STERLING's COROTROPE (MILRINONE) ORAL RECOMMENDED AS LAST-RESORT TREATMENT OF CONGESTIVE HEART FAILURE BY FDA CMTE.; AGENCY MAY REQUIRE ADDITIONAL STUDIES

Oral milrinone should be approved as a last-resort treatment for congestive heart failure, FDA's Cardio-Renal Drugs Advisory Committee agreed at its Dec. 7 meeting in Bethesda, Maryland. While the recommendation to approve Sterling's oral version of the inotropic agent carried by a narrow five-to-three vote, the committee unanimously supported approval of the intravenous formulation for short-term management of congestive heart failure. Sterling currently markets its first generation I.V. product Inocor (amrinone) for that use. "For patients who remain symptomatic on digitalis and diuretics, vasodilators or [angio-tension] converting enzyme inhibitors, or persons for whom digitalis is contraindicated or for whatever reason is toxic, I think [oral] milrinone might play a limited role," committee reviewer Milton Packer, MD, Mt. Sinai Medical Center, declared. "Under these circumstances, I could set it being approved pending further studies to clarify more widespread approvability." However, FDA remains unlikely to approve oral milrinone until certain safety questions are resolved, Cardio-Renal Drug Division Director Raymond Lipicky, MD, indicated. Specific issues include the identification of a target population and the drug's potential proarrhythmic effect. Citing the example of captopril (Squibb's Capoten), approved with restrictive labeling for hypertension in 1981 and congestive heart failure in 1982, Lipicky stated: "We have in the past approved a drug with [a limited] indication because of some safety reason . . . [and because it was] effective in the population where the risk and benefit ratio came out appropriate. It turns out [Squibb's] trials did have a population to find that out." The FDAer related subsequent regulatory developments. "The last time an issue of limiting the indication for safety reasons came to this committee, the committee said no," Lipicky continued. "If the trials don't include the patient population randomized for that indication, if the trials don't show that the drug is effective . . . there is no reason [for approval], so I guess that at this moment in time . . . the FDA would be reluctant to accept a recommendation [that oral milrinone be approved]. Sterling's NDA for the oral formulation, submitted to FDA in March 1987, include four clinical trials encompassing more than 1,500 patients. One three-month study of 230 patients (560 total), which evaluated the drug's efficacy as a substitute for digitalis in 32 centers, was considered pivotal. However, the committee could not identify a second trial to support the drug's approval. Additional studies are underway to evaluate oral milrinone in combination with and in comparison to ACE inhibitors and digitalis, Sterling said. The company is also conducting a long-term survival study. Like the pivotal trial, the other three studies enrolled patients who were still symptomatic when receiving digitalis and diuretics, but they differed somewhat either in design or principal endpoints. Results of those additional trials did not uniformly support the efficacy of milrinone, according to the panel. "We have problems trying to meet the letter of the regulations that require two well-controlled trials for the therapeutic indication," medical reviewer Joel Morganroth, MD, Hahnemann University, commented. "The question to the committee is whether or not the entire data base is sufficient." Considering the milrinone data base as a whole, Morganroth concluded, "we were willing to try 10 mg q.i.d." as a substitute for digitalis in New York Heart Association Class II and III patients whose ejection fraction was 20% or greater. "From a safety point of view, we were not convinced that there was evidence that milrinone decreased mortality," he added. While continuing diuretic therapy, patients in the pivotal trial were randomized into one of four treatment groups: digoxin alone, milrinone alone, digoxin plus milrinone, and placebo alone. The study's endpoints were exercise tolerance and frequency of cointervention. Complicating the analysis, Sterling said, was the fact that a disproportionate number of patients with poor ejection fraction rates were randomized into the milrinone group. "The distribution of patients by baseline ejection fraction, however, did reveal an imbalance of randomization, that is, more patients with reduced ejection fraction were randomized to receive milrinone," Sterling consultant Robert DiBianco, MD, Washington Adventist Hospital, explained. "This imbalance is important to recognize because of the observation that the baseline ejection fraction was the only significant independent prognostic indicator of cointervention and survival." DiBianco reported that in terms of exercise tolerance, patients on either milrinone or digitalis showed significant increase versus placebo, 83 seconds and 65 seconds, respectively. Combination treatment, that is milrinone plus digitalis improved exercise tolerance 48 seconds, but at the twelfth week, significance was not reached against placebo. About half of the placebo and milrinone patients completed the study. "Improvement of excercise tolerance with milrinone [in patients completing three months of therapy] was significantly better than with digitalis, which produced a 78 second increment, or combination treatment, which produced an increment of 58 seconds," DiBianco added. "These findings, however, are limited by the higher percentage of patients who completed 12 weeks of therapy on digitalis, 77%, and the higher number of patients who completed on combination therapy, 60%. Both were significantly greater than on milrinone, at 49%." DiBianco reported that 62 of the 230 randomized patients, or 27%, required cointervention. The mean ejection fraction in these patients was 17.4%, compared to 26.4% in the 168 patients not requiring cointervention. Adjusted for the imbalance of distribution by ejection fraction, the frequency of cointervention was greatest in the placebo group, at 45%. The lowest requirement for cointervention occurred with digitalis or milrinone/digitalis combination treatment, at 10% and 11%, respectively. Milrinone reduced the requirement approximately in half, from 45% in the placebo to 23%. "In the exercise trial, you really can't compare the digitalis-treated group to either digitalis alone or digitalis plus milrinone because the dropout rate in the digitalis-treated groups was much lower," Packer observed. "In fact, one finds that the patients who did not improve during the trials were more likely to be retained in the study on digitalis or digitalis plus milrinone and their exercise tests would [diminish] over the course of time, whereas patients who didn't improve, if they were treated with milrinone, tended to drop out of the study." Packer also noted that patients who did not get to two weeks of therapy were not carried forward in the study results and, therefore, did not contribute to the final analysis. "There is an imbalance in the four groups with respect to the number of people who reached the two-week endpoint -- of patients treated with placebo, nine did not; digitalis plus milrinone, seven; digitalis only, two; and milrinone, 12," he pointed out. "There were patients who were randomized to milrinone who apparently fell out of the study before getting to two weeks and if one looks why, it would appear that a number of those patients had worsening heart failure."