Interest Revives in Beta-Blockers for Heart Failure

Interest Revives in Beta-Blockers for Heart Failure

by David W. Sharp

WHAT'S HOT IN MEDICINE...

Rank	Paper	Citations This Period Nov- Dec 97	Rank Last Period Sep- Oct 97
1	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	40	2
2	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	39	4
3	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	37	1
4	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. and Canadian institutions] *VL459	36	5
5	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	29	6
6	M. Packer, et al., "The effect of carvedilol on morbidity and mortality in patients with chronic heart failure," New Engl. J. Med., 334(21): 1349-55, 23 May 1996. [7 U.S. institutions] *UL251	27	†
7	G.S. Omenn, et al., "Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease," New Engl. J. Med., 334(18):1150-5, 2 May 1996. [8 U.S. institutions] *UG831	26	†
8	A. Schömig, et al., "A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents," New Engl. J. Med., 334(17):1084-9, 25 April 1996. [Technical U. Munich, Germany] *UG457	26	†
9	K. Masuko, et al., "Infection with hepatitis GB virus C in patients on maintenance hemodialysis," New Engl. J. Med.., 334(23):1485-90, 6 June 1996. [6 Japanese institutions] *UN799	25	†
10	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	22	10

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

The sympathetic nervous system is activated in the debilitating illness of heart failure-for instance, the higher the concentration of norepinephrine in the circulation, the worse the prognosis. Yet drugs that block catecholamine receptors (beta-blockers) were for a long time avoided in patients with heart failure because these drugs were not selective for receptors in the heart. More selective agents are now available, and the 1990s have seen a reawakening of interest in these drugs for heart failure. Carvedilol, which has been around for a long time (it was first patented in 1979), is one of them.

Effect on Survival

The high citation rate achieved by the U.S. Carvedilol Heart Failure Study Group (paper #6) reflects the fact that, for the first time, a positive effect of a selective beta-blocker on survival in patients with heart failure, rather than just on symptoms or measurements of cardiac function, was demonstrated. Guidelines of the Working Group on Heart Failure of the European Society of Cardiology recommend carvedilol in a broad spectrum of patients with heart failure. Up to one-fifth of patients with heart failure in the United States may be receiving beta-blockers, mostly carvedilol.

"Specialists have been using carvedilol with an appropriate degree of caution," Dr. John Cleland, of the Glasgow (U.K.) Clinical Research Initiative in Heart Failure, tells Science Watch, "hence no evidence of an alarming increase in beta-blocker side-effects has been noted." Trials underway with this drug include a comparison of carvedilol with metoprolol on mortality in heart failure to determine whether the benefits of beta-blockade are a class effect or not.

Call up the U.S. National Library of Medicine's Medline listings for carvedilol on the PubMed website and you will see the growth of interest in this agent. Last year saw 33 publications with this drug as the focus. Of course, not all these are clinical trials; there are plenty of more physiological studies and even review articles and commentaries, for example.

A joint Australian/New Zealand group published an interim analysis in Circulation in 1995, and the final report came out a year ago (see The Lancet, 349:375-80, 1997). That study of carvedilol had survival as a secondary endpoint. The combined relative risk of mortality was lower (i.e., the benefit of the drug was greater) in the U.S. study than in the Australasian one. However, trialists these days no longer write simply "X% improvement"; they put confidence intervals around the number, and the intervals in these two trials overlap. These intervals can be plotted graphically for several studies and the data (summary [e.g., tabulated] as published or going back to individual patient data) are pooled. This would be a meta-analysis.

As far as I can tell, this has not been done for carvedilol in isolation, but something similar has been achieved for beta-blockers generally. R.N. Doughty and colleagues from New Zealand (see European Heart Journal, 18:560-65, 1997) found 24 trials, with 3,141 patients and 297 deaths. Among the vasodilating beta-blockers (the main one being carvedilol, which has some alfa-1 receptor-blocking activity) the effect on mortality was a 47% reduction. "In my experience," adds Dr. Cleland, "most patients with mild heart failure tolerate carvedilol very well. Initiation of carvedilol in patients with more severe heart failure requires greater care and effort and should be left to a specialist. Most patients appear to do well on treatment. The high prevalence of respiratory disease in my own practice means that a sizeable minority of patients cannot be treated with the agent."

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