Toronto, ON - Investigators testing 3,5-diiodothyropropionic acid (DITPA), a thyroid hormone analog, in patients with heart failure should be given an A+ for creativity, said one expert, even though their investigation was stopped early because the drug tended to worsen heart-failure symptoms. Despite the high discontinuation rate, the drug had positive secondary end points, which included reducing vascular resistance, weight, and cholesterol levels.

"Since I'm up here talking, I get to speculate about the future of DITPA or other thyroid hormone analogs, and one possibility is that you could continue with this agent at a lower dose and it would be better tolerated," said Dr Steven Goldman (Southern Arizona Veterans Affairs Health Care System, Tucson) during the late-breaking clinical trials session here at the Heart Failure Society of American 2008 Scientific Meeting. "The other obvious potential is to use thyroid analogs as weight-loss agents. . . . The other possibility is to use DITPA as an adjuvant to treat hypercholesterolemia in patients who are having trouble with statins."

Goldman and colleagues have been working with thyroid hormone and its analogs for many years and have shown that it improves left ventricular function in animal models. DITPA has also been shown to increase cardiac output, decrease vascular resistance, decrease left ventricular end-diastolic pressure, and increase angiogenesis.

Moving into this phase 2 randomized controlled trial, the investigators randomized 57 NYHA class 2-4 heart-failure patients to DITPA and 29 to placebo. In terms of the primary end point, a composite of heart-failure morbidity/mortality, change in NYHA class, or change in patient global assessment, DITPA tended to worsen heart-failure symptoms, a finding that was driven primarily by worsening patient assessments. The drug was not well tolerated—44% discontinued DITPA early—and the hospital review board stopped the study because of concerns about side effects and futility of reaching the primary end point. Interestingly, patients treated with thyroid hormone analog lost 11 lbs and reduced their total-cholesterol levels 20% and LDL-cholesterol levels 30% compared with placebo.

Goldman said, however, that the study results were "painful," and told the audience that the VA setting is not the place to conduct phase 2 studies with investigational compounds. He added they did not have the proper resources to conduct a dose-ranging study prior to this investigation, something that increased the likelihood the trial would fail. Dr Gary Francis (Cleveland Clinic, OH) gave the investigators the A+ for creativity, but a critical C+ for study execution.

Goldman has received a patent for DITPA, which was assigned to the University of Arizona. The university has licensed DITPA to Titan Pharmaceuticals, and Goldman owns stock in Titan and has previously received consultancy fees from the company.