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April 21, 2003 — The calcium channel blocker verapamil did not show significant increased effectiveness compared to a diuretic and beta-blocker in reducing the risk of cardiovascular events in patients with hypertension, according to an article in the April 23/30 issue of The Journal of the American Medical Association.
Patients diagnosed as having hypertension are often given a calcium channel blocker to reduce cardiovascular disease risk, but the benefit compared with other drug classes is controversial, according to background information in the article.
Henry R. Black, M.D., of Rush-Presbyterian-St. Luke's Medical Center, Chicago, and colleagues conducted a study to determine whether initial therapy with controlled-onset extended release (COER) verapamil is equivalent to atenolol (a beta-blocker) or hydrochlorothiazide (a diuretic) in preventing cardiovascular disease. The Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) Trial was a double-blind, randomized clinical trial conducted at 661 centers in 15 countries.
A total of 16,602 participants diagnosed as having hypertension and who had one or more additional risk factors for cardiovascular disease (such as diabetes or cigarette smoking) were enrolled between September 1996 and December 1998 and followed up until December 31, 2000. The trial included 8,179 participants who received 180 mg of COER verapamil and 8,297 who received either 50 mg of atenolol or 12.5 mg of hydrochlorothiazide. The primary endpoints were stroke, heart attack or cardiovascular disease-related death.
After an average follow-up of three years, the sponsor closed the study (two years early, "for commercial reasons") before unblinding the results, according to the authors.
"Systolic and diastolic blood pressure were reduced by 13.6 mm Hg and 7.8 mm Hg for participants assigned to the COER verapamil group and by 13.5 and 7.1 mm Hg for participants assigned to the atenolol or hydrochlorothiazide group. There were 364 primary cardiovascular disease-related events that occurred in the COER verapamil group vs. 365 in atenolol or hydrochlorothiazide group," they write. "The treatment regimens showed some minor and statistically nonsignificant differences in the incidence of each component of the primary end point. The incidence of acute (heart attack) was about 18 percent lower with COER verapamil than with the atenolol or hydrochlorothiazide group; this benefit was offset by a 15 percent higher risk of stroke."
In an accompanying editorial, Bruce M. Psaty, M.D., Ph.D., of the University of Washington, Seattle, and Drummond Rennie, M.D., Deputy Editor, JAMA, Chicago, address the issue of the CONVINCE trial being stopped two years early for commercial reasons by the sponsor. They acknowledge that there are important legitimate reasons to stop a clinical trial early, including evidence of clear harm or benefit or inadequate power. They question the early stoppage of CONVINCE.
"... the recruitment and involvement of human research participants places clinical trials in a category decidedly distinct from the customary swapping and trading of traditional goods and services. When patients or other research participants are recruited for scientific investigations, they agree willingly to expose themselves to risk. Individuals often participate out of a sense of altruism, and counted among the most important reasons for joining trials are the improvements in their own health, the contributions to science, and the improvement of the health of others," they write. "If CONVINCE had been continued to the originally planned completion, the improved blood pressure control associated with trial participation might well have produced substantial health benefits."
"The participants in CONVINCE were not only deprived of personal benefit from the completed trial, but also the social benefit of genuine scientific contributions from an adequately powered study. If the conduct of a seriously underpowered study is unethical, the willful creation of an underpowered study by the early stopping of CONVINCE seems unethical as well. What the company apparently treated as a simple commercial matter rendered the original promise to participate in research that contributes substantively to medical knowledge impotent, useless, or fraudulent."
"Medical research, even if it is conducted by the pharmaceutical industry, is not solely a commercial enterprise designed to maximize personal gain or company profits. The responsible conduct of medical research involves a social duty and a moral responsibility that transcends quarterly business plans or the changing of chief executive officers," they write. "The findings of CONVINCE have been hobbled by the early stopping of this trial. Not only is power inadequate, but the investigators were placed in the difficult position of closing out the trial safely and on short notice."
They add that in its current form, CONVINCE adds little new information to the other recent comparative trials.
They conclude: "In light of ALLHAT, switching appropriate patients to low-dose diuretic therapy would at once improve health outcomes for patients and, one prescription change at a time, whisper an evidence-based reminder to the pharmaceutical industry about the social value and the public health importance of large long-term trials that are successfully brought to completion."