Prevalence of valvular-regurgitation associated with dexfenfluramine three to five months after discontinuation of treatment.

OBJECTIVES: The goal of this study was to determine the prevalence of valvular regurgitation and abnormal valve morphology in patients three to five months after discontinuation of dexfenfluramine (Dexfen) therapy. BACKGROUND: We previously reported the results of a randomized, double-blind, placebo-controlled trial of valvular structure and function in 1,073 patients treated either with Dexfen, with an investigational sustained-release dexfenfluramine (Dexfen SR), or with a placebo, with echocardiograms performed approximately one month from the last dose. Using FDA criteria (aortic regurgitation [AR] > or =mild and/or mitral regurgitation [MR] > or =moderate) we found no statistical difference among the groups, but when all degrees of valvular regurgitation were considered and when the two Dexfen groups were combined, there was a higher prevalence of any degree of AR, any degree of MR, and restricted posterior mitral leaflet mobility. However, it was unknown whether these differences in prevalence persisted. METHODS: The double blind was maintained, and all patients were invited to return for a follow-up echocardiogram. Echocardiograms were acquired using a standardized protocol and assessed blindly to determine the degree of valvular regurgitation and valve leaflet thickness and mobility. We had an 80% power to detect a statistically significant change in paired proportions using the McNemar test (alpha = 0.05). RESULTS: Echocardiograms were obtained on 941 patients with a median of 137 days after drug discontinuation. Aortic regurgitation (of any degree) was present in 13.8% of Dexfen (p = 0.41 compared to placebo), 10.7% of Dexfen SR (p = 0.64 compared to placebo), and 11.9% of placebo patients. The minor differences between patients treated with active drug versus placebo, which were found in the previous study, were no longer significant even when the groups were combined (p = 0.83 compared to placebo). Mitral regurgitation (of any degree) was present in 71.5% (p = 0.15 compared to placebo), 69.8% (p = 0.30 compared to placebo), and 70.5%, respectively. This was also not significantly different from placebo when both Dexfen groups were combined (p = 0.16). There was no difference in the prevalence of restricted posterior mitral leaflet mobility among the three groups (p = 0.19). CONCLUSIONS: The small increase in prevalence of minor degrees of AR and MR in patients treated with two to three months of Dexfen previously reported is no longer present three to five months after discontinuation of medication. These data suggest that the degree of regurgitation observed in patients who used Dexfen for a relatively short duration does not progress over time.

Specificity of Doppler echocardiography for the assessment of changes in valvular regurgitation: comparison of side-by-side versus serial interpretation.

OBJECTIVES: We sought to determine the specificity of two different methods for assessing change in aortic (AR), mitral (MR) and tricuspid (TR) valvular regurgitation. BACKGROUND: Echocardiographic imaging with Doppler is the standard noninvasive diagnostic tool for assessing valvular structure and function. Change can be assessed using either independent evaluations (serial) or using a side-by-side comparison. METHODS: Subjects were from the placebo arm of a randomized, double-blind, clinical trial. Three echocardiograms over 10 months were performed. An initial and three-month echocardiogram were read as independent groups, blinded to all parameters except sequence. The initial and 10-month echocardiograms were read side-by-side, blinded to all parameters including sequence. RESULTS: Two hundred nineteen predominantly healthy, obese, white, middle-aged women had initial and three-month echocardiograms (acquisition interval 105 +/- 28 days) evaluated by the serial method (mean 167 +/- 61 days between interpretations). The same subjects had the initial and 10-month studies (acquisition interval 303 +/- 27 days) compared side-by-side. The specificity of the serial versus side-by-side method for determining change in MR grade was 55.8% versus 93.2% (p < 0.001); TR: 63.8% versus 97.6% (p < 0.001) and AR: 93.7% versus 97.6 (p = 0.08). Notably, most of the change occurred in a range (none versus physiologic/mild) that has limited clinical significance. Furthermore, the percentage of echocardiograms interpreted as nonevaluable was lower with the side-by-side method for MR (5.0% vs. 16.0%, p = 0.06), TR (4.6% vs. 15.5%, p < 0.001) and AR (4.1% vs. 12.3%, p = 0.002). CONCLUSIONS: The side-by-side method of assessing change in valvular regurgitation appears to be the more reliable method with a higher specificity and minimal data loss.

Cleft posterior mitral valve leaflet associated with counterclockwise papillary muscle malrotation.

Isolated clefting of the posterior mitral valve leaflet is an uncommon congenital malformation. We report a case of cleft posterior mitral valve leaflet with counterclockwise papillary muscle malrotation. Similar abnormalities in papillary muscle position have been described in association with atrioventricular septal defect but have not been previously reported accompanying isolated clefting of the posterior mitral valve leaflet.

Observer bias in the interpretation of dobutamine stress echocardiography.

BACKGROUND AND HYPOTHESIS: Blinded image analysis is typically utilized in published studies evaluating the accuracy of dobutamine stress echocardiography (DSE). However, in clinical settings, practical considerations may limit the use of blinded interpretations and thus the potential for observer bias arises. This study evaluated the relationships between clinical and blinded interpretations of DSE. METHODS: Wall motion analysis from clinical and blinded DSE interpretations were compared and factors associated with their concordance were investigated in 115 consecutive patients with known or suspected coronary artery disease. RESULTS: Clinical and blinded interpretations agreed on the presence or absence of inducible ischemia in 102 of 115 cases (88.7%: k = 0.76, p < 0.00001). In studies in which the clinical and blinded interpretations were in agreement, there was greater ST-segment depression (STD) in echocardiographically positive compared with negative studies (mean STD 0.73 +/- 0.65 vs. 0.42 +/- 0.67 mm; p = 0.008). In contrast, studies in which there was disagreement had significantly less ST-segment changes (mean STD 0.19 +/- 0.56 mm; p = 0.012) despite comparable results on blinded wall motion analysis. Multiple logistic regression for factors related to the results of clinical and blinded wall motion analysis disclosed that angina pectoris and ST-segment changes were related to clinical interpretations, whereas only angina pectoris was related to the findings on blinded analysis. CONCLUSIONS: Clinical interpretations of echocardiographic images during DSE overall demonstrate good agreement with the results of blinded analysis. Ancillary testing data may influence the analysis of wall motion abnormalities, and thus the potential for observer bias exists unless these interpretations are performed blinded to other clinical data.

An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. Sustained-Release Dexfenfluramine Study Group.

BACKGROUND: The appetite-suppressant drug fenfluramine, usually given in combination with phentermine, has been reported to be associated with cardiac valvular regurgitation. Concern has been raised that the d-enantiomer of fenfluramine, dexfenfluramine, may also cause this problem. We were able to study the question by modifying an ongoing trial comparing dexfenfluramine with regular dexfenfluramine and placebo. METHODS: We modified our randomized, double-blind, placebo-controlled study of dexfenfluramine to include echocardiographic examinations of 1072 overweight patients within a median of one month after the discontinuation of treatment. The patients (approximately 80 percent of whom were women) had been randomly assigned to receive dexfenfluramine (366 patients), investigational sustained-release dexfenfluramine (352 patients), or placebo (354 patients). The average duration of treatment was 71 to 72 days in each of the three groups. Echocardiograms were assessed in a blinded fashion. RESULTS: When all degrees of valvular regurgitation were considered and when the two dexfenfluramine groups were combined, there was a higher prevalence of any degree of aortic regurgitation (17.0 percent vs. 11.8 percent, P=0.03) and any degree of mitral regurgitation (61.4 percent vs. 54.4 percent, P=0.01) in the active-treatment groups than in the placebo group. These differences were primarily due to a higher prevalence of physiologic, trace, or mild regurgitation. Analyses that used the criteria of the Food and Drug Administration for aortic regurgitation of mild or greater severity and mitral regurgitation of moderate or greater severity found no statistically significant difference among the groups (P=0.14 to 0.75). These analyses showed that aortic regurgitation of mild or greater severity occurred in 5.0 percent of the patients in the dexfenfluramine group, 5.8 percent of those in the sustained-release dexfenfluramine group, 5.4 percent of those in the two active-treatment groups combined, and 3.6 percent of those in the placebo group. Mitral regurgitation of moderate or greater severity occurred in 1.7, 1.8, 1.8, and 1.2 percent, respectively. Aortic regurgitation of mild or greater severity, mitral regurgitation of moderate or greater severity, or both occurred in 6.5 percent, 7.3 percent, 6.9 percent, and 4.5 percent, respectively. CONCLUSIONS: The increased prevalence of aortic and mitral regurgitation in patients treated with dexfenfluramine was small, and the degree of regurgitation was usually classified as physiologic, trace, or mild. However, the duration of therapy was short, and whether therapy of longer duration would yield the same or different results is not known.

Natural history of valvular regurgitation 1 year after discontinuation of dexfenfluramine therapy. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Previous studies have reported small increases in the prevalence of low-grade aortic and mitral regurgitation in patients treated with dexfenfluramine compared with placebo. However, whether valvular abnormalities develop or progress 1 year after discontinuation of dexfenfluramine therapy has not been determined. OBJECTIVE: To assess change in valvular regurgitation and morphologic characteristics 1 year after discontinuation of dexfenfluramine therapy. DESIGN: Randomized, double-blind, placebo-controlled, multicenter study. SETTING: Outpatient obesity centers. PATIENTS: Obese persons who had been treated for 2 to 3 months with dexfenfluramine, sustained-release dexfenfluramine, or placebo. Blinding was maintained, and patients returned for repeated echocardiography at 1 year. MEASUREMENTS: Pairs of echocardiograms were evaluated with a side-by-side reading method for change in grade of valvular regurgitation, structure, and function. A standardized acquisition and reading protocol was followed, and a core laboratory was used. RESULTS: 914 patients who had initial echocardiography returned for repeated echocardiography 11.4 +/- 1.0 months (mean +/- SD) after discontinuing study medication (10.0 +/- 1.0 months after initial echocardiography). Compared with the placebo group, a greater proportion of patients in both dexfenfluramine groups had decreased aortic regurgitation (P = 0.003 for the dexfenfluramine group, P = 0.02 for the sustained-release group). No change in mitral regurgitation or any other measure of valvular structure or function was seen in any treatment group. CONCLUSIONS: After dexfenfluramine therapy is taken for 2 to 3 months and discontinued, development or progression of any valvular regurgitation over the following year is unlikely. Echocardiographic evidence suggests that aortic regurgitation regresses in some previously treated patients.