The impact in Japan of regulatory action on prescribing of dopamine receptor agonists: analysis of a claims database between 2005 and 2008.

BACKGROUND: Use of the ergot-derived dopamine receptor agonists (cabergoline and pergolide) is associated with an increased risk of cardiac valvulopathy. Pergolide was withdrawn from the US market in 2007 because of the risk of valvular heart disease, while the European Medicines Agency (EMA) required a reduction in the maximum daily dosage of cabergoline and pergolide from 6 mg/day to 3 mg/day in 2008. In Japan, the package inserts of both drugs were revised in April 2007 to request that physicians conduct periodic ultrasonic cardiography (UCG) examinations for patients taking cabergoline or pergolide. Also, through face-to-face communication with medical representatives of drug companies, physicians were informed that use of cabergoline and pergolide has increased the risk of valvulopathy. However, cabergoline and pergolide have remained in wide use, even following the regulatory actions. OBJECTIVE: The objective of this study was to assess the impact of actions, including the package insert revision in April 2007, to encourage periodic UCG. METHODS: Data on monthly claims (January 2005-October 2008) covering 330 000 patients were obtained from a Japanese database vendor. We selected patients ≥40 years of age with Parkinson's disease. The impact of the regulatory action on the proportion of patients with Parkinson's disease prescribed cabergoline or pergolide was assessed by segmented regression analysis and by a statistical model of the rates of UCG examination in patients taking/not taking cabergoline or pergolide before and after the action. We also compared the use of cabergoline and pergolide before and after the action with that of other antiparkinson drugs. RESULTS: Of 574 patients with Parkinson's disease, the proportion of patients prescribed cabergoline or pergolide did not decrease but rather tended to increase after the action when analysed by segmented regression analysis (p = 0.13). Similarly, the proportion of the prevalent and incident users of cabergoline or pergolide did not change between two 19-month periods before and after the action. The adjusted rates of UCG examination per person-year before and after the action were both 0.02 in those not prescribed cabergoline or pergolide, but 0.02 before the action and 0.09 after the action in those taking either drug. The excess UCG examination rate of cabergoline or pergolide attributable to the action was 0.08 per person-year (95% CI 0.03, 0.11). While 1 of 49 (2%) patients taking cabergoline or pergolide had a UCG up to 19 months before the action, 9 of 36 (25%) patients taking cabergoline or pergolide had a UCG up to 19 months after the action. Annual sales from 2004 to 2008 were 195, 195, 170, 110 and 75 billion yen, respectively, and the number of valvulopathy events, including incompetence of aortic/mitral/tricuspid valves and cardiac valve disease, per annual sales from 2004 to 2008 were estimated at 0.23, 0.03, 0.08, 0.25 and 0.19 per billion yen, respectively. CONCLUSIONS: Following the actions in April 2007, no decrease in the use of cabergoline or pergolide occurred, although more patients administered the drug underwent a UCG. However, those undergoing a UCG represented one-quarter of the total number prescribed cabergoline or pergolide. To mitigate the risk, additional risk management tools such as patient registration may be needed to secure careful clinical examination (including UCG examination, if necessary) for cardiac function.

Assessment of valvulopathy in Parkinson's disease patients on pergolide and/or cabergoline.

OBJECTIVE: To assess the effect of ergot derivatives on cardiac valves in patients with Parkinson's disease (PD). MATERIALS AND METHODS: Echocardiography was performed on 46 PD patients who used either pergolide or cabergoline (MonoPD) or both (MixPD) for a minimum of 1 year and 49 age-matched healthy controls. Valvular regurgitation was graded as mild, moderate and severe. MonoPD and MixPD groups were compared with regard to demographic features, drug profile and valvulopathy. RESULTS: The PD group had a mean age of 63 years, agonist duration of 3.8 years and agonist equivalent dose of 3.5mg/day. Moderate regurgitation in all three valves was significantly more common in the PD group than the controls. Severe valvular regurgitation was not observed in either group, with the exception of one PD patient. The frequency of valvulopathy and doses of agonists did not differ between MixPD and MonoPD groups. CONCLUSION: PD patients on dopamine ergot agonists are prone to moderate valvular regurgitation more than age-matched controls. However, the frequency of valvulopathy was similar in patients who used either one or more agonists.

[Reactivity and communication of Health Authorities toward health professionals: a public health priority]. / Réactivité et communication des décisions de pharmacovigilance des autorités de santé vers les professionnels de santé: exemples du pergolide et du célécoxib.

OBJECTIVE: evaluate the impact of Health Authorities' communication on medical practices through 2 examples: celecoxib, taking into account the recent countra indication related to cardio vascular risks; pergolide, taking into account the risk of cardiac valvulopathy. MATERIAL AND METHOD: Use of the Pays de Loire Health Insurance Administration data base to monitor the number of cardio vascular patients at risk who receive celecoxib, and cardiac surveillance of pergolide exposed patients. RESULTS: Communication from Health Authorities resulted in a major decrease (71.9%) of the number of risking patients who take celecoxib, and a significant 14% decrease of pergolide treated patients needing cardiac monitoring CONCLUSION: Unlike the information related to pergolide, the information related to celecoxib was fully taken into account. The difference seems to come from the fact that one was widely relayed by medias, not the other.

L-DOPA-induced excessive daytime sleepiness in PD: a placebo-controlled case with MSLT assessment.

A 74-year-old patient with idiopathic Parkinson's disease was evaluated for unintended sleep episodes that occurred after long-term treatment with 400 mg/day of L-dopa. Overnight sleep studies and multiple sleep latency testing were carried out under double-blind administration of either L-dopa or placebo. Mean sleep latency with L-dopa was 7 minutes, in contrast to a normal value of 19 minutes, 25 seconds with placebo. The authors' results suggest that L-dopa may cause daytime somnolence in some patients with Parkinson's disease.

Cost-effectiveness of pergolide compared to bromocriptine in the treatment of Parkinson's disease: a decision-analytic model.

OBJECTIVE: To develop a decision-analytic model to assess the cost-effectiveness of pergolide versus bromocriptine in the treatment of Parkinson's disease (PD). METHODS: A Markov decision-analytic model is used to examine cost-effectiveness. The model ran for 20 cycles of 6 months' duration, and the patients progress through six stages: Hoehn-Yahr stages 1-5 and death. The transitional probabilities for each stage are derived from a 12-year longitudinal study of patients with PD. The costs in the model are derived from an expert panel containing six Australian neurologists. A review of the randomized controlled trials comparing the efficacy and safety of pergolide versus bromocriptine was undertaken. Five studies were identified, with four showing that pergolide offers superior efficacy when compared to bromocriptine. The Mizuno et al. (1995) study was the largest of the controlled trials and also measured patient Hoehn-Yahr status before and after treatment. This was identified as the most appropriate source of relative efficacy data for the model. The model examined various scenarios based on alternate durations of superior clinical benefit with pergolide compared to bromocriptine. The main analysis assumed that patients in each arm of the model would have identical Hoehn-Yahr status by the fifth year. Sensitivity analysis was used to determine cost-effectiveness in the case where the therapeutic benefit was of a shorter duration. RESULTS: The Mizuno study indicates that an additional 19.09% of patients improved by at least one stage on pergolide over bromocriptine, with an odds ratio of 2.26 (p < .01). The total health care cost per patient over the 10-year period was $46,323 in the pergolide treatment arm and $47,351 in the bromocriptine treatment arm, an incremental saving of $1028. Patients also spent extra time in Hoehn-Yahr stages 1, 2, and 3. In sensitivity analyses, when the benefit from pergolide expired between 6 months and 5 years after treatment cessation, cost savings ranged from $68 to $2535. CONCLUSION: Pergolide is cost saving and more efficacious than bromocriptine, and is therefore cost-effective.

Cost-effectiveness analysis of dopamine agonists in the treatment of Parkinson's disease in Japan.

BACKGROUND: Dopamine agonists such as bromocriptine or pergolide are often used in Japan to treat Parkinson's disease. Dopamine agonists are relatively expensive drugs; economic evaluations are required. OBJECTIVE: To evaluate the cost effectiveness of dopamine agonists for the treatment of Parkinson's disease in Japan. DESIGN AND SETTING: We used a Markov model to simulate the course of Parkinson's disease and to compare the cost effectiveness of dopamine agonists added to levodopa with that of levodopa alone in Japan. The model assumed that 60-year-old men with Parkinson's disease in Hoehn-Yahr (HY) stages 2 to 5 using levodopa were administered dopamine agonists or continued on levodopa alone. The incremental cost effectiveness of dopamine agonists used for 10 years was then estimated. STUDY PERSPECTIVE: Societal. MAIN OUTCOME MEASURES AND RESULTS: In the patients in HY stage 2, the incremental cost effectiveness of dopamine agonists was 18,610,000 to 19,320,000 yen per quality-adjusted life-year (QALY) [$US 172,300 to $US 178,900/QALY; 1998 values] . In patients in HY stage 3 or higher, the use of dopamine agonists was dominant over levodopa alone mainly due to reduced cost for care. In sensitivity analyses, costs and effectiveness of dopamine agonists significantly influenced the results. The use of a generic formulation of bromocriptine was dominant over levodopa alone even in the patients with HY stage 2 disease. CONCLUSIONS: Dopamine agonists appear to be cost effective in advanced Parkinson's disease, although their use is sensitive to the costs and effectiveness of dopamine agonists. If factors discouraging the prescription of generic drugs in Japan were removed, the treatment of Parkinson's disease would become more cost effective.