Carvedilol, what is it? Wonder drug or just a high-priced beta blocker?
Cost-effectiveness remains a question
The new drug carvedilol promises to enhance clinical outcomes for patients with congestive heart failure (CHF), but whether the therapy will prove cost-effective remains to be seen. A month ago, carvedilol (Coreg) won preliminary approval from the U.S. Food and Drug Administration (FDA) in Rockville, MD, for use for CHF. The third-generation beta blocker already had FDA approval for treating hypertension, but its manufacturers, Boehringer Mannheim Therapeutics in Gaithersburg, MD, and SmithKline Beecham in Philadelphia decided to keep Coreg off the market until it was approved for CHF patients. In recent months, carvedilol has been cleared for marketing for heart failure in Canada, Denmark, Spain, Sweden, Norway, and other countries.
Just an expensive beta blocker?
New drugs typically are more expensive than ones that have been on the market for awhile. Cost Management in Cardiac Care asked Penelope Carlson, RN, BSN, cardiovascular research coordinator at Florida Hospital in Orlando, what she thought of carvedilol’s cost-effectiveness. "It’s too early to tell, but if carvedilol’s benefits live up to expectations, indeed they may outweigh the economic issues," she says.
Medications for heart failure are generally in the $600 to $1,000 a year range. Whether carvedilol will fall in that range remains to be seen. A manufacturer’s representative says the agent, when marketed, will likely be competitively priced.
If carvedilol were applied to the 2-to-3 million Americans who have heart failure, "we’re talking about spending $2 billion per year for the one drug," says John Wilson, MD, a cardiologist at Vanderbilt University in Nashville, TN. Vanderbilt was one of the centers running clinical trials on the appropriateness of carvedilol’s use for CHF until the multicenter trials were discontinued about a year ago. (See the related story on carvedilol’s clinical trials, p. 44.) "The manufacturer may argue that the drug offers benefits worth the $2 billion," says Wilson. "It’s not clear from the data so far whether frequency of hospitalization may be reduced. And if the drug prolongs survival, that will increase the total cost of health care from a practical standpoint. The question remains: Is carvedilol a unique substance that is worth the additional cost, or just an expensive beta blocker?"
When carvedilol comes on the market for use for heart failure, physicians likely will prescribe it in quantities of 12.5 mg to 50 mg. The typical hypertensive patient would probably take about 50 mg.
"Heart failure and hypertension dosages can overlap," says Wilson, "but the majority of patients with heart failure do not have hypertension." Many patients have hypertension before they develop heart failure, but once CHF develops, the failure of the ventricle eliminates hypertension.
Carvedilol is a multiple-action cardiovascular agent designed to improve the biology of the failing heart. The agent produces two complementary pharmacologic actions mixed venous and arterial vasodilatation and non-cardioselective blockade. "Carvedilol is an antioxidant, and that may contribute to its therapeutic effect," says Wilson. Carvedilol may be superior to pure beta-blockers in the treatment of CHF through its mechanism of action by blocking not only beta receptors but also alpha receptors, which would allow vasodilatation to reduce the afterload on the failing heart.
"The original design of the trial was not to see if patients would live longer," says Wilson. "Its purpose was to see if the agent made them feel better, as measured by exercise testing and quality-of-life questionnaires." (See charts on the effect of carvedilol on CHF, above, and the death rate from CHF, p. 43.)
It’s customary for a safety committee to monitor clinical trials to see if patients who are taking either the tested drug or the placebo are suffering untoward outcomes due to their participation. In this case, the committee watched to see if participants were getting worse on carvedilol. To their surprise, they found that the drug was demonstrating a survival benefit. There was a considerably higher death rate in the placebo group than in the carvedilol group over 48 months, suggesting the drug was helping people live longer. When the numbers became statistically significant, the study was discontinued prematurely on ethical bases.
FDA approves drug
The survival information was taken to the FDA. At first, approval was delayed when agents there determined that, though the finding was striking, the numbers were not high enough to justify a final decision regarding carvedilol’s efficacy. Typically, a study that looks at survival in heart failure contains more than 1,000 participants. The four studies on carvedilol were limited to 400-500. Unapproved at that point, the drug was distributed free on the basis of compassionate use to heart-failure patients. Meanwhile, the New England Journal of Medicine published an article favorable to the agent and states that the drug reduced mortality in heart failure patients by 65%.1 An editorial in the same issue urged caution.2 In February, carvedilol’s manufacturer presented to the approval committee data from the clinical trials and new analyses of previous data. FDA officials concluded that carvedilol reduced death and hospitalization rates in patients by 35%.
"Whenever you launch a new drug, there are unanticipated side effects," says Wilson. "We saw some with carvedilol. Large doses at the outset can cause a serious drop in blood pressure and worsen heart failure. Dosages need to be titrated upward very gradually over long periods of time to make certain patients can handle the drug."
For these and other reasons, investigators worry that if carvedilol is released for general consumption by every physician treating heart failure, the drug may cause problems initially. Some experts propose that carvedilol not be released for general consumption, but be limited to professionals who take care of heart failure exclusively. "Such limits are unlikely, however," Wilson says.
From a cost-effectiveness standpoint, then, overprescribing when carvedilol first comes on the market could cause an expensive jump in hospital admissions for hypotension and other side effects."The original design of the study was to show reduced hospitalization, improved symptomatology, and the traditional benefits," says Wilson. "The study was stopped, not because those were achieved, but because the drug had a beneficial effect on survival. It’s effect on the other factors is still unclear."
For disease management
CMC asked Wilson if carvedilol should be considered more of a preventive than a treatment, as asserted in an editorial that accompanied publication of the four clinical trials. "If the agent prolongs survival, we have to call it a treatment," he says. "However, carvedilol should not be used acutely to treat heart failure but should be used to manage the disease."
The agent should not be used on patients with severe unstable heart failure, bronchial asthma, or certain cardiovascular conditions including flaws in the electrical conduction of the heart, or bradycardia. Those caveats hold for ACE inhibitors as well. They are not used in large doses for acutely ill patients because of their dramatic adverse effects.
CHF affects 4.7 million Americans and is the single most frequent cause of hospitalization for the over-65 population.
References
1. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334:1,349-1,355.
2. Pfeffer MA, Stevenson LW. Beta adrenergic blockers and survival in heart failure (editorial). N Engl J Med 1996; 334:1,396.
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