Long Unsuccessful Heart Failure Drug Once Again At Center Of Controversy

–The long, strange 30-year journey of BiDil.

It’s been buried in the avalanche of related news but there’s an interesting and somewhat bizarre cardiology angle to the debate over Trump’s nomination of Tom Price to be the next HHS Secretary.

ProPublica reported on Friday that last summer Price went to bat for the makers of an unsuccessful heart failure drtug after receiving a campaign donation from the drug’s manufacturer. For more than a decade now the drug, BiDil (the combination of two generic drugs, hydralazine and isosorbide dinitrite, or H-ISDN) has been a controversial and spectacularly unsuccessful cardiology drug.

BiDil is now owned by Arbor Pharmaceuticals, which is headquartered in Price’s Atlanta district. According to ProPublica’s Robert Faturechi, Price pressured the federal Agency for Healthcare Research and Quality (AHRQ) on numerous occasions to remove a 2009 study about the drug from the agency’s website. The episode is “the latest example of how public policy and industry matters converged in the congressional career of Price, who is a physician,” writes Faturechi.

One bizarre part of the story is that the paper Price and Arbor want removed is extremely innocuous, and unlikely to influence, either favorably or unfavorably, any intelligent decision about use of the drug. At face value the study, which was also published in Clinical Therapeutics, appears negative. The paper concludes that there was no improvement with BiDil in mortality or hospitalization based on race or ethnicity. The problem for Arbor, of course, is that BiDil’s entire raison d’être is that it has a uniquely beneficial effect on African-Americans with heart failure.

But the study authors scrupulously acknowledge the inevitable limitations of their retrospective cohort study: “It is possible, or even likely, that unmeasured differences in important risk factors—particularly heart failure severity and left ventricular dysfunction—between the group that received H-ISDN and the one that did not masked a beneficial effect of H-ISDN. Therefore, our conclusions must be regarded as hypothesis generating and need to be tested in subsequent randomized trial(s).”

This is a model for responsible publishing of observational studies. It’s difficult to imagine how removal of the paper from the AHRQ website could benefit the drug, though I suppose that the demonstration of the company’s political muscle might convey some broader message to regulators and others vulnerable to political pressure.

BiDil’s Important Past

What will inevitably— and understandably— be lost in any discussion about this episode is the fact that BiDil, despite its commercial failure, has an important history going back more than 30 years. Indeed, BiDil played a key role in two major medical revolutions.

Thirty years ago in 1986 the V-HeFT 1 trial sparked a transformation in the treatment of heart failure. It was the first trial to demonstrate that drug therapy (using the generic drugs that now compose BiDil) could save lives in heart failure. It’s hard to fully appreciate the impact of this trial now, since many different classes of drugs now have been shown to significantly extend the lives of heart failure patients. V-HeFT was soon followed by a series of trials showing that a new class of drugs, ACE inhibitors, could also improve mortality. Subsequently, the V-HeFT-2 trial showed that ACE inhibitors were superior to H-ISDN. Inevitably, nearly all interest in generic H-ISDN faded as research and commercial interests swivelled to the superior and highly profitable new drug classes.

Prior to V-HeFT-1 many cardiologists and other experts thought that treatment for people with advanced heart failure should focus exclusively on palliative measures, since it was widely believed and feared that heart failure was irreversible and not amenable to therapy.

There was one strand of research that kept interest in H-ISDN from dying out entirely. At the time, many cardiologists suspected that ACE inhibitors were less effective in African-American patients, since data showed a diminished response in African-Americans with hypertension. They believed that African-Americans were less likely to respond to these drugs and more likely to respond to vasodilator drugs like H-ISDN. This line of thought gained support from a controversial subgroup analysis of the V-HeFT study, which suggested to some that African-Americans responded better than others to H-ISDN. But this difference did not achieve statistical significance and was not broadly accepted.

This was one of the earliest and, even then, highly controversial examples of what is now known as precision or genetic-based medicine. A company, Nitromed, was founded to develop H-ISDN exclusively for African-Americans. But critics said that the African-American indication pursued by the company was based not on data but on the commercial opportunity based on the company acquiring intellectual property rights to the indication. Despite its early promise NitroMed was never able to turn BiDil into a successful product. In 1997 the FDA turned down approval of the drug for African-American heart failure patients. The widely criticized subgroup analysis of V-HeFT 1 did not meet the FDA’s standard for approval. NitroMed then performed a new study, the African-American Heart Failure Trial (A-HeFT), which was positive and served as the basis for the drug’s approval in 2005.

But with the exception of doctors with ties to NitroMed the overwhelming majority of cardiologists had little interest in the drug. For one, many questioned the scientific usefulness of a race-based indication. Perhaps even more important, cardiologists and patients objected to the higher cost of the brand name drug. In 2009 NitroMed failed.

It’s unclear what Arbor hopes to gain from this drug, which has consistently failed to deliver on all hopes and promises of commercial success, though I have heard that the company is making a profit on the drug.

The involvement of Price at this time suggests that BiDil is once again surfing the crest of another historical wave. Price has often claimed that he wants to remove all barriers between doctors and their patients, but in practice he appears only to be concerned about the role of government in this relationship. He certainly does not appear to have any concerns about commercial involvement, though, as evidenced by the recent revelations about his numerous relationships with pharmaceutical companies. There should be no illusion that in seeking to remove a paper critical of BiDil from the AHRQ website Price is supporting the best interests of either doctors or heart failure patients. Price’s actions are fueled by commercial considerations alone; there is simply no significant pent up interest in BiDil in the clinical community.