Researcher says cost not the objective of study
July 1, 1999 5 minutes read
Researcher says cost not the objective of study
Carvedilol, metoprolol compared but not for price
There has been a lot of press about a recent beta-blocker study conducted at Mount Sinai School of Medicine in New York City and Veterans Affairs Medical Center in Bronx, NY. Researchers randomized 25 CHF patients each to receive either metoprolol or carvedilol to compare the difference in oxidative stress or difference in ejection fraction.
The team first worked up the CHF patients on standard therapy before titrating the beta-blocker. The researchers also measured:
CHF symptoms;exercise;
ejection fraction;
thiobarbituric acid-reactive substances (TBARS) as an indirect marker of free radical activity.
The researchers concluded that aside from carvedilol’s causing greater decline in patient heart rate, there were no clinical differences in the result of the two drugs; both gave the patient the same amount of benefit.
But the message many reports took away from the study: Beta-blockers had the same good effects even when carvedilol cost about three times as much as metoprolol. That, say researchers and some observers, may be too big a jump to make right now.
"The spin on the press has been cost control," says lead researcher Marrick L. Kukin, MD. "But that was not the intention of the study."
Cost analysis was not part of the study design, he says. Rather, it was set up or "powered" so a sample of 50 patients — randomized so half received either of the drugs — would have 80% power to detect the difference in TBARS or ejection fraction beyond what could be expected to happen by chance.
Kukin says the antioxidative properties of carvedilol intrigued him because no one is certain if it has a clinical significance or if it is simply "window dressing" that comes along with the established benefits such as reducing the neurohormonal response to heart failure and improving survival.
TBARS were measured twice at the start of the study, two weeks apart and before any exercise that day. They were then measured again after four and six months on the respective beta-blocker, as well as the other clinical and quality of life measures. Kukin and his team found a parallel decline in TBARS between the two patient groups.
Titrating the beta-blockers
Patients initially took a daily dose of 6.25 mg of beta-blocker for a week. The metoprolol group received 6.5 mg once a day, and the carvedilol group received 3.125 mg twice a day. For the second week, the dose was doubled. In following weeks, the dose was up titrated by doubling the twice-daily dose to a target of 25 mg each. Patients who weighed more than 85 kg were up-titrated to receive 50 mg BID.
There was a difference in delivery of the medication. Carvedilol was available in a dose of 3.125 mg dose, while the initial doses of metoprolol had to be prepared by the pharmacist. But should doctors use only carvedilol to begin titration since it’s available in the smaller dose, then switch to the cheaper drug when higher doses are achieved? Kukin says there is no scientific data showing an advantage of doing so.
If researchers could find such data demonstrating an advantage to switching beta-blockers, pharmacists would be pleased for many reasons, says David S. Roffman, PharmD, BCPS, associate professor of pharmacy practice and science at University of Maryland’s School of Pharmacy in Baltimore and therapeutic consultant for the medical system’s cardiac care unit.
The pharmacist would be happy for a lot of practical reasons, he says. For one, because breaking 50 mg tablets into quarters is inaccurate, he says his pharmacy has to make up 12.5 mg doses from 50 mg tablets.
And, to the pharmacist, cost does become an issue, he says. Metoprolol is cheap and carvedilol isn’t, but there are no convincing trials available now that compare the two.
Furthermore, Roffman says researchers know that beta-blockers provide a shopping list worth of benefit to CHF patients, but which one (or combination of benefits) increases survival isn’t known. And while this study looked at how TBARS change during CHF treatment, both Roffman and Kukin say nobody knows what role antioxidants may play in the treatment of CHF.
Also, it may be significant that this study used equal dosages of both beta-blockers, but at the same dose, both drugs may not be equally effective. Other reports have tested metoprolol at higher doses.
Kukin notes the COMET (Carvedilol or Metoprolol European Trial) study, which is ongoing with 3,000 participants, should provide more answers in how these two beta-blockers compare.
Contributions to CHF management
"I think it is an interesting study," says Tarik M. Ramahi, MD, "but I don’t think it will influence medical management." The director of Yale University’s heart failure and transplant cardiology department says doctors already know both beta-blockers are beneficial. But the study was too small and was not double-blinded to set up comparisons of the two drugs. "This doesn’t tell me that one is better." Ramahi, like Kukin, notes the COMET study should be able to address how the two drugs compare.
Ramahi says the study was designed to look at the difference in TBARS, but it’s still not known how good a predictor they are for antioxidant activity. Still, there may be something to the role of antioxidants in heart failure. But six months may not be a long enough follow-up to begin to see differences in how the different beta-blockers are going to work against oxidative stress.
"The story of antioxidants is a big story," he says. "But it may require longer follow-up to see the outcome effect." There was no difference in effect between the two beta-blockers at the end of this study, but carvedilol could still eventually produce a unique antioxidative effect if given enough time to do so.
The results from the two beta-blockers were as follows:
Metoprolol.— Ejection fraction: Increased from 18 +/- 6.3% to 23 +/-8.7%.
— TBARS decreased from 4.7 +/-0.9 nmol/mL to 4.2+/-1.5 nmol at four months. At six months, TBARS dropped to 3.9+/-1.0 nmol/mL.
— Ejection fraction: Increased from 19+/-8.5% to 25+/-9.9%.
— TBARS were reduced 4.7+/-1.4 to 4.2+/-1.3 at for months. At six months, TBARS fell to 4.1 +/- 1.2 nmol/mL.
Suggested reading
1. Kukin ML, et al. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction and oxidative stress in heart failure. Circulation 1999; 99:2,645-2,651.
2. Di Leonarda A, et al. Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left-ventricular dysfunction dispite chronic metoprolol. J Am Coll Cardiol 1999; 33:1,921-1,933.
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