BERLIN, Jan. 4 -- The ergot-derived dopamine agonists Permax (pergolide) and Dostinex (cabergoline) are associated with an increased risk of cardiac-valve regurgitation, two groups of European researchers reported.
The frequency of clinically important valvular heart disease was significantly increased in patients taking these drugs but not in those taking non-ergot-derived dopamine agonists, according to two independent reports in the Jan. 4 issue of the New England Journal of Medicine.
In the first study, Ren Schade, M.D., of Charit-Universittsmedizin Berlin, and colleagues, used data from the United Kingdom General Practice Research Database to identify a population-based cohort of 11,417 patients, 40 to 80 years old, treated with anti-Parkinson's drugs from 1988 to 2005.
In a nested case-control analysis within this cohort, each patient with newly diagnosed cardiac-valve regurgitation was matched with up to 25 controls from the cohort, according to age, sex, and year of entry into the cohort. The mean age at study entry was 69, and the mean duration of follow-up was 4.2 years.
Using conditional logistic-regression analysis, the researchers found that the potent 5-hydroxy-tryptamine 2B (5-HT2B) agonists, Permax and Dostinex, were significantly associated with cardiac valve disease affecting the mitral, aortic, and tricuspid valves.
Of 31 case patients with newly diagnosed cardiac-valve regurgitation, six were currently taking Permax, six were taking Dostinex, and 19 had not been exposed to any dopamine agonist within the previous year.
The rate of cardiac-valve regurgitation increased with current use of Permax (incidence rate ratio, 7.1; 95% confidence interval [CI], 2.3 to 22.3). Dostinex also increased the incidence rate ratio (4.9; CI, 1.5 to 15.6).
However, the risk was not increased among patients treated with other ergot-derived dopamine agonists, bromocriptine or Dopergine (lisuride) or with dopamine agonists that are not derived from ergot, Requip (ropinirole) or Mirapex (pramipexole), the researchers found.
The current use of amantadine was the only other significant risk factor and was found in five patients. However, three patients also had current exposure to Dostinex, and one had been treated with Permax. The unexpected finding of an increased risk with amantadine requires further investigation, the researchers said, because this drug is not known to activate 5-HT2B receptors.
Preferential activation of this receptor has been shown to induce prolonged mitogenic effects in fibromyoblasts, which could induce valvular fibroplasia, the investigators said.
There are mechanistic grounds for believing that not all dopamine agonists are equally likely to be implicated in the development of a heart-valve disorder, Dr. Schade's team wrote. Some agents in this class, such as bromocriptine and Dopergine have antagonistic properties, and others, such as Requip and Mirapex have a low affinity for the 5-HT2B receptor.
Reviewing the study limitations, the researchers mentioned the problem of recall bias. Also, they said, detection bias could be a cause for concern, because Permax was discussed as a possible cause of cardiac valvulopathy before the end of the study period. An alert published in 2003 may have led to an increased use of diagnostic measures to detect valve disease. However, a subgroup analysis of patients diagnosed before 2003 did not change the results.
Finally, they said the study may have underestimated the incidence of asymptomatic cases and the true risks, because the findings were not based on echocardiographic monitoring of all the patients.
In conclusion, the researchers said that treatment with either Permax or Dostinex, particularly at daily doses greater than 3 mg and for periods of six months or longer, was associated with a substantially increased risk of cardiac-valve regurgitation.
In the second report, an echocardiographic prevalence study, researchers in Milan, Italy, found that clinically significant regurgitation in all three heart valves occurred only in patients taking Permax or Dostimax.
The team led by Renzo Zanettini, M.D., studied evidence from 155 Parkinson's patients taking dopamine agonists. Of these, 64 patients took Permax, 49 took Dostinex, and 42 took non-ergot-derived dopamine agonists. Ninety controls did not have Parkinson's disease and had never been treated with dopamine agonists or anorectic drugs.
Valve regurgitation was assessed according to American Society of Echocardiography recommendations. The mitral-valve tenting area was also measured and used as a quantitative index for leaflet stiffening and apical displacement of leaflet coaptation.
Clinically important regurgitation (moderate to severe, grades 3 to 4) in any valve was found with significantly greater frequency in 23.4% of patients taking Permax, and in 28.6% of those taking Dostinex, but not in any patients taking non-ergot-derived dopamine agonists, versus 5.6% in the controls.
The relative risk for moderate or severe valve regurgitation in the Permax group was 6.3 for mitral regurgitation (P=0.008), 4.2 for aortic regurgitation (P=0.01), and 5.6 for tricuspid regurgitation (P=0.16).
The corresponding relative risks in the Dostinex group were 4.6 (P=0.09), 7.3 (P
The unexpected finding of a significantly greater mitral tenting area in the non-ergot group than in the controls could be evidence of a weak agonist effect by this entire drug class of serotonin receptors that is not sufficient to produce the valve damage observed in patients taking ergot-derived drugs, the researchers said. The mean mitral tenting area in the non-ergot group was similar to that observed in patients in the ergot group who had grade 0 to 1 valve regurgitation.
In conclusion, the researchers emphasized that in addition to the significantly increased risk of heart-valve regurgitation in patients taking ergot-derived agonists for Parkinson's disease, the finding of an increased mitral tenting area bears watching.
The increase not only in patients treated with ergot-derived drugs, but also in patients treated with non-ergot-derived dopamine agonists "suggests that follow-up echocardiographic monitoring is advisable in all patients with Parkinson's disease who are treated with dopamine agonists."
In a commentary in the same NEJM issue, Bryan Roth, M.D., Ph.D., of the NIMH psychoactive drug screening program at the University of North Carolina in Chapel Hill, wrote that two studies have independently verified the association of valvular heart disease with Permax and Dostinex.
Commenting on Dr. Schade's study, Dr. Roth noted that Dopergine, which is an agonist at two related serotonin receptors but is not a 5-HT2B agonist, was not associated with valve disease, thereby further implicating 5-HT2B in valve disease.
Also, the finding that amantadine was associated with an increased risk of valve disease suggests that it will be important to determine whether amantadine (or one of its metabolites) also activates 5-HT2B receptors.
In Dr. Zanettini's study, clinically significant regurgitation was found only in patients taking Permax and Dostinex. In both studies, drug-induced insufficiency was evident in mitral, aortic, and tricuspid valves.
These two studies reinforce the notion of a causal association between HT2B agonists and valvular heart disease, Dr. Roth said. Such an association has now been seen with drugs for diverse indications, including anorectic agents (fenfluramine), antimigraine drugs (dihydroergotamine, Sansert [methysergide], and ergotamine), and the two anti-Parkinson drugs in these studies.
"On the basis of these findings," he wrote, "my colleagues and I have urged pharmaceutical companies and regulatory agencies to screen candidate drugs and their major metabolites at 5-HT2B receptors comprehensively before launching clinical trials, in order to prevent 'fen-phen'-type disasters."
Furthermore, Dr. Roth said, "practitioners should avoid prescribing drugs that are potent 5-HT2B-receptor agonists" -- a growing list of medications, he said, that now includes ergot derivatives (ergotamine, Sansert, and dihydroergotamine), dopamine agonists (Permax and Dostinex), and amphetamine derivatives (fenfluramine and methylenedioxy-methamphetamine [MDMA, or "ecstasy"]).
In the Italian study, coauthors Silvana Tesei, M.D., reported receiving lecture fees from GlaxoSmithKline; Angelo Antonini, M.D., reported receiving consulting fees from Pfizer, Boehringer Ingelheim, Novartis, and Glaxo and lecture fees from Boehringer Ingelheim, Novartis, and Pfizer.
No disclosures reported by the editorialists.