The Calcium Channel Blocker Verapamil (COVERA HS) For High Blood Pressure - Manufacturer Halts Important Clinical Trial

On April 23, 2003, the Journal of the American Medical Association published the available results of an aborted clinical trial comparing controlled release verapamil (COVERA HS), a calcium channel blocker, to the diuretic (water pill) hydrochlorothiazide (HYDRODIURIL) or the beta-blocker atenolol (TENORMIN). This trial goes by the acronym CONVINCE (Controlled Onset Verapamil Investigation of Cardiovascular End Points) and was designed to test the effects of these drugs in preventing stroke, heart attack, or cardiovascular disease related death in patients with high blood pressure.

The manufacturer of Covera HS, who was also the sponsor of the CONVINCE trial, gave only “commercial reasons” for stopping the trial early.

The original manufacturer of Covera HS was the G.D. Searle Company, a subsidiary of Monsanto. Monsanto was purchased by Pharmacia, now in merger negotiations with Pfizer, Inc. If the merger goes through, and it almost certainly will, Pfizer will be the owner of two popular, and expensive, calcium channel blockers that have not been shown to be as good as inexpensive diuretics in preventing heart attack and stroke in patients with high blood pressure. The other Pfizer drug is amlodipine (NORVASC). See the February 2003 newsletter about the comparison between amlodipine and diuretics.

In this article, the CONVINCE trial will be examined on two levels. First, what was learned from this trial, even though it was not completed? Second, what are the ethics of a drug company who recruited subjects (patients) into a clinical trial that is stopped for commercial reasons?

CONVINCE involved 16,602 patients, all over age 55, with high blood pressure and one or more risk factors for cardiovascular disease (for example, diabetes or cigarette smoking.) This study was large and well designed. It would have helped to answer meaningful questions for both patients and physicians about which drug or drugs are best for reducing the serious risks that accompany chronic high blood pressure such as heart attack and stroke.

Because CONVINCE was stopped early its results are inconclusive and it cannot count as a long-term trial. Unfortunately, it adds little new information. However, Covera HS was associated with higher risks for heart failure and death or hospitalization for bleeding. Comparing Covera HS to hydrochlorothiazide and atenolol together, the results were similar in preventing stroke, heart attack, or cardiovascular disease related death. But, low-dose hydrochlorothiazide may be better than Covera HS for preventing cardiovascular illness and deaths.

CONVINCE does provide additional support to what the National Institutes of Health and the Health Research Group have been saying for years: low-dose hydrochlorothiazide should be the first drug used in the treatment of mild to moderate high blood pressure.

The premature stopping of CONVINCE for commercial reasons raises an important ethical issue. Patients who consent to be research subjects in clinical trials may do so for purely altruistic reasons. They often expect nothing for themselves. They are helping to advance medical science and their actions may help other people just like them at some time in the future because important questions have been answered.

However, these unselfish human research subjects do expect that the data, results, and answers that can only be generated because of them will be widely distributed to the medical community for the benefit of the public. The stopping of CONVINCE early violated the trust and implicit expectations of those who volunteered to participate in the trial. An important question that should have been answered was not answered for commercial reasons.

CONVINCE is only one example of the inherent conflict between the ethics of business and the ethics of science. Human research volunteers are being treated by the pharmaceutical industry as commercially expendable pawns in the development and promotion of drugs. If the research is positive the industry will follow the ethics of science and gladly distribute the results. On the other hand, if the research does not shine a bright light on the economic potential for a drug, the industry reverts to the ethics of business and the research may never see the light of day.

Although there are sound ethical reasons for prematurely terminating clinical trials, a commercial reason is not one of them. If it is clear from the analysis of interim results that a drug is dangerous a trial must be stopped early. Likewise, if it is clear from interim results that a drug offers a substantial benefit, ethics demands that the trial be stopped and those subjects in the control group not on the beneficial drug be offered it.

Pharmaceutical industry research is losing credibility in part because human research subjects are viewed as simple cogs in a commercial process. As the industry’s credibility continues to erode, physicians will become more reluctant to suggest to their patients that they participate in clinical trials and patients will be less willing to become human research subjects. New drug development cannot proceed without patients who agree to participate in clinical trials.

Is there a solution to the industry’s sagging credibility? There is and it will not come from the marketplace. The drug laws and regulations that have evolved in this country over the last century have done two things. First, they have usually protected Americans from shoddy, untested dangerous drugs. Second, they have prevented the marketing of poor quality pharmaceuticals that were not tested for safety or that made claims about effectiveness that could not be supported. These regulations have literally given the pharmaceutical industry credibility and because these regulations are science based they dragged drug companies into the scientific age.

The problem of early termination of the CONVINCE trial and the industry’s failure to publish economically unfriendly research about their products can only be solved by regulation. The informed consent document that all human subjects must sign before participating in a clinical trial must contain language that clearly states that a trial will not be stopped for commercial reasons and that all results of the trial will be widely disseminated to the medical community. If a company violates this language, human research subjects will have the option of litigation against a company for failing to live up to its research agreement.

What You Can Do

With regard to the incomplete results of CONVINCE: You should be started on a low-dose thiazide diuretic if you have been diagnosed with mild to moderate high blood pressure. If you are now being treated for high blood pressure and your treatment does not include a thiazide diuretic, ask your physician why not.

With regard to clinical trials: You should not participate in clinical trials unless there is a written assurance in the informed consent document that the study will be complete and the results widely distributed to medical professionals.