Toronto, ON - A long-acting preparation of carvedilol (Coreg-CR, GlaxoSmithKline) designed for once-daily administration is "noninferior" to the off-patent twice-a-day version of the beta blocker with respect to LV hemodynamics in patients with systolic heart failure, according to COMPARE, a randomized study presented here at the Heart Failure Society of America 2008 Scientific Meeting [1]. Its researchers say the controlled-release (CR) carvedilol, compared with the immediate-release (IR) version, is a step forward for the drug in heart-failure patients, many of whom are less likely to stick with a pill prescription that calls for more than once-daily administration, since poor drug compliance tracks with poorer outcomes.

The similar effects the two preparations had on echocardiographic results and biomarker changes in the 24-week trial "demonstrate comparable efficacy between the CR and IR preparations and support the use of Coreg-CR in treating patients with systolic heart failure," Dr Barry H Greenberg (University of California, San Diego Medical Center) said when presenting the study. "The demonstrated benefits of a once-daily preparation on compliance raise the possibility that use of Coreg-CR may further improve outcomes in heart-failure patients with systolic dysfunction."

Some at the meeting who viewed Greenberg's presentation cautioned that the trial looked primarily at end points that were only rough surrogates for outcomes and didn't actually test whether once-daily dosing would promote treatment compliance. Other observers questioned the motivations behind the trial and whether it was really needed, given what seem like comparable effects from beta blockers generically available at a much lower cost.

Clinical-trial data support the use of only bisoprolol, metoprolol succinate, and carvedilol in systolic heart failure out of all the available beta blockers, observed Dr Gregg C Fonarow (Ahmanson- University of California, Los Angeles Cardiomyopathy Center), who presented a commentary on COMPARE after Greenberg's presentation.

The FDA has already stated that CR carvedilol can be given for the same mortality-reduction indication in systolic heart failure and post-MI LV systolic dysfunction that it had approved for the twice-daily version based on its pharmacokinetic and pharmacodynamic definitions of bioequivalence, Fonarow observed. Under the FDA's definitions, he said, clinical comparability is assumed from the bioequivalence.

COMPARE, according to Fonarow, suggests that in heart-failure patients the FDA's assumption may be right. Although the trial has important limitations, he noted, it was well-designed and demonstrated noninferiority of the CR version of carvedilol with respect to the primary end point of change in LV end-systolic-volume index (LVESVI). And "the two carvedilol preparations appeared comparable for a variety of secondary end points—including LVEF and B-type natriuretic peptide [BNP]—and adverse events in the context of a controlled trial. This study provides additional data to suggest comparable clinical efficacy of these two preparations."

But the trial had limitations, Fonarow observed. As Greenberg had reported, its primary end point was altered midstream, from change in LV ejection fraction [2] to change in LVESVI, when an interim analysis showed higher-than-expected end-point variability and patient dropouts. Also, Fonarow said, the trial featured mostly surrogate end points and "did not actually test the influence of once-daily dosing of carvedilol CR on left ventricular function" or on treatment compliance. COMPARE was not only double-blind, but to ensure it stayed that way, it was "double-dummy," in that patients randomized to the CR preparation still had to take placebos replicating the IR version.

"Whether there are meaningful clinical differences in the real world of a once-daily preparation administered once daily, that remains to be determined," Fonarow said.

Also to be determined is whether a lot of physicians will prescribe a proprietary CR preparation that replicates the effects of the generically available version. Speaking from the audience after Greenberg and Fonarow, Dr Sidney Goldstein (Henry Ford Hospital, Detroit MI) commented that "in my understanding, carvedilol actually resides on the [beta] receptor for very long time, so the fact that it's given twice a day is somewhat questionable in general."

The twice-daily standard dosing for carvedilol, he offered, was probably due to the twice-daily dosing used in the clinical trials, not necessarily because of its biochemical action. "In fact, you can probably get the same effect with once-a-day [IR] carvedilol than you can with twice-a-day [IR] carvedilol, because of its residual time on the receptor," Goldstein said.

"I'm concerned that this [trial] really is a very good way of removing generic carvedilol twice daily, and a good sales pitch for the once-a-day long-acting carvedilol. It's somewhat disturbing to me," particularly, he said, when the justification is once-daily use for better compliance. "You could give [IR] carvedilol once a day, it's almost the same pharmacologic effect as the bid dose, without having to go to the added expense of giving a once-a-day carvedilol preparation."

Greenberg replied, "Without getting into a great debate here, I would challenge that comment about the adequacy of carvedilol in the IR preparation in occupying the receptor for a 24-hour period, and I think there is an advantage in giving a once-daily preparation as far as compliance is concerned."

But then, Dr Udho Thadani (University of Oklahoma Health Sciences, Oklahoma City) stood up and drily persisted with the issue of cost. "I can send my patients to Wal-Mart for four-dollar carvedilol. And I'm going to recommend to them to spend a hundred dollars on the CR preparation, especially when the banks are going bust?"

Greenberg acknowledged that it was a "good point" that the trial didn't show better clinical efficacy with the CR preparation, but said, "I think that in some patients, particularly those who are younger and taking fewer medications, switching to a once-daily drug does improve compliance, and I believe that with better compliance, better outcomes could be expected."

The 253 patients who completed the COMPARE trial had stable, chronic, mild to severe ischemic or nonischemic heart failure and an LVEF <40%. They had been randomized to receive carvedilol CR (10 mg once daily, titrated to a maximum of 80 mg once daily) or carvedilol IR (3.125 mg twice daily, titrated to a maximum of 25 mg twice daily), with placebos according to the double-blind, double-dummy design.

Echocardiographic, hemodynamic, and biomarker changes in COMPARE trial, CR vs IR carvedilol

End point	CR carvedilol, n=125	IR carvedilol, n=128	p
Change in LVESVI* (mL/m2)	-20.8	-18.4	0.98
Change in LVEF (percentage points)	+8	+8	NS
Change in systolic BP (mm Hg)	+7.5	+1.4	0.0005
Change in BNP (pg/mL)	-96.7	-102.8	NS

The only finding that would be unexpected for two bioequivalent drugs, Fonarow observed, was the relative increase in systolic blood pressure with the CR preparation. "You could speculate potentially that differences in the release kinetics, peaking with carvedilol IR a little earlier than carvedilol CR, and the timing relation to study medication could account for this difference, but the caveats are that this was a single measurement and it was not assessed repetitively over the course of this study," he said, and all the other measured parameters were consistently comparable. "With all those caveats, perhaps this was just a statistical fluke."

Trial steering committee members Greenberg, Dr Edward M Gilbert (University of Utah, Salt Lake City), Dr Mandeep Mehra (University of Maryland School of Medicine, Baltimore), and Dr John Teerlink (University of California, San Francisco) report "receiving honoraria for their efforts as consultants for COMPARE"; the trial was sponsored by GlaxoSmithKline. Fonarow discloses that he has consulted for GlaxoSmithKline, Medtronic, Novartis, and Scios; has received research support from Medtronic, GlaxoSmithKline, and Pfizer; and has received honoraria from GlaxoSmithKline, Medtronic, Pfizer, Novartis, and Merck.