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Elevated Rates of Heart Valve Problems Reported in PD Patients Taking Ergot-Derived Dopamine Agonists

Parkinson disease patients taking two commonly prescribed ergot-derived dopamine agonists may be at increased risk of heart valve disease, symptoms of which may escape the attention of neurologists because they are similar to those experienced in PD and can be confirmed only by echocardiogram, two new studies indicate.

Reporting in the Jan. 4 issue of the New England Journal of Medicine, Italian researchers found a significant increase in moderate to severe valve regurgitation in patients taking pergolide (Permax) or cabergoline (Dostinex), but not in patients taking non-ergot-derived dopamine agonists, when compared with untreated control subjects (N Engl J Med 2007;356:39–46).

Echocardiograms performed on 155 patients—64 taking pergolide, 49 on cabergoline, 42 on non-ergot-derived dopamine agonists—were compared with 90 age- and sex-matched controls:23.4 percent of patients taking pergolide and 28.6 percent of those taking cabergoline had clinically important moderate to severe (grades 3 to 4) regurgitation in one or more of three (aortic, mitral, and tricuspid) valves, compared to 5.6 percent of controls and none of the patients taking non-ergot-derived agonists

Figure

CROSS SECTION OF LEFT VENTRICLEBecause of increased risk of heart valve disease in patients taking pergolide or cabergoline, experts advise that neurologists refer patients for echocardiograms prior to starting them on these medications.

Parkinson researchers Renzo Zanettini, MD, Angelo Antonini, MD, PhD, and their colleagues at the Instituti Clinici di Perfezionamento in Milan, reported that patients treated with ergot derivatives who had grade 3 to 4 regurgitation of any valve received a significantly higher mean cumulative dose of pergolide or cabergoline than had patients with lower grades.

The relative risk (RR) for moderate or severe valve regurgitation was statistically significant for mitral valve regurgitation in pergolide users (RR, 6.3; p =0.008) and aortic regurgitation (RR, 4.2; p = 0.01). In patients taking cabergoline, only the risk of aortic regurgitation was found significant (RR, 7.3; p < 0.001).

The researches also found that the mean mitral-valve tenting area, which indicates fibrotic stiffening of the valve's wing-like flaps or “leaflets” — was significantly greater in ergot-treated patients and showed a linear correlation with severity of regurgitation. In cardiac valve disease, the valves do not close completely, causing blood to flow backward instead of forward through the valve. This perturbation of flow creates turbulence and a heart murmur; the regurgitation can indicate serious valve problems that must be evaluated by echocardiography. Serious defects impede the heart's ability to pump blood adequately and can lead to heart failure. Early symptoms include fatigue, dizziness, and difficulty walking, all of which are familiar to most PD patients.

“Our study and the other retrospective analysis show not only the risk of valvular disease, but also suggest that this risk can easily be overlooked by neurologists treating Parkinson disease,” author Angelo Antonini, MD, PhD, a clinical research neurologist in the department of neurosciences, told Neurology Today in a telephone interview.

“Patients with PD are often fatigued and have trouble walking, but these symptoms could also be caused by cardiac disorders. The issue hasn't been fully explored, but I suspect the prevalence is much greater than we know. Our impression is that in most patients the cardiac condition is masked by PD.”

The researchers did not expect to find such a high rate, he noted. “We were surprised. Neurologists need to be aware of the risk, discuss the risk with patients before putting them on the drugs, and refer all patients taking ergot-derived dopamine agonists for periodic echocardiograms. That is our consensus,” said Dr. Antonini, who directs the Clinical Research Center in the department of neuroscience at the Hospital.

INCIDENCE EVALUATED

In a second study, German researchers led by Edeltraut Garbe, MD, PhD, and René Schade, MD, of Charité-Universitätsmedizin, in Berlin, reviewed data on 11,417 patients registered with the United Kingdom General Practice Research Database who were prescribed the drugs between 1988 and 2005. They found a significant increase in cardiac valve regurgitation during a mean follow-up of 4.2 years, particularly at daily doses greater than 3 mg and for periods of six months or longer (N Engl J Med 2007;356:29–38).

Annual incidence of newly diagnosed cardiac valve regurgitation was significantly higher with pergolide (30 per 10,000 patients) and cabergoline (33 per 10,000 patients) than in untreated patients (5.5 per 10,000). In 31 patients with newly diagnosed valve regurgitation, six were currently taking pergolide, six were taking cabergoline, and 19 had not taken a dopamine agonist within a year. The rate of cardiac-valve regurgitation increased with current use of pergolide (incidence rate ratio, 7.1; 95 percent confidence interval) while cabergoline use increased the ratio by 4.9 percent.

No difference was observed in patients taking the dopamine agonists bromocriptine or lisuride, or non-ergot-derived dopamine agonists, ropinirole or pramipexole. Current amantadine use was identified as the only other significant risk factor in five patients, but four of them reported current use of either pergolide or cabergoline.

Figure

Dr. Angelo Antonini: “Patients with PD are often fatigued and have trouble walking, but these symptoms could also be caused by cardiac disorders. The issue hasnt been fully explored, but I suspect the prevalence is much greater than we know. Our impression is that in most patients the cardiac condition is masked by PD.”

ECHOCARDIOGRAMS NECESSARY

Joseph Tenenbaum, MD, Edgar M. Leifer professor of clinical medicine at Columbia University College of Physicians and Surgeons in New York City, and chief of medicine at New York-Presbyterian/The Allen Pavilion, said the findings are reminiscent of those that led to the withdrawal of the appetite-suppressant combination fenfluramine-phentermine, or fen-phen, ten years ago.

In 1997, Mayo Clinic researchers reported that 24 patients developed heart valve disease after taking fen-phen, and in patients who had valve replacement surgery, the diseased valves were found to have features similar to those seen in the current studies. And although the new studies are different in many respects, the risk needs to be taken seriously, he said.

In 2003, the FDA published a warning letter from Eli Lilly and Company stating that a small number of patients taking pergolide had developed valve problems during treatment, including some who required valve replacement. Pathological examination of the diseased valves was consistent with those removed from fen-phen patients and migraine patients taking methysergide and ergotamine for long periods, as well as those associated with carcinoid syndrome, in which high levels of different hormones are secreted into the bloodstream and can damage valves. The company has included a warning insert to this effect.

“The current two studies are in different settings, both showing significant risk in these patients. If you look in the neurology literature there is a convincing set of trials showing these risks, and neurologists should be referring patients for echocardiograms prior to starting them on any of these meds,” he told Neurology Today in a telephone interview.

The importance of the new studies is five-fold, he said. “First, although it appears to be a relatively small number of patients, the risk is significant. Second, for the most part these valve problems cannot be detected by physical examination alone — it takes echocardiography. Third, if there are pre-existing valve problems, there needs to be a monitoring plan in place that includes echocardiograms. Fourth, all patients taking these medications at the doses and treatment periods described need to be examined and referred for echocardiograms. Although not all of these patients developed valve problems; a subset of patients appears to be more susceptible. And finally, it's important for neurologists to screen carefully for co-morbid [cardiac] disease in all treated patients.”

He said he expects the FDA and cardiology societies to develop statements to this effect within the year, but he hopes there is not a repeat of what happened with statin medications, where only one to two percent of patients developed muscle problems, but news reports caused many patients to stop therapy.

“Here we are using drugs as a second-line therapy, but they are important for many of these Parkinson patients. I doubt that there will be a headlong rush to discontinue treatment, but neurologists need to be aware of this.”

YOUR PRACTICE MANAGEMENT QUESTIONS ANSWERED

The AAN Medical Economics and Management Committee (MEM) receives scores of questions from members about how to code properly and other practice management concerns.

For a new regular column in Neurology Today, MEM committee members provide the most up-to-date answers to common questions. See page 28 for answers to questions on coding for critical care after stroke by MEM committee members Bruce Sigsbee, MD, and Marc Nuwer, MD.

ARTICLE IN BRIEF

  • ✓ New studies report a significant increase in moderate to severe valve regurgitation in patients taking pergolide or cabergoline, but not in patients taking non-ergot-derived dopamine agonists, when compared with untreated control subjects.

REFERENCES

• Zanettini R, Antonini A, Pezzoli G, et al.Valvular heart disease during treatment with dopamine agonists for Parkinson's disease. N Engl J Med 2007;356:39–46.
    • Schade R, Andersohn F, Garbe E, et al. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007;356:29–38.