Alpha blockers increase CHF risk in older hypertensive patients; FDA committees to review COX-2 inhibitor risk-benefit profile

A community-based study confirmed that alpha antagonist monotherapy for the treatment of hypertension is associated with an increased risk of congestive heart failure (CHF) compared to thiazide diuretic monotherapy. Study authors stated that this increased risk is only partly explained by differences in blood pressure control. The increased risk was observed in women but not in men in this prospective cohort study.

Alpha blockers increase CHF risk in older hypertensive patientsA community-based study confirmed that alpha antagonist monotherapy for the treatment of hypertension is associated with an increased risk of congestive heart failure (CHF) compared to thiazide diuretic monotherapy. Study authors stated that this increased risk is only partly explained by differences in blood pressure control. The increased risk was observed in women but not in men in this prospective cohort study.

The age-adjusted risk of CHF was 90% greater (P=.04) with alpha blocker monotherapy compared to thiazide diuretic monotherapy. Adjusting for systolic blood pressure (SBP) attenuated the increased risk associated with alpha antagonist monotherapy. The age-adjusted increased risk of CHF with alpha antagonist monotherapy was apparent only in women, with a hazard ratio of 2.85 (95% CI, 1.15-7.04), which again was attenuated when adjusting for SBP.

Among subjects without a history of cardiovascular disease at baseline, women had an age-adjusted increased risk of incident CHF (HR=3.6; P=.05) with alpha-1 antagonist use compared to thiazide diuretic use; however, there remained no significant increased risk among men in this group.

The authors note that the average SBP of subjects taking a thiazide diuretic was 4 mmHg less than for those taking an alpha-1 antagonist, and in women, the average SBP was 10 mmHg less in the thiazide diuretic recipients compared to the alpha antagonist recipients.

No statistically significant difference in risk was observed between users of alpha antagonists and thiazide diuretics for the cardiovascular end points of angina pectoris, myocardial infarction, stroke, and cardiovascular death.

Among the men who used alpha-1 antagonists for prostatism, there was no increase in the age-adjusted risk of incident CHF compared to those not taking an alpha-1 antagonist.

The Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT), which found an increased number of major cardiovascular events in patients randomized to the alpha blocker doxazosin compared to the thiazide diuretic chlorthalidone, found no such differential in events by gender, "raising the possibility that we failed to observe as strong of an effect in men by chance," said lead author Chris L. Bryson, MD, MS. In the current study, the difference in the CHF hazard ratio between men and women who took alpha-1 antagonists was marginally significant, Dr Bryson observed.

The small number of events in the study-64 total, 14 in the alpha blocker monotherapy group-prevents the exclusion of residual or unaddressed confounding to explain the difference found between men and women, added Dr Bryson, acting instructor, general internal medicine, University of Washington, and Health Services Research and Development investigator and staff physician, VA Puget Sound Healthcare System, Seattle, Wash.

SOURCE Bryson CL, Smith NL, Kuller LH, et al. Risk of congestive heart failure in an elderly population treated with peripheral alpha-1 antagonists. J Am Geriatr Soc. 2004;52:1648-1654.

FDA committees to review COX-2 inhibitor risk-benefit profile In a joint meeting scheduled for February 14-16, FDA's Arthritis Drugs and Drug Safety & Risk Management Advisory committees plan to review the inclusion of gastrointestinal (GI) protective claims in COX-2 inhibitor labeling, as well as the cardiovascular risks associated with the class. More specifically, the committees will discuss whether the suggested GI benefits of the COX-2 inhibitors celecoxib (Celebrex, Pfizer) and valdecoxib (Bextra, Pfizer) outweigh the potential cardiovascular risks and whether sufficient data have been collected to merit labeling that states a GI-protective effect.

The push for a more rigorous review of cardiovascular effects began after FDA announced findings in mid-December from the Adenoma Prevention with Celecoxib trial (APC) that demonstrated an increased risk of major fatal and non-fatal cardiovascular events with the use of celecoxib. The study-designed to assess the efficacy of celecoxib treatment in preventing colorectal cancer-enrolled over 2,000 patients who received celecoxib 200 mg, celecoxib 400 mg, or placebo, twice daily. Preliminary results have shown that participants who took the 400-mg dose (n=671; 95% CI, 1.2-1.8) and the 200-mg dose (n=685; 95% CI, 1.0-6.3) of celecoxib had 3.2 and 2.5 times the risk for cardiovascular events (death, heart attack, or stroke) of those who took placebo, respectively. For patients taking either dose (n=1,356; 95% CI, 1.2-6.7), the relative risk was 2.8. In the groups of patients receiving placebo, 200-mg celecoxib, and 400-mg celecoxib, there were 6, 15, and 20 cardiovascular events, respectively.

As a result of the findings, Pfizer complied with an FDA request to halt all direct-to-consumer advertisements for celecoxib.

After the preliminary APC trial results were released, FDA initiated a review of all studies involving COX-2 inhibitors to ensure that adequate study precautions were properly implemented and to determine whether increased cardiovascular risk may be a "class effect" among the COX-2 inhibitors.

Preliminary results from 1 trial among more than 40 reviewed by independent institutional review boards upon FDA's request showed that naproxen had a higher risk of cardiovascular events compared to placebo, while celecoxib showed no increased risk.

The National Institute on Aging's Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT)-designed to test anti-inflammatory medications for the prevention of Alzheimer's disease-demonstrated that patients taking naproxen 220 mg, twice daily experienced 50% higher cerebrovascular and cardiovascular risks compared to those taking placebo. The trial, sponsored by the National Institutes of Health (NIH), randomized 2,400 patients to naproxen 220 mg twice daily, celecoxib 200 mg twice daily, or placebo, for a period of 3 years. The randomization ratio was 1:1:1.5 (1.5=placebo). Among all 3 arms, approximately 70 enrollees experienced MI or stroke. John C Breitner, MD, MPH, ADAPT principal investigator, said: "There were 23 deaths in the overall trial. Not a particularly noteworthy difference among treatment groups. Nothing statistically meaningful."

An independent safety/monitoring committee had noticed that for some time the data had exposed a weak signal showing a possible increased risk of cardiovascular and cerebrovascular events with the use of naproxen, but no signal was perceptible for celecoxib. According to Dr Breitner, however, "The risks that seem to be evident in naproxen with this trial do not approach the level of that reached with Celebrex in the APC trial."

Because of the apparent increased risk of events with the use of celecoxib in the APC trial, ADAPT trial investigators were motivated by practical considerations to suspend the use of celecoxib, despite no evidence of increased cerebrovascular or cardiovascular risk with the use of celecoxib. Investigators stopped naproxen treatment after emerging data indicated increased cerebrovascular and cardiovascular outcomes with its use.

NIH director Elias Zerhouni, MD, said: "In the context of a human subject investigation, the benefits did not warrant taking the risk of continuing long-term uses. It is very different in the context of users for helping them with problems-it is different from doctors who are using their best judgment."

Although participants were taken off the trial drugs, the trial will continue so that study investigators can obtain results for the secondary outcome, cognitive decline.

SOURCES FDA website. Joint meeting of the arthritis advisory committee and the drug safety and risk management advisory committee [press release]. Available at http:// http://www.fda.gov/oc/advisory/accalendar/2005/cder12532ddd 0216171805.html.

Nicole Saiontz, National Cancer Institute press office, unpublished data [oral communication], January 4, 2005.

National Institutes of Health. NIH halts use of COX-2 inhibitor in large cancer prevention trial [telebriefing], December 17, 2004.

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