ACC 2009: Peptide Vasodilator for Acute HF Encourages With Performance in Dose-Finding Trial

March 29, 2009

March 29, 2009 (Orlando, Florida) — Given the less-than-rewarding continued search for effective, safe, IV drugs to give to patients with acute heart failure, the outcomes of a limited, dose-finding study of the vasodilating peptide relaxin (Corthera, San Mateo, CA) just might have a lot of clinicians in the field crossing their fingers.

In the Preliminary Study of Relaxin in Acute Heart Failure (Pre-RELAX-AHF), which was scheduled for presentation here today at the American College of Cardiology 2009 Scientific Sessions, a 48-hour infusion of the drug alleviated more dyspnea when given on top of standard medications, at least at one of the tested dosage levels, with the difference just achieving significance at p=0.044. It also seemed to cut the cardiovascular death rate significantly at six months (p=0.046); a potential reduction in rate of cardiovascular death or readmission within 60 days fell short of significance (p=0.053).

Pre-RELAX-AHF is published today online in the Lancet [1] to coincide with its oral presentation by primary investigator Dr John R Teerlink (University of California and Veterans Affairs Medical Center, San Francisco).

Conducted in only a few hundred patients, the study provides no final answers. But it was encouraging in that it was placebo-controlled and double-blind and showed no sign that relaxin, at all but the highest dosage tested, caused kidney or liver dysfunction, hypotension, arrhythmias, electrolyte disturbance, or any other clinically important adverse effect out to 30 days.

Based on the outcomes and safety data, Teerlink and colleagues identified the relaxin dosage of 30 µg/kg per day as optimal for future exploration in more definitive randomized trials.

The designers of the trial, compared with those of prior drug trials in acute heart failure, broke new ground in several ways. One of them was in prospectively entering a specifically defined population, which they followed for a broad collection of clinical end points, not ones based on hemodynamic changes, fluid output, or other surrogates for meaningful clinical outcomes.

"We acknowledged we were going to be underpowered for looking at any one clinical end point," Teerlink told heartwire . "But what we could do is look at the pattern of clinical responses to the therapy and see whether it would perform in a manner consistent with how we thought it should perform."

The clinical end points tracked included symptom relief, worsening of heart failure, hospital length of stay, and clinical outcomes after discharge.

In the end, almost all the outcomes--whether significant or not-- pointed in the "right" direction. "That's the overall pattern we were looking out for."

Selected Effects of Relaxin on the Trial's Primary Treatment Targets vs Placebo (N=60); Results for 10 µg/Kg/Day (N=40) Omitted

End point 30 µg/kg/d (n=42) 100 µg/kg/d (n=37) 250 µg/kg/d (n=49)
Proportion with moderately or markedly better dyspnea at 6 h, 12 h, and 24 h (%) 40, p=0.044 14, p=0.28 22, p=0.86
Worsening heart failure through day 5 (%) 12, p=0.29 14, p=0.40 10, p=0.15
60 d: cardiovascular death or readmission, HR (95% CI) vs placebo 0.13 (0.02–1.03), p=0.053 0.46 (0.13–1.66), p=0.23 0.32 (0.09–1.17), p=0.085
180 d: cardiovascular death, HR (95% CI) vs placebo 0.00 (0.00–0.98), p=0.046 0.23 (0.01–1.79), p=0.17 0.56 (0.09–2.47), p=0.53
180-d all-cause death, HR (95% CI) vs placebo 0.54 (0.14–2.03), p=0.36 0.41 (0.09–1.91), p=0.25 0.08 (0.26–2.47), p=0.70

Eligibility for Pre-RELAX-AHF required that patients have acute heart failure with compromised renal function and systolic blood pressure in at least the normal range--that is, higher than 125 mm Hg. Heart failure had to be confirmed not only on the basis of symptoms but also by increased natriuretic peptide levels.

Past drug trials in acute heart failure have nearly always included a less narrowly defined, heterogeneous population with systolic blood pressures often below, say, 90 mm Hg, Teerlink observed. "Whereas in the real world, that's not usually how it happens." Patients in Pre-RELAX-AHF, he said, reflect a kind of patient frequently seen in clinical practice.

Dr Clyde W Yancy (Baylor University Medical Center, Dallas, TX), who wasn't involved in Pre-RELAX-AHF, told heartwire that the trial deserves kudos for requiring that its patients be randomized to therapy in short order--within 16 hours of admission. That's much earlier than in prior drug trials in acute heart failure.

"That means this is not a study done in patients with failed initial therapy or patients who've been hospitalized for a day or two, who were allowed some acute benefit that was already realized," Yancy said. The trial, he said, "represents a milestone in incorporating many past lessons in the design. . . . One of the huge lessons learned in acute heart failure is how heterogeneous the patient population is. . . . These investigators were thoughtful about their end points, and they were thoughtful about the patient phenotype--which I think is most provocative about the work."

That doesn't mean the drug is ready for emergency rooms everywhere. Yancy cautioned that Pre-RELAX-AHF was only a phase 2 study. "We have to be very careful about how we interpret data from such a small subset and appropriately use the data for the intended purpose, which was to target a dose and then take that dose forward in larger prospectively randomized trials."

An editorial accompanying Teerlink et al's paper [2], from Drs Adrian F Hernandez and Christopher B Granger (Duke Clinical Research Institute, Durham, NC), says that "by targeting patients with normal or raised blood pressure . . . the investigators have focused on patients for whom this type of therapy might be most likely to work. This population is more likely to have preserved left-ventricular systolic function and has much lower mortality than do patients with lower blood pressure."

But, the editorialists continue, "the results of Pre-RELAX-AHF need to be interpreted in light of its exploratory nature, particularly in view of the history of small heart-failure trials in which benefits turned out to be the play of chance. The results are probably too good to be true, in view of the lack of a dose-dependent effect and the surprising effect of a short treatment on postdischarge outcomes, including 180-day cardiovascular mortality. . . . In the final analysis, however, the signals that relaxin was reasonably safe with trends of clinical improvement warrant further investigation in proper outcomes studies."

Interviewed, Teerlink speculated on how short-term relaxin therapy could have a long-lasting clinical effect. "It may be due to chance, but there is biological plausibility and observational consistency suggesting that there may well be a beneficial long-term effect. That biological plausibility is that the patients who were treated and had more rapid improvement in their symptoms also had more rapid improvement in their congestion."

Also, he said--careful to call it more speculation--"by calming the storm of acute heart failure early on, relaxin might be able to decrease the amount of oxidative stress and of potential small but cumulatively important end-organ damage that can occur during the acute heart-failure episode and that can have long-term sequelae."

Teerlink reports receiving research grants from Bristol-Myers Squibb, CardioDynamics, Corthera, Cytokinetics, GlaxoSmithKline, Merck, the National Institutes of Health , and Sanofi-Aventis; and consulting fees from Abbott, Biogen Idec, Corthera, Cytokinetics, Geron, Merck, Niles Therapeutics, Novartis, Sanofi-Aventis, and Scios. Disclosures for the other authors are in the published report. Yancy reports receiving honoraria from theheart.org.

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