Patients with Parkinson's disease who received the drugs pergolide or cabergoline had profoundly higher rates of clinically significant valvular heart disease than did those taking other dopamine agonists, in two European studies.
The valve dysfunction described in the studies appears to closely resemble what was seen in the “fen-phen” cases and in patients exposed to ergot derivatives used to treat migraine headaches, said Dr. Brian Griffin, director of the valve management clinic at the Cleveland Clinic.
“The valve is thickened and leaks a lot, but isn't narrowed at the same time,” Dr. Griffin said in an interview.
One report involved an Italian echocardiographic prevalence study of 155 patients with Parkinson's disease that detected moderate to severe (grade 3 or 4) valvular regurgitation in 23.4% of patients who had taken pergolide and 28.6% of those who had taken cabergoline for at least 12 months, compared with none of the patients taking a non-ergot-derived dopamine agonist (pramipexole or ropinirole) and 5.6% of 90 control patients who did not have Parkinson's disease.
A significant association was seen between the cumulative dose of either pergolide or cabergoline and the severity of valve regurgitation, according to Dr. Renzo Zanettini and associates in the cardiac rehabilitation unit and Parkinson Institute of the Istituti Clinici di Perfezionamento, Milan.
“Our findings confirm safety concerns related to the use of pergolide and show that an increased risk of cardiac valvulopathy also exists in patients taking cabergoline,” the authors concluded.
In the U.S., pergolide carries an FDA warning of possible cardiac valvulopathy and fibrotic complications that discourages its use in patients with a history of valvular heart disease and recommends a baseline cardiovascular evaluation and periodic echocardiograms.
Cabergoline has been the subject of case reports and one case-control study from Japan (Neurology 2006;67:1225–9), suggesting an association with valvulopathy.
Dr. Zanettini and colleagues noted the presence of increased mitral tenting, a geometric measure of the position of the leaflets that can be an early indicator of valvular dysfunction, in patients receiving ergot-derived dopamine agonists such as pergolide and cabergoline. Patients receiving non-ergot-derived dopamine agonists also had increased mitral tenting.
Although the latter patients did not have evidence of elevated rates of frank regurgitation, this finding “suggests that follow-up echocardiographic monitoring is advisable in all patients with Parkinson's disease who are treated with dopamine agonists,” they wrote (N. Engl. J. Med. 2007;356:39–46).
The second study, a nested case-control study drawn from the United Kingdom General Practice Research Database, calculated incidence rates of newly diagnosed cardiac valve regurgitation in 11,417 patients who had received prescriptions for antiparkinsonian medications.
Cardiac valve regurgitation rates were elevated with current use of pergolide (adjusted incidence-rate ratio 7.1; 95% confidence interval 2.3 to 22.3) and cabergoline (adjusted incidence rate ratio 4.9; 95% confidence interval 1.5 to 15.6), but not with current use of any other dopamine agonist.
In what investigators termed an “unexpected” finding, concurrent use of amantadine also had a significant association with regurgitation (adjusted incidence rate ratio 3.5 (95% confidence interval 1.1 to 11.3), although they said the role of this antiviral/antidyskinetic medication “requires further investigation.”
Daily doses of greater than 3 mg of either pergolide or cabergoline, or the use of either drug for 6 months or more, conferred a “particularly elevated” adjusted incidence-rate ratio, reported Dr. René Schade of the department of clinical pharmacology, Charité-Universitätsmedizin, Berlin (N. Engl. J. Med. 2007;356:29–38).
In both New England Journal of Medicine studies, valvular abnormalities in patients taking pergolide or cabergoline were seen in the mitral, aortic, and tricuspid valves. Pergolide and cabergoline are potent agonists of 5-hydroxytryptamine2B (5-HT2B) serotonin receptors, unlike dopamine agonists that were not associated with elevated cardiac valve disease in the study. They share this mechanistic pathway with fenfluramine and dexfenfluramine, antiobesity drugs withdrawn from the market in 1997 due to reports of valvular heart disease and pulmonary hypertension in patients taking the so-called “fen-phen” combination.
“Clearly, practitioners should avoid prescribing drugs that are potent 5-HT2B-receptor agonists—a growing list of medications that now includes ergot derivatives (ergotamine, methysergide, and dihydroergotamine), dopamine agonists (pergolide and cabergoline), and amphetamine derivatives (fenfluramine and methylenedioxymethamphetamine [MDMA, or “ecstasy”]),” Dr. Bryan L. Roth wrote in an accompanying editorial (N. Engl. J. Med. 2007;356:6–9).
Amantadine, which was associated with an elevated risk of valvular heart disease in the Berlin study, should be investigated to see whether it activates 5-HT2B receptors, said Dr. Roth, whose research group at the University of North Carolina, Chapel Hill, has been instrumental in unraveling the molecular mechanisms underlying valvulopathic drugs.
In the editorial, he and his colleagues “urged pharmaceutical companies and regulatory agencies to screen candidate drugs and their major metabolites at 5-HT2B receptors” before initiating clinical trials of new drugs “to prevent “fen-phen”-type disasters.”
In the meantime, “I recommend that physicians do not prescribe medications with 5-HT2B agonist activity,” he said in an interview.
Dr. Griffin called the journal studies “a little worrying,” since they affirm what had been postulated to be a class effect of drugs that act as agonists at the 5-HT2B receptor.
Patients exposed to pergolide and cabergoline have echocardiograms, said Dr. Griffin, noting more information is needed before he would call for a moratorium on their use.
Less troubling is evidence in one study of tenting in patients exposed to other dopamine agonists, he said. While they may prove to be partial agonists of the 5-HT2B receptor, other anti-Parkinsonian drugs do not appear to have the same potential impact on the valves as pergolide and cabergoline, he said.
Neurologist Dr. Irene Litvan, Raymond Lee Lebby Professor of Parkinson Disease Research at the University of Louisville (Ky.) and director of the movement disorder program there, said in an interview that these articles confirm the importance of not using 5HT2b agonists in general. Neurologists have other options for treating Parkinson's.
“Ropinirole and pramipexole are excellent DA [dopamine agonists] and recently approved inhibitors of MAO-B have expanded our armamentarium,” she said.
Further studies are needed to assess the risk of a valvulopathy when using amantadine, Dr. Litvan said.
“These findings will have little impact in my practice. Due to the risks of retroperitoneal and pleural fibrosis I have tended not to use ergot derived DA and following the 2004 reported risk of a fibrotic valvulopathy secondary to pergolide I discontinued the use of pergolide in patients who were referred to me who were on this drug. There are no appropriately powered head-to-head studies that evaluate if there are differences between ergot and non-ergot derived DA, but in practice non-ergot derived DA are as good as ergot-derived DA. I had difficulty switching pergolide to a non-ergot derived DA in a small number of patients and only one preferred to remain on this drug despite the warnings. Routine echocardiograms seem indicated for patients who opt to continue to be treated with DA that are 5HT2b agonists,” she said.
Pergolide, marketed in the United States as Permax, is manufactured by Valeant Pharmaceuticals International. Cabergoline, marketed as Dostinex, is manufactured by Pfizer Inc. Valeant no longer promotes the product, but still makes it available for those who prescribe it.
FDA has approved Pfizer's revised label for Dostinex (cabergoline) (www.fda.gov). The new labeling includes: “As with other ergot derivatives, pleural effusion/pulmonary fibrosis and valvulopathy have been reported following long-term administration of cabergoline.”
The Milan study was supported by the Italian Parkinson Association, the Grigioni Foundation for Parkinson's Disease, and Istituti Clinici di Perfezionamento. Investigators disclosed support from GlaxoSmithKline, Pfizer, Boehringer Ingelheim, and Novartis. The Berlin-based study, which included investigators from Berlin and McGill University Health Centre in Montreal, was supported by Schering, GlaxoSmithKline, Boehringer Ingelheim, Astra-Zeneca, Novartis, and Organon.
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