The widely used dopamine agonist pergolide (Permax) is facing increased scrutiny for safety as published reports suggest pergolide-associated valvular heart disease (VHD) is far more common than first believed even a year ago.
As of June 2003, only 15 cases were documented in the literature after 14 years of pergolide use by 500,000 patients worldwide. Now one year later, dozens of new cases are appearing in the literature.
In one echocardiographic study of 78 Parkinson disease (PD) patients on pergolide, a research group in Brussels, Belgium, reported earlier this year that 33 percent of patients had valvular heart disease (Lancet 2004;363:1179–1183). That compares to a zero incidence of valve disease for PD patients on non-ergot-derived drugs in the same study. (See sidebar, Pergolide: Reports of VHD.)
That incidence is similar to what led to the removal of the appetite suppressants fenfluramine and dexfenfluramine (fen-phen) from the market in the United States in 1997. The two drugs were removed following a 30-percent incidence of abnormal echocardiograms, even though they had no symptoms, the Food and Drug Administration reported.
Nearly all researchers who have written about pergolide-associated valvulopathy note that the valvular disease and the pathogenesis are similar to that of fen-phen.
“This situation is scientifically uncomfortable, because there is sufficient information to be concerned and to reconsider benefit-risk ratios but not enough data to allow objective, well-balanced and undisputed conclusions,” Olivier Rascol, MD, PhD – of the Department of Clinical Pharmacology, Pharmacovigilance Center, and Clinical Investigation Center at Toulouse University Hospital in Toulouse, France – wrote with colleagues in an editorial in the June Movement Disorders (2004;19(6):611–613).
In fact, in numerous interviews, in correspondence, and in this summer's crop of peer-reviewed articles on the issue, researchers and clinicians in Europe and United States report they have begun taking steps to minimize risks in their own practice and research settings.
Many leading movement disorder neurologists are either taking patients off the drug, or ordering annual echocardiograms for those that remain on the drug. And, they say, these recommendations also apply for any patient on the other ergot-derived drugs, bromocriptine in the United States and cabergoline and lisuride in Europe. The challenge is that in PD, the replacement drugs, ropinirole and pramipexole, also carry some potentially knotty side effects, such as sudden sleep attacks, common to all dopamine agonists, whether ergot derived or not.
ASSOCIATED VALVULAR HEART DISEASE
In June, there was a report of four cases of severe multivalvular heart disease and pergolide (Mov Disord 2004;19(6):656–662). Coauthor Anthony E. Lang, MD, Director of the University of Toronto Movement Disorders Unit in Ontario, Canada, and his associates wrote: ''These cases add to a rapidly growing and worrying list of similar published reports, suggesting that we may well be facing a novel, yet unrecognized, complication of this class of agents, which are widely used not only in Parkinson's disease but also in restless legs syndrome and various common endocrine dysfunctions.
“Therefore, until more is known about the true prevalence of this side effect, we propose that an assessment of cardiac function be performed before and in the course of a long-term therapy with ergot-derivative dopamine agonists.”
At the University of Goettingen in Kassel, Germany, Claudia Trenkwalder, MD, Medical Director of the Paracelsus-Elena-Klinik Center of Parkinsonism and Movement Disorders, said in an e-mail: “Right now we are in close contact with Lilly Germany and discussing further procedures regarding safety issues.”
Dr. Trenkwalder has seen many patients on the drug for years. In addition, she was first author on a yearlong study of 100 patients with restless legs syndrome at European and Australian centers – the Pergolide European Australian RLS (PEARLS) study. The study concluded that low-dose pergolide appeared to be well tolerated with long-term efficacy (Neurology 2004;62:1391–1397).
“We are currently preparing to do echocardiograms on our patients,” she said. However, concerned about the side effects of switching the drug for fear of worsening PD symptoms, she said she does not plan to completely stop treatment of the drug.
“In the meantime we will act carefully and check our already treated patients. For RLS patients with low dosages (usually less than .75 mg), I do not see a great risk, but we have not yet proven the dose dependency.”
However, Charles H. Adler, MD, PhD, Chair of the Mayo Foundation Division of Movement Disorders, advised against using pergolide at all for RLS patients. “Given the fact there are other dopamine agonists available, I think that until the situation regarding pergolide and cardiac valve disease is further studied that it behooves us to use either pramipexole or ropinirole for treating restless leg syndrome.”
‘A SERIOUS SITUATION’
Stanley Fahn, MD, Director of the Center for Parkinson's Disease and Other Movement Disorders at Columbia University in New York, NY, told Neurology Today: “This is a serious situation. Fortunately, it doesn't happen in every patient, but it happens frequently enough for us to be concerned.”
Dr. Fahn, who lectured on this issue in April at the AAN Annual Meeting in San Francisco, said: “Pergolide has been an effective drug for Parkinson disease. I have used a lot of it, but because of this problem, I certainly don't start anybody on it anymore.”
He noted that the first published report in the Mayo Clinic Proceedings dates to 2002, and involved three patients with severe tricuspid valve regurgitation, typically combined with some degree of regurgitant left-sided VHD.
“Two of the patients who had undergone valve replacement surgery demonstrated fibrotic valvular changes, a pattern consistent with the known adverse effects of pergolide – pericardial, retroperitoneal, and pleural fibrosis,” William L. Lanier, MD, Editor-in-Chief of the Mayo Clinic Proceedings wrote in a June 2003 editorial.
WHY EFFECTS WEREN'T FOUND BEFORE
Guy Van Camp, MD, was first author on the Lancet paper that reported a 33- percent incidence of abnormal echocardiograms in Parkinson disease patients on pergolide. In an e-mail, Dr. Van Camp noted that pergolide was the first dopamine agonist in Belgium for the treatment of PD, and his hospital has used it for 10 years. When asked why the valvular disease was not discovered earlier, Dr. Van Camp said it was a matter of age and common comorbid conditions.
“We are dealing here with an older population: leaking valves are very common due to degenerative valvular heart disease. This is completely different from the fen-phen story in younger patients, where the smallest regurgitant jet is abnormal in these younger patients. In older patients, leaking valves with regurgitant jets are common enough that it doesn't catch the echocardiographist's attention.”
But he said, since his paper was published, several cardiologists and neurologists have detected restrictive VHD in pergolide treated patients. “Since our paper we had to stop pergolide in two patients because we observed an evolution of the RVHD,” he added.
Another case controlled study was published in Neurology in July (2004;63:301–304) and was presented as an abstract at this year's AAN Annual Meeting in San Francisco.
Richard B. Dewey, Jr., MD, Associate Professor of Neurology at University of Texas Southwestern Medical Center in Dallas, said his group compared 46 pergolide patients to an age-matched control group derived from the Framingham Study. In that comparison, he told Neurology Today, “We found a major difference in incidence, so we think we're getting at the issue of how common this problem is.”
They reported a 14-fold risk of tricuspid valve regurgitation in pergolide treated patients compared to control patients, and a two- to three-fold risk of other valvular regurgitation. A chart with his paper suggests the amount of risk is associated with length of exposure.
“The longer you take it and the higher dose you take, the greater likelihood you are going to have valvular regurgitation. So there does seem to be a biologically plausible mechanism by which this drug enters the cardiac valve,” Dr. Dewey said.
Still, he cautioned against being too alarmist. “If you are talking about asymptomatic valvular regurgitation which could over time get worse and become symptomatic, it is not rare,” Dr. Dewey explained. “If you are talking about development of a severe valvulopathy that leads to open heart surgery for valve replacement, then I think this is a rare event.”
Following the report of the first three cases of RVHD, two editorials in the Mayo Clinic Proceedings noted the uncanny similarities with the early reports that linked use of fenfluramine-phentermine with a very similar valvular heart disease.
In the June 2003 editorial, Dr. Lanier said fen-phen and pergolide may share a serotonin-mediated pathogenesis. He also noted that Mayo Clinic researchers were the first to report in 1997 the case series of 24 women taking fenfluramine-phentermine to lose weight. It too was followed up with echocardiographic case-controlled studies.
TO SWITCH OR NOT
But, the data notwithstanding, not all neurologists, including Dr. Van Camp in Belgium, are removing all patients from pergolide. “We didn't switch all our patients to a non-ergot treatment because our neurologist believes that pergolide is an excellent treatment for PD, and sometimes the conversion to a non-ergot treatment results in problems and degradation of the PD symptoms,” Dr. Van Camp said, echoing concerns expressed by Dr. Trenkwalder. But Dr. Van Camp, cautioned, “If you continue the drug, follow-up by echocardiogram is important.”
Some movement disorders experts are concerned about the side effects of switching the drug for fear of worsening PD symptoms.
One group has attempted to address this switching dilemma, and developed a conversion chart for approximate dose equivalents for the five main dopamine agonists. Reporting in a June 11 online edition of Movement Disorders, Katherine Grosset, MBChB, of the Institute of Neurological Sciences at Southern General Hospital in Glasgow, UK, and her colleagues said they found those patients who were switched at equivalent doses guided by the conversion chart were less likely to experience adverse effects and more likely to stay on the replacement drug.
Donald Grosset, MD, co-author on the paper, told Neurology Today that his group is finalizing a conversion concept based on “units of dopamine agonist” that is based on this published chart. “This will assist in thinking about the equivalences of the various agonist drugs,” he said. “It is not a perfect science, because we do not have head-to-head comparisons of the agents.”
In their study, they also found that when informed about the risks and benefits, most patients chose to switch from an ergot drug to a non-ergot drug, even though many had good symptom control. Of 99 patients on ergot-derived dopamine agonists who were informed about their long-term side effects, 88 chose to switch.
Twenty-six percent experienced adverse effects. After 11 months, 82 percent were on their switch agonist and 93 percent were on any agonist.
The side effect they particularly cited as a motivating factor for organizing this switching study was fibrotic reactions associated with ergot-based dopamine agonists.
“We recognized that switching therapy – despite good symptom control without evidence of side effects – is against prevailing practice,” the authors wrote in their paper, “but consider the fibrotic reaction issue sufficient justification to inform patients and offer treatment change.”
PERGOLIDE: REPORTS OF VHD
Neurology, July 2004:
- Echocardiograms were conducted on 46 patients and scores for valvular regurgitation were compared with those from an age-matched control group derived from the Framingham Study.
- For each of the three valves for which there are control data, there was an approximately two- to three-fold increased risk of concerning tricuspid regurgitation.
Movement Disorders, June 2004
- Four new cases of valvular heart disease in PD patients treated with pergolide were found.
- Based on similar echocardiographic and histopathologic features, the authors suggest ergot-derived dopamine agonists may cause valvular heart disease nearly identical to those reported in appetite suppressants fenfluramine and dexfenfluramine.
The Lancet, April 2004
- Restrictive valvular heart disease (RVHD) of any type was present in 26 (33 percent) patients in the pergolide group and none in controls (p = 0.0025).
- Important disease (score 1 or 2) was present in 15 (19 percent) patients in the pergolide group and none in controls (p = 0.066). A score of 1 represents proven ergot-like restrictive valvular heart disease, and 4 represents no disease.
- In six patients, pergolide treatment was stopped because of RVHD, in two of whom regression of disease was shown.