Company Fails To Disclose Details About Heart Failure Risk of Drug Reply

Boehringer Ingelheim failed to fully disclose data suggesting that one of its drugs, pramipexole,  a dopamine agonist sold under the brand name of Mirapex, is associated with a significantly increased risk of heart failure, according to a recent news report. The drug, which was originally developed for the treatment of Parkinson’s disease, is now also used to treat Restless Legs Syndrome.

Although cardiac failure was an adverse event observed during clinical trials with Mirapex, and is mentioned in the drug’s label, a more definite association had not been established in the literature until recently. According to Pharmalot’s Ed Silverman, however, Boehringer Ingelheim appears to have been aware of the stronger association previously but made no effort to publish or disseminate its findings.

A study published in Pharmacoepidemiology & Drug Safety found an increase risk of cardiac failure associated with pramipexole and another dopamine agonist, cabergoline. But buried in the text of the report lies evidence that the finding should not have come as a surprise to Boehringer. Silverman writes:

The introduction to the study, which was entitled ‘Dopamine Agonist Use and The Risk of Heart Failure,’ noted that, “recently, adverse events of heart failure have been observed in association with the dopamine agonist pramipexole (the chemical name of Mirapex) in randomized trials.” The authors cited Boehringer “internal data” and a “personal communication from Dr. Bartels.”

The reference was to Dorothee Bartels, who is corporate vice president and head of global epidemiology at the drugmaker. She provided the results of a pooled analysis from randomized Mirapex trials. Specifically, the introduction mentions a “signal of a potential risk of heart failure arose in pooled data from 26 placebo-controlled, randomized trials” in Parkinson’s and RLS patients.

Those trials involved 4,157 patients who were taking Mirapex and another 2,280 on a placebo, but the outcome was too small to draw reliable conclusions, the authors wrote, and raised questions about the potential for the risk to occur with other dopamine agonists. This led them to conduct the study. Yet those 26 trials were never made available. It is also not clear how far back they go in time.

A study author told Silverman that Boehringer did not supply him with the underlying data. The author told Silverman that “the only data I have are in the paper – rates, numbers, etc.”

Silverman asked Boehringer about the data, but only received information about new product labeling for the drug which contains “language related to cardiac events, and specifically heart failure or cardiac failure. Post-marketing surveillance studies continue to assess the safety and efficacy of our products… We continue to work closely with the FDA to ensure our products are appropriately labeled and are used safely.”

Silverman notes that the current label is identical to the 2006 label, but with the addition of one sentence in the post-marketing experience section: “In a pharmacoepidemiological study, pramipexole (Mirapex) use was associated with an increased risk of cardiac failure compared with non-use.”

Silverman quotes extensively from Harlan Krumholz, who spoke about the issue:

I am disturbed that there seems to be a pooling of internal data indicating a potential problem with heart failure and there has been no opportunity for independent review.

This is an ideal situation where sharing of individual patient-level data with the entire research community, or at least with independent investigators, can provide information about the risk that was conveyed in the company’s personal communication to their consultant.

Such sharing would deflect concerns that the company is hiding something and allow a fair evaluation of the risk. With no record in the medical literature and no sharing of the data, we are left to wonder about these risks and the reason that the company has not been more forthcoming. I applaud them for doing analyses on harm, but they need to go further.

The privilege of selling a product should be accompanied by the responsibility to share data you have that is germane to the risks and benefits of the drug. Patients deserve access to information that could influence their decisions about clinical strategies. If it is true that the company has data from their trials that is relevant to concerns about the drug’s safety profile and that data has not been shared, then I hope they will move quickly to make it available.

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