Official Title: “Observational Study to Investigate the Prevalence of Cardiac Abnormalities and Valvular Regurgitation in Patients With Prolactinomas Treated Chronically With Cabergoline”

Dopamine agonists are first-line agents for the treatment of prolactinomas (1) and Parkinson's disease (2). There is evidence supporting a causal relationship between the occurrence of drug-induced "restrictive" valvular heart disease and treatment with pergolide (3): in several cases, the valvulopathy improved when pergolide was discontinued (4).

Valvular heart damage has also been reported with the ergot-derived dopamine agonists bromocriptine and cabergoline (5,6).

Two recent studies (7,8) have further demonstrated that both pergolide and cabergoline are associated with an increased risk of new cardiac valve regurgitation in patients treated for Parkinson's disease.

The valvular abnormalities seen with ergot-derived dopamine agonists are similar to those observed in patients receiving ergot alkaloid agents (such as ergotamine and methysergide) in the treatment of migraine, or fenfluramine and dexfenfluramine in the treatment of obesity.

These abnormalities also closely resemble carcinoid-related valvulopathies (9).

Cardiac valve disease has never been reported in patients with prolactinomas who require treatment with dopamine-agonists even life-long (1). At variance with patients with Parkinson's disease, patients with prolactinomas are younger and are treated with an average dose of dopamine-agonists that is significantly lower (median bromocriptine dose 5 mg/day and median cabergoline dose 1 mg/week). Because of the young age of treatment beginning (most patients with microprolactinomas start dopamine-agonist treatment in early adulthood), treatment might be continued for over 3 decades: the cumulative risk of low doses of dopamine agonists for such a long period of treatment is currently unknown.

To assess the prevalence of cardiac valve disease in patients treated with cabergoline, we wish to perform an echocardiography screening in a large representative sample of patients with prolactinoma who were treated with cabergoline for at least 12 months and in a group of control subjects recruited prospectively. We wish to evaluate the severity of regurgitation for the mitral, aortic, and tricuspid valves. Changes in cardiac valve apparatus was compared with treatment duration and cumulative cabergoline dose.

Study Type: Observational

Study Design: Case Control, Prospective

Within one week from a clinical observation in the outpatient service, all patients will be admitted to the hospital for a complete endocrine screening, a cardiological visit that will include an electrocardiogram and an echocardiogram.

The endocrine profile will include measurement of IGF-I, PRL, FSH, LH, 17-β-estradiol, testosterone, FT3, FT4, TSH, and cortisol at 8.00 in the morning after an overnight fasting.

The clinical profile will include blood pressure measurement at the right arm, with the subjects in relaxed sitting position. The average of six measurements (three taken by each of two examiners, in the same day of echocardiography, between 8.00-9.00 in the morning) with a mercury sphygmomanometer will be used in all analysis. According with the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (10), hypertension, if present, is classified as mild (Stage 1) when the SBP or DBP were between 140 and 159 mmHg and between 90 and 99 mmHg, respectively; severe (Stage 2) when the SBP or DBP were >160 and >100 mmHg respectively; pre-hypertension is defined as SBP >120¬ and <140 and DBP >80 and <90 mmHg. Heart rate will be also measured.

Intervention(s) in this Clinical Trial

• Drug: Cabergoline
  • According with our previous studies, in the patients with microprolactinoma and in those with non-tumoral hyperprolactinemia, cabergoline treatment was administered orally at a starting dose of 0.25 mg twice weekly for the first two weeks and then 0.5 mg twice weekly. After 2 months of treatment, dose adjustment was carried out every 2 months on the basis of serum PRL suppression.

Arms, Groups and Cohorts in this Clinical Trial

• : 1
  • Patients already receiving treatment with cabergoline.
• : 2
  • healthy controls sex and age-matched with the patients

Primary Measures

• Prevalence of regurgitation (graded as mild, moderate, severe) at any cardiac valve.
  • Time Frame: 9 months
    Safety Issue?: Yes

Inclusion Criteria:

• Patients with documented hyperprolactinemia receiving continuous treatment with cabergoline only for at least 12 months
• Newly diagnosed patients with prolactinoma never previously receiving dopamine agonists treatment

Exclusion Criteria:

• A history of cardiac valve abnormalities,
• Previous use of anorectic drugs or other ergot-derived drugs,
• Treatment with cabergoline for less than 12 months,
• Valve calcification, valve regurgitation associated with annular dilatation or excessive leaflet motion,
• Mitral regurgitation associated with left ventricular wall-motion abnormalities or left ventricular dilatation,
• Withdrawal from cabergoline treatment for longer than 1 month, according with our treatment protocol (11).

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: Federico II University

Overall Clinical Trial Officials and Contacts

Annamaria AL Colao, Prof. Principal Investigator Federico II University  

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00460616

Study ID Number: NeuroendoUnit-2

ClinicalTrials.gov Identifier: NCT00460616

Health Authority: Italy: National Monitoring Centre for Clinical Trials - Ministry of Health