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Published in New England Journal of Medicine January 4 th , 2007

Dopamine Agonists and the Risk of Cardiac Valve Regurgitation. Published in New England Journal of Medicine January 4 th , 2007. Rene Schade, M.D., Frank Andersohn, M.D., Samy Suissa, Ph.D. Wilhelm Haverkamp, M.D., Ph.D., and Edeltraut Garbe, M.D., Ph.D.

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Published in New England Journal of Medicine January 4 th , 2007

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  1. Dopamine Agonists and the Risk of Cardiac Valve Regurgitation Published in New England Journal of Medicine January 4th, 2007 Rene Schade, M.D., Frank Andersohn, M.D., Samy Suissa, Ph.D. Wilhelm Haverkamp, M.D., Ph.D., and Edeltraut Garbe, M.D., Ph.D.

  2. Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Background • Pergolide and cabergoline are potent agonists of the 5-hydroxytryptamine 2B receptor expressed on heart valves, whereas other agents in this class, such as bromocriptine and lisuride have antagonistic properties. • Previous case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists pergolide and cabergoline, in the treatment of Parkinson’s disease and restless legs syndrome, may increase the risk of cardiac-valve regurgitation. Schade, et al New Engl J Med. 2007; 356 (1) 29-38.

  3. Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Study Design 12,794 patients 40-80 years of age prescribed two antiparkinsonian drugs between 1988-2005, each patient newly diagnosed with cardiac valvular disease was matched with up to 25 control patientsaccording to age, sex, and date of entry Nested. Case-Control. Medical Records from GPRD > 6.3 million patients from > 350 general practices. Exclusion Criteria: Hx of RHD, congenital HD, CHF, dilated cardiomyopathy, endocarditis or myocarditis, carcinoid syndrome, IV drug abuse, heart valve abnormalities (ie: MV prolapse and murmurs), receiving drugs associated with valvulopathy, <12 months of recorded data before date of exit, MI within 3 years of diagnosis of valvular regurgitation, prexisting valvular HD, or no confirmation of diagnosis Case Patients (newly diagnosed with valvular disease: 6 pergolide, 6 cabergoline, 19 no dopamine agonist exposure within 1 yr) n=31 Control Patients (matched 25:1 Case Patient) n=663 • Primary Endpoint: New diagnosis of valve disease Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.

  4. Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Baseline Characteristics* *Plus-minus values are means ± SD. Case patients and controls were matched for age, sex, and year of entry into the study cohort. Percentages may exceed 100 because of overlap between categories Schade, et al New Engl J Med. 2007; 356 (1) 29-38.

  5. Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Baseline Characteristics* *Case patients and controls were matched for age, sex, and year of entry into the study cohort. Percentages may exceed 100 because of overlap between categories ‡This category includes use during the 6 months before the index date. Schade, et al New Engl J Med. 2007; 356 (1) 29-38.

  6. Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Case Patient Valvular Regurgitation Characteristics Characteristics of 31 Case Patients with Cardiac-Valve Regurgitation, According to Use of A Dopamine Agonist †Percentages may exceed 100 because of overlap between the categories Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.

  7. Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Primary Endpoint Current Use of Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation *The incidence-rate ratio was adjusted for the use of other dopamine agonists or amantadine ‡This is the reference category, defined as no use of dopamine agonist during the 12 months before the index date. Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.

  8. Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Primary Endpoint (cont.) • The rate of cardiac-valve regurgitation was elevated among patients who were currently exposed to either pergolide (adjusted incidence-rate ratio, 7.1; 95% CI, 2.3 to 22.3) or cabergoline (adjusted incidence-rate ratio, 4.9, 95% CI, 1.5 to 15.6), but not among those who were currently exposed to other dopamine agonists. • For amantadine, the only concurrent medication found to have a significant association with cardiac –valve regurgitation, the adjusted incidence-rate ratio was 3.6 (95% CI, 1.1 to 11.3). Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.

  9. Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Primary Endpoint (cont.) Influence of the Daily Dose of Pergolide or Cabergoline *The incidence-rate ratio was adjusted for the use of other dopamine agonists or amantadine. †This is the reference category, defined as no use of a dopamine agonist during the 12 months before the index date. Schade, et al New Engl J Med. 2007; 356 (1) 29-38.

  10. Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation: Primary Endpoint (cont.) Influence of the Cumulative Duration of Use on the Risk of Cardiac-Valve Regurgitation. *The incidence-rate ratio was adjusted for the use of other dopamine agonists or amantadine. †This is the reference category, defined as no use of a dopamine agonist during the 12 months before the index date. Schade, et al. New Engl J Med. 2007 Jan; 356(1): 29 – 38.

  11. Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Primary Endpoint (cont) • The adjusted incidence rate ratios were particularly elevated for daily doses greater than 3mg of pergolide (37.1; 95% CI, 1.5 to 15.6) and 3mg of cabergoline (50.3; 95% CI, 6.6 to 381.4), as well for a duration of use of 6 months or more. Schade, et al New Engl J Med. 2007; 356 (1) 29-38.

  12. Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Limitations • Detection bias could be a concern, since pergolide was discussed in September 2003 by the British Committee on Safety of Medicines as a possible cause of cardiac valvulopathy before the end of the study period leading to an increase in use of diagnostic measures in patients receiving this drug; however, a subgroup analysis was completed with patients diagnosed prior to September 2003 showing no material change in results. • Underdiagnosing the incidence of asymptomatic cases could have occurred, since it was not based on echocardiographic monitoring of all patients in the cohort, thus underestimating the true risks associated with pergolide and cabergoline. Schade, et al New Engl J Med. 2007; 356 (1) 29-38.

  13. Dopamine Agonists and the Risk of Cardiac Valve Regurgitation: Summary • This study showed that the use of pergolide or cabergoline, particularly at does greater than 3mg and for 6 months or longer, was associated with a significantly increased risk of newly diagnosed cardiac-valve regurgitation. • There was no evidence of increased risk among patients treated with other ergot derived dopamine agonists (such as bromocriptine or lisuride) or with dopamine agonists that are not derived from ergot (such as ropinirole or pramipexole). • These findings are supported by a number of other case reports and echocardiography studies. Schade, et al New Engl J Med. 2007; 356 (1) 29-38.

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