CLINICAL STUDIES
Prevalence of valvular-regurgitation associated with dexfenfluramine three to five months after discontinuation of treatment
Neil J. Weissman, MD, FACC*,
John F. Tighe, Jr., MD, FACC*,
John S. Gottdiener, MD, FACC* and
John T. Gwynne, MD
* Division of Cardiology, Georgetown University Medical Center, Washington, DC, USA
Department of Clinical Research, Wyeth-Ayerst Research, Philadelphia, Pennsylvania, USA
Manuscript received February 19, 1999;
revised manuscript received June 24, 1999,
accepted August 27, 1999.
Reprint requests and correspondence: Neil J. Weissman, Cardiovascular Research Foundation, Suite 4B-1, 110 Irving Street, NW, Washington, DC 20010
njw1{at}mhg.edu
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Abstract
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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]  mild and/or mitral regurgitation [MR] 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.
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Abbreviations and Acronyms
| | AR | = aortic regurgitation | | BID | = twice a day | | Dexfen | = dexfenfluramine | | Dexfen SR | = sustained-release formulation of dexfenfluramine never marketed | | kg/m2 | = kilogram per square meter | | LVOT | = left ventricular outflow tract | | MR | = mitral regurgitation | | phen-fen | = phentermine/fenfluramine |
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Dexfenfluramine (Dexfen) and other anorectic agents have been used alone or in combination for appetite suppression. In July 1997, physicians at the Mayo Clinic/Merit Care (1) reported valvular abnormalities in 24 patients treated with phentermine/fenfluramine (phen-fen) (2). Since that time, many other reports have addressed various aspects of this issue and have provided a wide range of estimates for the prevalence of heart valve abnormalities associated with appetite suppressants (3–27).
At the time Dexfen was voluntarily withdrawn from the market (September 1997), an ongoing, randomized, double-blind, placebo-controlled study comparing Dexfen, an investigational sustained-release formulation of dexfenfluramine never marketed (Dexfen SR), and placebo was amended to discontinue study medication and perform echocardiographic examinations. Using Food and Drug Administration (FDA) criteria (AR [aortic regurgitation] mild and/or MR [mitral regurgitation] moderate), an analysis of the echocardiograms, performed approximately one month after study medication was discontinued, found no statistical difference among the groups. 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 (p = 0.03), any degree of MR (p = 0.01), and restriction of posterior mitral leaflet mobility (p = 0.02) (28). To determine whether the increased prevalence of minor valvular abnormalities in treated patients as compared to placebo persisted after discontinuation of Dexfen, the double blind was maintained and all patients from the original study were invited to return for a follow-up echocardiogram approximately three months after the first echocardiogram. We report the echocardiographic findings performed three to five months after study medication was discontinued.
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Methods
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Study design.
This study was originally designed as a randomized, double-blind, parallel group, placebo-controlled study comparing the efficacy and safety of investigational sustained-release dexfenfluramine (Dexfen SR) (30 mg once a day) with the immediate release formulation of Dexfen (15 mg BID [twice a day]) and placebo. The study design and demographics of the original trial have been reported previously (28).
Patients.
Patients who participated in the randomized study were men and women 18 years of age or older with a body mass index of at least 30 kg/m2 (kilogram per square meter) or 27 kg/m2 accompanied by hypertension, hyperlipidemia, and/or diabetes mellitus. Patients were ineligible on entry if they had unstable cardiovascular or other systemic disorders, or had obesity secondary to endocrinopathy. Patients with a history of pulmonary hypertension or other disorders listed in the product labeling were ineligible to participate in the original study. The recent or concurrent use of selective serotonin reuptake inhibitors, other anorectic agents or Dexfen (ReduxTM) within six months of randomization in the study was prohibited, and patients agreed not to begin these medications until after the follow-up echocardiogram was complete.
Echocardiographic assessments.
Echocardiograms were performed locally using a standardized imaging protocol as previously described (28). The degree of mitral (MR), aortic (AR), and tricuspid regurgitation was assessed by color Doppler in multiple views. Technical inability to evaluate one valve did not preclude examination of the remaining valves. Severity of MR was visually rated as none, physiologic, mild, moderate, severe, or not evaluable (29). Severity of AR was visually rated as none, trace, mild, moderate, severe, or not evaluable (30). Mitral, aortic, and tricuspid valve leaflet thickness and mobility were also assessed in multiple views as previously described (28, 31). Pulmonary artery pressure was estimated from tricuspid regurgitation velocity using the modified Bernoulli equation and assuming a right atrial pressure of 10 mm Hg (32). Echocardiographic interpretations were performed at an independent central laboratory by cardiologists (N.J.W., J.F.T., J.S.G.) blinded to patient treatment.
Reader variability.
Echocardiograms were evaluated by a second independent reviewer when any of the following criteria were met: thickening of any valve leaflet; restricted valve leaflet mobility moderate; AR mild; MR moderate, or tricuspid regurgitation moderate. All discrepant readings were resolved by consensus readings. A random sample of additional echocardiograms were read by two readers to evaluate interreader agreement, and each reader reread a random sample of echocardiograms to evaluate intrareader agreement.
Statistical analyses.
Demographics among treatment groups at the follow-up visit were compared using analysis of variance and chi-square tests. The FDA criteria of mild or greater AR and/or moderate or greater MR was used to dichotomize valvular regurgitation as present or absent. The proportions of patients in each group who met the FDA criteria were calculated, and the Fisher exact test was used to determine whether significant differences existed among the three treatment groups. The 95 percent confidence intervals (CIs) for crude odds ratios (ORs) for each active treatment group versus placebo were calculated using large-sample normal approximations. The nonparametric Kruskal-Wallis test was used to determine whether significant treatment differences existed with respect to any grade of valvular regurgitation. Separate analyses were performed for the aortic, mitral, and tricuspid valves. The Kruskal-Wallis test was also used to determine significant treatment differences with respect to the four grades of restricted mobility (none, minimal, moderate, and severe). The McNemar test for correlated proportions was used to determine whether significant changes existed in valvular regurgitation from the initial to the follow-up echocardiogram. We performed a power analysis to estimate the necessary sample size to detect a statistically significant change in prevalence. Based on a sample size of n = 300 per treatment group, we had an 80% power to detect a statistically significant change in paired proportions using the McNemar test with alpha = 0.05, two-tailed, and a difference in proportions of 5%, with 10% of the pairs discordant.
The Kruskal-Wallis test was used to compare the change distribution between the treatment groups and the control group. Kappa statistics and percent concordance were used to assess inter- and intrareader variability for echocardiographic parameters. All reported p-values were nominal. All statistical analyses were performed using the SAS statistical software (SAS Corp., version 6.09, Cary, North Carolina).
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Results
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Of the 1,213 patients from the original study, 941 returned for the follow-up echocardiogram. The baseline demographic characteristics (Table 1) and median duration of treatment (77 to 78 days) were similar for all groups. These patients were predominantly obese, white, middle-aged women who had an echocardiogram within a median of 137 days after drug discontinuation (138 days for placebo, 136 for Dexfen, and 136 for Dexfen SR). Overall, 85.3% of patients were treated for eight weeks or longer, and 38.5% percent for at least 12 weeks.
Two hundred and seventy-two patients (90 Dexfen, 90 Dexfen SR, 92 placebo) did not return for the follow-up echocardiogram. The reasons for not returning were equally distributed across the three groups, 167 refused, 92 were lost to follow-up, 10 patients had echocardiography outside the dates defined for this analysis; there was one death (gunshot wound), one technical error (tape did not record), and one patient was randomized but never took the assigned drug.
Of the 941 patients who had an echocardiogram at three months, 919 had a previous one, and for the remaining 22 patients, the three-month echocardiogram was their first ultrasound evaluation. At baseline the prevalence of FDA criteria AR (4.8% vs. 4.9%, p = 1.0) and prevalence of FDA criteria MR (1.3% vs. 3.5%, p = 0.063) were not statistically different from those who did or did not return, respectively. However, those who did return for echocardiography were slightly older, were on therapy longer, were more often hypertensive and less obese than were those who did not, but none of these differences were statistically significant.
Echocardiographic results.
Valvular regurgitation
Most valves were adequately visualized. The aortic valve could be evaluated for regurgitation in 881 echocardiograms (93.6%) and mitral valve in 888 (94.4%).
Using the FDA criteria of mild or greater AR, the prevalence rates (p-value vs. controls) for Dexfen, Dexfen SR, and placebo-treated patients were 7.5% (p = 0.16), 4% (p = 0.84), and 4.5%, respectively (Table 2). Using the FDA criteria of moderate or greater MR, the prevalence rates were 1.7% (p = 1.0), 3.3% (p = 0.30), and 1.7% in these same groups (Table 2). No significant differences among treatment groups were found using this FDA classification for the aortic or mitral valves. In addition, we examined valvular regurgitation by all degrees of severity (Table 3). Aortic regurgitation of any severity (including trace) was detected in 41/295 (13.8%) Dexfen-treated patients, 32/300 (10.7%) Dexfen SR-treated patients, and 34/286 (11.9%) placebo-treated patients, and there were no cases of severe AR. Mitral regurgitation of any severity (including physiologic/trace) was detected in 211/295 (71.5%) Dexfen-treated patients, 211/302 (69.8%) Dexfen SR-treated patients, and 205/291 (70.5%) placebo-treated patients. Most cases of MR were physiologic (53.6% to 61.2%) and mild (7.6% to 14.9%), and there were no cases of severe MR. No statistically significant differences existed in grade (Kruskal-Wallis test) for AR or MR among the three treatment groups including pairwise comparisons. Furthermore, we undertook additional analyses combining the two active treatment groups, and there were still no statistically significant differences versus the placebo group for either MR or AR (Tables 2 and 3).
Similarly, no differences occurred in the prevalence or severity of tricuspid or pulmonary regurgitation between treated groups versus placebo.
Valve morphology and mobility
All evaluable valve leaflets were assessed for the presence or absence of leaflet thickening and degree of restricted mobility. Aortic valve morphology was similar among the three treatment groups. Restricted mobility of any aortic leaflet was rare ( 1%) and not different among groups. No differences existed in the prevalence of restricted posterior or anterior mitral leaflet mobility among the three groups. No patient had thickening or restricted mobility of the tricuspid leaflets.
Pulmonary artery pressure
Two hundred and sixty-four patients, equally distributed among treatment groups, had sufficient tricuspid regurgitation to estimate pulmonary artery pressure. No significant difference was seen in mean systolic pulmonary artery pressure (Dexfen 30.9 ± 7.6 mm Hg, Dexfen SR 30.9 ± 6.3 mm Hg, and placebo 30.5 ± 5.8 mm Hg) among the treatment groups. Pulmonary artery pressure greater than 40 mm Hg occurred in seven, five, and five patients treated with Dexfen, Dexfen SR, and placebo, respectively.
Paired analysis
We examined the change in AR and MR for the subgroup of patients who had both an initial and follow-up echocardiogram (Table 4). The data in Table 4 suggest that there may be a regression of AR in the Dexfen SR group, but this is not statistically significant when compared to placebo (p = 0.15). The trend for an upward shift in the detection of MR (Table 4) over time, predominantly due to the detection of physiologic regurgitation, is confirmed in the placebo group (p < 0.001). Nonetheless, these data support the absence of progression of either AR or MR in any treatment group when compared to placebo.
Reader variability
Interreader variability was assessed using a random sample from all echocardiograms (n = 76) as well as echocardiograms that met criteria for a second evaluation (n = 133). There was agreement on the presence or absence of AR and/or MR (FDA criteria) in 75 of 76 (98.7%) of these echocardiograms. When evaluating the presence or absence of AR and/or MR (FDA criteria) in 111 of 133 selected echocardiograms, there was a concordance of 83.5% (average kappa = 0.74). For intrareader variability, there was 88.6% concordance (n = 79) in assessing the presence or absence of AR and/or MR (average kappa = 0.69). These variability results are similar to those previously reported (28). Each cardiologist evaluated approximately 15 tapes (n = 40), read approximately three months apart, to measure intrareader variability over time. There was no statistical difference between the first and second evaluation of the aortic valve (p = 0.53). When evaluating the mitral valve, however, there was a statistically significant trend toward a more severe interpretation of the valve during the second reading (p = 0.005). This change was predominantly due to the detection of physiologic regurgitation.
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Discussion
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This current study found no difference between treated groups and placebo for regurgitation or restricted leaflet mobility after three to five months, even when considering all degrees of valvular regurgitation and combining Dexfen groups. This is in contrast to the previous study where we also reported no statistical difference using the FDA criteria (AR mild and MR moderate) but did report a higher prevalence of any degree of AR and any degree of MR when all degrees of valvular regurgitation were considered (28). Although regression of minor valvular changes is possible, many other factors could explain these findings.
All patients from the original study were invited to return for an echocardiogram at both one and three months; of these, 1,073 returned for the one-month echocardiogram and 941 returned for the second echocardiogram. This decrease was due to patient choice not to return and not to serious adverse events. The drop-out rate at both time intervals was equally distributed among treatment and placebo groups. Nonetheless, the smaller patient population may have resulted in a reduction of statistical power to detect subtle differences at the later time period.
Moreover, there were subtle changes in the study population that do not appear to have biased the assessment of prevalence at follow-up. Of the 941 patients who underwent an echocardiogram at three months, 919 had a previous one and for the remaining 22 patients, the three-month echocardiogram was their first ultrasound evaluation. The time between initial and follow-up examinations for the 919 patients who had two examinations was similar among groups. Because the prevalence of FDA criteria for AR and MR in these subjects was not statistically different from those subjects who did not return, it is unlikely that selection bias was introduced.
However, once results from the initial echocardiograms were reported, there was the potential for both echocardiographic acquisition and interpretation to be skewed toward positive findings. Examination of the prevalence of valvular regurgitation in the placebo group for the one-month and three-month echocardiograms demonstrates that this may have occurred. For example, in the placebo group, MR of any severity increased from 54.4% to 70.4%. This shift was predominantly due to the detection of physiologic regurgitation in a higher proportion of these subjects. Because of the temporal drift, the validity of paired analysis to detect change within the treated group may have been compromised. In future studies, to minimize temporal drift, echocardiograms should be interpreted concurrently, and blinded to sequence.
Comparison to prior reports.
The prevalence of valvular abnormalities in this study is low and similar to most prior reports. Because small degrees of valvular regurgitation are prevalent in the general population (33), and because of the inherent variability in echocardiography, studies with sufficient sample size and adequate controls are necessary. Large cohort studies (34–37) (greater than 100 subjects per group) with adequate controls reported a prevalence (using FDA criteria) of AR and MR similar to our results. Nonetheless, there remains a wide range of reported prevalence rates (38, 39) and this may be due to differences in study population, treatment drug, combination therapy, duration, selection or reader bias, or possibly other factors.
Little information is available regarding the natural history of regurgitation occurring in anorexigen-treated subjects. Connolly et al. (2) reported severe symptoms in some patients leading to valve replacement despite the fact that therapy had been discontinued. In contrast, Cannistra (40) reported regression of multivalvular regurgitation in a woman who had received phentermine/fenfluramine (phen-fen). Although there are no prospective studies assessing the natural history, a large, randomized, blinded, controlled study, in patients treated with fenfluramine for three months, reported by Davidoff and colleagues (41), failed to find a difference in the prevalence of regurgitation between treated and untreated subjects five years after cessation of therapy. Shively (36) reported a lower prevalence of regurgitation in patients with late as opposed to early echocardiograms after discontinuation of Dexfen therapy, suggesting the possibility of regression. Little information has been reported on sequential echocardiograms on patients who used appetite suppressants (42). Wee and colleagues performed a retrospective survey of the echocardiographic databases in two large hospitals and identified only 46 patients who had an echocardiogram prior to and after appetite-suppressant therapy (42). Using the FDA case definition, two patients (4.3%) showed progression and two patients showed regression. Of the two patients who showed progression, one had mild AR that progressed to moderate in the presence of a bicuspid valve and there was an eight-year period between echocardiograms in the other patient. The present double-blind study provides longitudinal echocardiograms acquired in a large, controlled population. For patients treated with Dexfen for two to three months, we found no difference in prevalence of valvular regurgitation between treated patients and controls three to five months after drug was discontinued, suggesting that progression is extremely unlikely.
Study limitations.
This study continues to have the limitations discussed in our previous report (28). These include the relatively short duration of treatment (median of 77 to 78 days) and the lack of pretreatment echocardiograms. Furthermore, this study does not address combination treatment (phen-fen).
Clinical implications.
The results of this study are reassuring for the population of patients treated with Dexfen for three months or less. After discontinuation of treatment for three to five months, there was no difference in prevalence of either AR or MR of any severity between treated and control patients, suggesting that progression is unlikely. Nevertheless, patients treated with appetite suppressants who present with a new murmur or clinical symptoms should undergo the appropriate evaluation as outlined in the American College of Cardiology/American Heart Association Guidelines (43) (Appendix).
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Appendix
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Echocardiographic criteria for mitral valve leaflet mobility (28).
| Posterior |
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| Normal |
Full excursion of the leaflets to the posterior wall. |
| Mildly impaired |
Slightly decreased mobility that does not impair excursion to the posterior wall by more than 50%. |
| Moderately impaired |
Impaired motion by >50%, but mobility of part of the leaflet body is maintained. |
| Severely impaired |
Complete immobility of the posterior leaflet. |
| Anterior |
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| Normal |
Full excursion of the leaflets into the left ventricular outflow tract (LVOT). |
| Mildly impaired |
Mild diastolic doming or decreased mobility that does not impair excursion into the LVOT by more than 50%. |
| Moderately impaired |
Impaired motion by >50%, but mobility of part of the leaflet body is maintained. |
| Severely impaired |
Complete immobility of the anterior leaflet. |
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Acknowledgments
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We would like to thank John Vance, MD, Susan Perras, MSN, Harvey Kushner, PhD, Maria Mattern, RN, and Jan Kitzen, PhD, for their assistance in the preparation of this manuscript, and Jonathan Tall, CNMT, CCRC, for the coordination of the Central Echo Laboratory.
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Footnotes
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This work was sponsored by a research grant from the Wyeth-Ayerst Research Division of Wyeth Laboratories, Philadelphia, Pennsylvania.
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References
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Abstract
Methods