Boston, MA - Two case-control studies published simultaneously in the January 4, 2007 issue of the New England Journal of Medicine provide some of the strongest-yet evidence that treatment with the ergot-derived dopamine agonists pergolide and cabergoline, commonly used in Parkinson's disease, can cause cardiac valve dysfunction [1,2]. They also suggested that the adverse effect is not caused by some other prescribed dopamine agonists, especially those not derived from ergot.

According to a Perspective accompanying the two studies, the new findings support prior clinical and mechanistic evidence for a link between a histologically distinct fibrotic valvulopathy and treatment with drugs that block the serotonin receptor 5-hydroxytryptamine 2B (5-HT_2B) [3]. Pergolide and cabergoline have that biochemical action in common, while the other studied dopamine agonists don't have significant effects on 5-HT_2B, writes the Perspective's author, Dr Bryan L Roth (University of North Carolina, Chapel Hill).

The two "very careful clinical studies" validate the earlier work and "nail down" 5-HT_2B agonism as the mechanism behind the valvulopathy that has been associated with dopamine agonists and some other drugs, Roth told heartwire. The observed effects were huge, he said. "They were not minor incidences for a side effect. When you consider that these drugs have been on the market now for decades, you wonder how this could possibly have been missed."

In his article, Roth describes how earlier research from his group and others had helped define the biochemical mechanisms behind 5-HT_2B-related valvulopathy and determine that an active metabolite of fenfluramine is a potent agonist of the receptor. That drug in combination with phentermine constituted the diet pill "fen-phen," which was pulled from the market during the late 1990s after reports that fenfluramine and its isomer dexfenfluramine were a likely cause of valvular disease. The underlying biochemical processes were unrecognized at the time.

An association between 5-HT_2B agonism and valve disease, Roth writes, "has now been seen with drugs for diverse indications. . . . Clearly, practitioners should avoid prescribing drugs that are potent 5-HT_2B-receptor agonists, a growing list of medications that now includes ergot derivatives, dopamine agonists, and amphetamine derivatives" used to treat such disorders as migraines, obesity, and Parkinson's disease.

In one of the new studies, Dr René Schade (Charité-Universitätsmedizin Berlin, Germany) and associates identified 31 cases of clinically or echocardiographically diagnosed, new-onset cardiac-valve regurgitation among 11 417 patients in the General Practice Research Database (GPRD) who were prescribed anti-Parkinson's-disease agents from 1988 to 2005.

To be included in the valve-dysfunction cohort, patients had to be free of a variety of heart conditions that can promote the disorder, including rheumatic and congenital heart diseases, some cardiomyopathies, myocarditis, and heart failure; also excluded were those who had taken fenfluramine, dexfenfluramine, phentermine, and ergotamine.

The GPRD, the group explains, encompasses the records of more than 6.3 million patients from 350 general practices in the UK and has been validated and widely used to study a number of diseases.

Each case with valve disease was matched with up to 25 control patients from the large anti-Parkinson's-therapy cohort according to sex, age, and year of entry into the database.

Of the 31 cases, six had been on pergolide and six had been on cabergoline in the previous 12 months. Their adjusted valve-disease incidence rates were sharply and significantly increased compared with the remaining 19 cases who had not been on either drug or any other dopamine agonist—which in this analysis could have included bromocriptine, lisuride, pramipexole, or ropinirole.

In the other new study, from Dr Renzo Zanettini (Istituti Clinici di Perfezionamento, Milan, Italy) and colleagues, 155 Parkinson's patients who had been exclusively taking pergolide, cabergoline, or non-ergot-derived dopamine agonists for at least 12 months and 90 control subjects without the movement disorder underwent echocardiographic assessments of cardiac-valve function performed by blinded operators. The cohort excluded any patient with a history of valvular dysfunction or prior use of ergot-derived agents or the aforementioned diet drugs.

The prevalence of clinically significant valvular regurgitation and of valve-leaflet thickening was significantly increased among patients taking either pergolide or cabergoline, but not those on non-ergot-derived agents, compared with those in the control group, according to Zanettini et al. The mean mitral-valve tenting area, an index for mitral-leaflet stiffening, they explain, was significantly increased compared with controls in all three drug groups and linearly correlated with the severity of mitral regurgitation.

The relative risks of clinically significant regurgitation of the mitral, aortic, and tricuspid valves ranged from 4.2 to 6.3 for patients who received pergolide compared with controls; the corresponding relative risks for the cabergoline group ranged from 4.6 to 7.3. For neither drug did the tricuspid-regurgitation relative-risk increase reach significance, according to the investigators. For both ergot-derived drugs, however, the severity of regurgitation of any valve went up with the mean cumulative dose.

Now that the valvulopathy's molecular basis has been confirmed, according to Roth, "we can make sure that no drugs get on the market that have that action." He said his group has identified a number of "commonly used medications" with 5-HT_2B-agonist activity that could potentially lead to valve dysfunction. With the research submitted for publication but as yet unaccepted, he said, Roth declined to name the drugs or the drug families to which they belong. "Once we publish that data, it will be interesting to go back and do the sorts of large patient studies these two groups did to see whether there is an increased risk of valvular heart disease [in patients taking those drugs]."