Hypertension Control: How Far—and, Indeed, How?

Hypertension Control:
How Far—and, Indeed, How?

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Mar- Apr 99	Rank Last Period Jan- Feb 99
1	S.M. Hammer, et al., "A controlled trial with two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less," New Engl. J. Med., 337(11):725-33, 11 September 1997. [15 U.S. and U.K. institutions] *XV174	48	1
2	P.M. Ridker, et al., "Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men," New Engl. J. Med., 336(14):973-9, 3 April 1997. [Harvard Medical Sch., Boston, MA; Harvard Sch. Public Health, Boston; Brigham and Women’s Hosp., Boston, MA; U. Vermont, Burlington] *WR385	29	3
3	J.R. Downs, et al., "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS," JAMA-J. Amer. Med. Assoc., 279(20):1615-22, 27 May 1998. [7 U.S. institutions] *ZP489	29	10
4	F.J. Palella, et al., "Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection," New Engl. J. Med., 338(13):853-60, 26 March 1998. [5 U.S. institutions] *ZD284	28	5
5	L. Hansson, et al., "Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial," The Lancet, 351(9118):1755-62, 13 June 1998. [10 institutions worldwide] *ZU444	27	†
6	M. Sano, et al., "A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease," New Engl. J. Med., 336(17):1216-22, 24 April 1997. [6 U.S. institutions] *WV332	26	9
7	S.A. Rosenberg, et al., "Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma," Nature Medicine, 4(3):321-7, March 1998. [NCI, NIH, Bethesda, MD] *ZN163	26	†
8	B. Pitt, et al., "Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE)," The Lancet, 349(9054):747-52, 15 March 1997. [7 institutions worldwide] *WN124	25	4
9	E. Gurfinkel, et al., "Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS pilot study," The Lancet, 350(9075):404-7, 9 August 1997. [Favalaro Fdn, Buenos Aires, Argentina; Hosp. Durand, Buenos Aires] *XQ248	24	†
10	O. Nygard, et al., "Plasma homocysteine levels and mortality in patients with coronary artery disease," New Engl. J. Med., 337(4):230-6, 24 July 1997. [Haukeland U. Hosp., Bergen Norway; U. Bergen, Norway] *XL994	23	†

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

wenty years ago, at a time when a medical article could still be written by a single author, a physician from the northwest of England warned that having a blood pressure that had been reduced too far might be a bad thing. Dr. I.McD.G. Stewart’s paper ("Relation of reduction in pressure to first myocardial infarction in patients receiving treatment for severe hypertension," The Lancet, 1:861-5, 1979) was the start of what was to become a long-running debate on the so-called "J-curve," a reference to the shape of the line plotting risk against blood pressure. The Hypertension Optimal Treatment (HOT) trial that appeared in the same journal almost two decades later (paper #5) was in part triggered by the persisting concern that going below a diastolic pressure of 90 mm Hg might not be safe and/or might not confer any added benefit.

No question that the 19,000 or so HOT patients were hypertensive, for their diastolic pressures were in the range 105 to 115 mm Hg. They were randomized not so much to different drugs as to three different target pressures that were less than or equal to 90, 85, or 80 mm Hg. Physicians (almost 2,000 took part) tried to achieve the target in five steps of increasingly powerful drug therapy. The start drug was the calcium-channel antagonist felodipine, manufactured by the trial’s main sponsor, Astra, but it was the blood-pressure targets that were on trial rather than the regimens used to get there.

This was an attempt at real-world medicine within the strictures of a randomized design. Any attempt to summarize carries the risk of oversimplification, but there is no doubt that the HOT study team thought that 80 to 85 mm Hg diastolic was safe and worth aiming at. For them perhaps the J-curve debate may have seemed settled. Not so, argued hypertension specialist Dr. Norman Kaplan ("J-curve not burned off by HOT study," The Lancet, 351:1748-9, 1998).

Some of the earliest citations of any paper are likely to be in the journal’s correspondence section, and eight weeks after this publication The Lancet hosted a hot debate on HOT with no fewer than eight letters plus a reply from the trial group. A common complaint was that the trial results were essentially negative, and several correspondents felt that the extra cardiovascular benefit was not proved. "We contend that the HOT trial investigators' conclusion is not justified on the basis of the reported results," began one of the letters, from Israeli researchers Ehud Grossman and Uri Goldbourt. The two went even further, stating that "the HOT study should be interpreted as a warning against aggressive reduction of blood pressure to below 140/90 mm Hg." (See The Lancet, 352:571-5, 1998.)

Not responding specifically to Kaplan’s view on the J-curve, the HOT trialists replied with vigor. "We are aware that, as in any trial, the HOT study has not definitely solved all the problems it set out to investigate," wrote lead authors Lennart Hansson and Alberto Zanchetti. "Nonetheless, it can hardly be disputed that, by a liberal use of all available classes of antihypertensive drugs often in combination, the HOT study succeeded in bringing down diastolic blood pressure to below 90 mm Hg in over 92% of patients, with an event rate by far the lowest of those in all other trials of antihypertensive treatment." And they quoted with approval Kaplan’s remark that HOT study questions "may still be alive, but so will more hypertensive patients if the appropriate conclusions of the HOT data are applied to their care."

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