Reference
Subjects
Treatment duration
Main findings
[14]
257 patients
239 controls (unexposed)
4.9 months (dexfenfluramine)
26.5 months (dexfenfluramine and phentermine)
Odds ratio for cardiac valve abnormalities 12.7 for dexfenfluramine, 24.5 for dexfenfluramine/phentermine, and 26.3 for fenfluramine/phentermine
[15]
718 patients
354 controls (placebo)
78 months
Mitral regurgitation found in 5.4 % of dexfenfluramine patients and 3.6 % of controls; aortic regurgitation found in 6.9 % of dexfenfluramine patients and 4.5 % of controls
[16]
412 patients
172 controls (unexposed)
6.9 months
Odds ratio for aortic/mitral regurgitation 3.82
[17]
1163 patients
672 controls (untreated for 5 years)
11.2 months
Odds ratio for cardiac valve abnormalities 6.2 for treatment duration greater than 720 days
[18]
711 patients
431 controls (untreated)
6.1 months (dexfenfluramine)
12 months (phentermine and fenfluramine)
Aortic regurgitation in 7.8 % of dexfenfluramine and 4.4 % of phentermine/fenfluramine patients versus 1.9 % of controls
An increased risk of heart valve abnormalities at echocardiography was also found by Weissman et al. in obese patients taking dexfenfluramine compared to unexposed controls in the setting of a randomized controlled study [15]. In this study, the prevalence of any degree of aortic regurgitation was significantly higher in exposed versus unexposed individuals (17.0 % versus 12 %) and similar results were obtained when mitral regurgitation of any degree was considered (61 % versus 54 %). Of note, the degree of aortic or mitral regurgitation was often minimal to mild, perhaps owing to the limited duration of treatment (mean 72 days) with dexfenfluramine.
Shively et al. [16] evaluated by echocardiography (interpreted by at least three independent assessors) the prevalence and determinants of valvulopathy in 172 patients treated with dexfenfluramine and 172 matched controls. FDA grade regurgitation (at least mild aortic regurgitation or at least moderate mitral regurgitation) was significantly more frequent in dexfenfluramine patients (7.6 % versus 2.1 %), with an OR of 3.82. Older age, higher diastolic blood pressure, and shorter time from drug discontinuation to echocardiography appeared to be related to heart valve regurgitation. These findings suggest that dexfenfluramine-induced heart valve changes can be aggravated by older age and higher blood pressure, and that cardiac valvulopathy can at least partially regress following the withdrawal of the offending drug.
Jollis et al. examined 1163 patients who had taken fenfluramine-phentermine and 672 controls who had not taken the drug combination within 5 years. Aortic regurgitation of mild or more severe degree was found to be significantly more frequent in treated patients (8.8 %) than in controls (3.6 %). Moderate or greater mitral regurgitation was found in 2.6 % of treated patients and 1.5 % of controls, but the difference did not reach significance. Duration of treatment was an important determinant of heart valvulopathy, since the adjusted OR compared with controls of aortic regurgitation significantly increased according to duration of treatment (181–360 days, 2.4; 361–720 days, 4.6; >720 days, 6.2).
A multicentric study aimed to investigate the prevalence of valvular abnormalities, as assessed by clinical cardiovascular parameters and echocardiography, in patients treated for obesity with dexfenfluramine or the combination phentermine/fenfluramine [18]. Four hundred and seventy-nine and 455 individuals had taken dexfenfluramine and the combination phentermine/fenfluramine, respectively, continuously for 30 days or more over the previous 14 months, while 539 untreated matched subjects were chosen as controls. In this study, cardiovascular signs and symptoms were similar among patients and controls. Aortic regurgitation was more prevalent in subjects treated with appetite suppressants (8.9 % in the dexfenfluramine group and 13.7 % in the phentermine/fenfluramine group versus 4.1 % in the untreated group), whereas no differences in prevalence were observed for mitral regurgitation, thickening or decreased mobility of any valve leaflet, pulmonary artery systolic pressure, left ventricular ejection fraction, or serious cardiac events.
Taken together, the findings derived from controlled studies suggest that dexfenfluramine and fenfluramine may induce cardiac valve regurgitation that is associated with longer disease duration and may regress, at least in part, following cessation of exposure to the medications. In line with these data, a meta-analysis of observational studies has shown that 1 of 8 patients treated for longer than 3 months with fenfluramine develop drug-induced cardiac valve disease [21]. Both fenfluramine and dexfenfluramine have been taken off the drug market in the USA following the ascertainment of their link with fibrosing heart valve disease.
14.4.2 Ergot Alkaloids
14.4.2.1 Ergotamine
14.4.2.2 Methysergide
The ergot alkaloid methysergide has been linked to a number of fibrosing disorders. A review of 481 cases of retroperitoneal fibrosis found that 12 % of them were attributable to methysergide intake [29]. Methysergide has also been linked to myocardial [30] and endocardial [30–32] fibrosis, valvular heart disease [30, 32–34], and pleuropulmonary fibrosis [1, 35–37].
14.4.2.3 Ergot-Derived Dopamine Agonists
An association with heart fibrosing disorders has been found with ergot-like dopamine agonists, such as bromocriptine, cabergoline, and pergolide [2, 38–45], but not with nonergot dopamine agonists (apomorphine, pramipexole, ropirinole, rotigotine) [12]. Lisuride, an ergolinic dopamine receptor agonist with 5-HT2B receptor antagonist properties, has not been mapped to heart valve disease [46]. Likewise, a meta-analysis found no increased risk of fibrosis with nicergoline, a semisynthetic ergot derivative [47].
Numerous controlled studies have investigated the association of ergot-like dopamine agonists with heart fibrosing disorders (Table 14.2).
Table 14.2
Main controlled studies on fibrotic heart valvulopathy induced by ergot dopamine agonists
Reference | Subjects | Treatment duration | Main findings |
|---|---|---|---|
[44] | 36 patients 36 controls (treated with nonergot dopamine agonists) | Not stated | Patients had more frequent aortic, mitral, and tricuspidal valvulopathy |
[40] | 49 patients 38 controls (untreated) and 36 taking nonergot dopamine agonists | >9 months | Aortic regurgitation found in 12 % versus 0 % Mitral regurgitation found in 14 % versus 3 % |
[41] | 58 patients 20 controls (untreated) | 39 months (bromocriptine) and 54 months (pergolide) | Aortic regurgitation found in 4.5 % (bromocriptine) and 11 % (pergolide) versus 0 % |
[42] | 75 patients 49 controls (untreated), 33 treated with ropirinole or pramipexole | 30 months (cabergoline) and 61 months (pergolide) | Valvular regurgitation found in 47 % (cabergoline) and 31 % (pergolide) versus 10 % (untreated) and 13 % (nonergot dopamine agonists) |
[38] | 78 patients 18 controls (untreated) | 18.2 months | Any restrictive heart valve disease found in 33 % of patients versus none of the controls |
[43] | 113 patients 90 controls (untreated) and 42 treated with nonergot dopamine agonists | 24 months (cabergoline) and 63 months (pergolide) | Valvular regurgitation found in 23 % (pergolide) and 29 % (cabergoline) versus 0 % of nonergot dopamine agonists treated and 5.6 % of untreated controls |
[39] | 82 patients 85 controls (untreated) as well as 16 pramipexole treated and 27 past–treated | 35 months (cabergoline) and 52 months (pergolide) | Valvulopathy found in 69 % of cabergoline group and 29 % of the pergolide group versus 18 % of the controls |
Van Camp et al. investigated by echocardiography 78 patients with Parkinson’s disease treated with pergolide and 18 controls that had never been treated with an ergot-derived dopamine agonist [38]. Restrictive valvular heart disease of any type was found in 26 (33 %) patients in the pergolide group, but in none of the controls. For the mitral valve, tenting distance and tenting areas were measured as indicators for apical displacement of the leaflet coaptation and leaflet stiffness, similarly to what is done for mitral regurgitation in ischemic heart disease. A significant correlation was noted between cumulative doses of pergolide and tenting areas of the mitral valves. Mean systolic pulmonary artery pressure was significantly higher in pergolide-exposed versus unexposed subjects. The reversibility of pergolide-induced cardiac lesions could not be assessed in the setting of this study.
Peralta and coworkers investigated by transthoracic echocardiography the prevalence of heart valve regurgitation in 75 patients with Parkinson’s disease treated with pergolide (n = 29), cabergoline (n = 13), pramipexole or ropinirole (n = 33), and 49 age-matched unexposed controls [42]. Valvular regurgitation was graded from 1 to 3 based on parameters of regurgitation volume, regurgitation fraction, and effective regurgitation orifice following the recommendations issued by the American Society of Echocardiography. The exposure to pergolide and cabergoline was associated with higher frequencies of valvular regurgitation grades 2 and 3 (31 % and 47 %) compared with age-matched controls (13 %), while there was no increase of valvular regurgitation grades 2 and 3 in patients treated with nonergot compounds (10 %). Evidence for restrictive valvulopathy was rare, being found in one patient treated with pergolide and cabergoline each.
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