MA; U. Oxford, U.K.] *UG831	25	†
8	R.G. Will, et al., "A new variant of Creutzfeldt-Jakob disease in the UK," The Lancet, 347(9006):921-5, 6 April 1996. [7 European institutions] *UD591	23	†
9	U.A. Liberman, et al., "Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis," New Engl. J. Med., 333(22):1437-43, 30 November 1995. [12 institutions worldwide] *TG445	23	†
10	M. Yoshiba, H. Okamoto, S. Mishiro, "Detection of the GBV-Chepatitis virus genome in serum from patients with fulminant hepatitis of unknown aetiology," The Lancet, 346(8983):1131-2,28 October 1995. [Toshiba Gen. Hosp., Tokyo, Japan; Showa U.,Yokohama, Japan; Jichi Med. Sch., Tochigi, Japan] *TB549	22	6

SOURCE: ISI's Hot Papers Database. Read the full legend.

Both preventive cardiology and the citation league tables in medicine (papers #2 and #5) are dominated by a class of cholesterol-lowering drugs called "statins." But that is not the only way to avoid a heart attack, whether you already have some history of coronary heart disease (secondary prevention) or not (primary). Diet, non-smoking, and exercise, for example, should not be forgotten. A newcomer to the Top Ten, the Cambridge Heart Antioxidant Study (CHAOS, paper #6) tackles cholesterol and prevention from a different angle.

"Bad" cholesterol is the form carried in the blood as low-density lipoprotein (LDL-C). Oxidation of LDL-C-and if we were talking in kitchen terms we would call it rancid fat-is thought to be a key to atherogenesis, the dangerous process by which lipid is deposited on the inner walls of coronary arteries. So why not give an antioxidant and so prevent heart attacks? Investigators in the CHAOS study chose natural a-tocopherol (vitamin E) at the high dose of 800 IU, reduced to 400 IU, daily. As with the early trials of statins, this is an exercise in secondary prevention. The patients already had severe ischemic heart disease, confirmed angiographically at a hospital providing a cardiovascular referral service for a scattered population, by British standards, of 2,200,000.

Serum a-tocopherol levels rose by about two-thirds in patients randomized to vitamin E rather than placebo. When data collection ceased in June of 1995, there had been 41 non-fatal myocardial infarctions (heart attacks) in the controls but only 14 in those randomized to the vitamin, each group numbering roughly 1,000. There was no advantage for vitamin E in respect of cardiovascular deaths, however, and the vitamin group had more total deaths (36 versus 26). Further study is required, of course, but the findings supported the use of high-dose a-tocopherol in the secondary prevention of non-fatal heart attacks. So far, so good, but on June 14, 1997, along came the Alpha-tocopherol Beta-carotene Cancer Prevention (ATBC) study from Finland (see The Lancet, 349:1715-20, 1997) to complicate the picture.

The ATBC trial permitted a look, via a sub-study of those with a history of myocardial infarction, at cardiovascular developments in male smokers originally recruited in a study of the prevention of lung cancer. As the name shows, there was another agent in the design, and the men were randomized to one, both, or neither. The a-tocopherol was synthetic and the dose was 50 mg, which CHAOS had decided was too low. Nonetheless, circulating a-tocopherol levels were much the same in the vitamin groups in the two studies. Both CHAOS and ATBC seem to agree that there is not much future in a-carotene for this purpose, but the Finnish group, understandably anxious about an increase in cardiovascular deaths in those supplemented, would rule out either agent.

When The Lancet published ATBC it invited the lead author of CHAOS, Dr. Nigel Stephens, to do a commentary. Confessing the possibility of a "special pleading (from a CHAOS author)," Stephens stuck to his guns over the potential of a-tocopherol. Science Watch decided to ask the lead author of ATBC, Dr. Janne M. Rapola, from the National Public Health Institute, Helsinki, to comment on CHAOS.

Rapola began by noting that CHAOS and ATBC are not dissimilar. In CHAOS, as Rapola tells Science Watch, "there were more deaths, including cardiovascular deaths, in the a-tocopherol group than in the placebo group, though the difference was small and not statistically significant. True, CHAOS had too few deaths to reliably assess mortality; still I find it confusing that such improvement in non-fatal myocardial infarctions is not in any way reflected in coronary heart disease mortality." If dose is a weakness in ATBC (though Rapola adds that "it should be kept in mind that even with such a small dose, there were more deaths from hemorrhagic stroke in ATBC"), the length of follow-up, 5.3 years as opposed to 1.4 years, is a strength.

I would not want Science Watch readers to go away with the impression that here we have two research groups in confrontation. Both Stephens in his commentary on ATBC and Rapola's remarks on CHAOS (which space does not allow me to do justice to) are very balanced summaries of the two studies. Both papers will surely from now on be cited with equal frequency.

Mr David W. Sharp, M.A. (Cambridge),
is a Deputy Editor of The Lancet, London, U.K.