International Journal of Obesity (1999) 23, 926±928 ß 1999 Stockton Press All rights reserved 0307±0565/99 $15.00 http://www.stockton-press.co.uk/ijo Dose-effect of fen¯uramine use on the severity of valvular heart disease among fen-phen patients with valvulopathy RLi1*, MK Serdula2, DF Williamson3, BA Bowman2, DJ Graham4 and L Green5 1Epidemic Intelligence Service, Epidemiology Program Of®ce and Division of Nutrition and Physical Activity; 2Division of Nutrition and Physical Activity; 3Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, USA; 4Epidemiology Branch, USA; and 5Reports Evaluation Branch, Division of Pharmacovigilance and Epidemiology, US Food and Drug Administration, USA OBJECTIVE: To determine whether the severity of valvulopathy was associated with the dosage of fen¯uramine taken by fen¯uramine-phentermine users with valvulopathy. DESIGN: Out of 105 suspected valvulopathy case reports received by the US Food and Drug Administration (FDA) among fen¯uramine-phentermine users, 74 patients meeting FDA case de®nition for valvulopathy were included in this study. Patients with severe valvulopathy were classi®ed as those either undergoing valve replacement surgery or having severe aortic or mitral regurgitation; all other patients were considered to have less severe valvulopathy. RESULTS: The proportion with severe valvulopathy increased from 20 ± 66% with increasing fen¯uramine dosage from 40 mg=dto60 mg=d. Compared with patients taking<40 mg=d fen¯uramine, patients taking 60 mg=d had an adjusted odds ratio of 9.2 (95% con®dence interval 2.1 ± 40.8) for severe valvulopathy. CONCLUSION: Compared to patients with less severe valvulopathy, those with severe valvulopathy were substan- tially more likely to have taken 60 mg=d fen¯uramine. Keywords: dose ± effect; fen¯uramine-phentermine; severity of valvulopathy Introduction provides information about the dose-effect. The pur- pose of this study was to determine whether the severity of valvular heart disease among fen-phen Fen¯uramine is a serotonin-based appetite-suppres- users was associated with the dosage of fen¯uramine. sant drug which is widely used in combination with phentermine, commonly called fen-phen. On 8 July 1997, the Mayo Clinic reported 24 cases of valvular heart disease in women treated with fen-phen,1 who Subjects and methods had no history of valvulopathy. Subsequently, the US Food and Drug Administration (FDA) issued a Public Because the striking feature of the case reports Health Advisory requesting that physicians report received by FDA was the consistent involvement of additional cases of valvulopathy through MED- left-sided cardiac valve lesions, FDA established its WATCH, a medical product reporting system estab- case de®nition as the existence of either mild or 2 lished by FDA. Based on results from the prevalence greater aortic regurgitation (AR), or moderate surveys, which consistently found a higher than or greater mitral regurgitation (MR), or both as expected prevalence of valvulopathy among persons determined by echocardiography. At the time when 3 exposed to fen¯uramine or dexfen¯uramine, FDA fen¯uramine and dexfen¯uramine were voluntarily announced the voluntary withdrawal of fen¯uramine withdrawn from the market, FDA had received 105 and dexfen¯uramine from the market on 15 Septem- fen-phen case reports. Among them, 88 (84%) met ber 1998. FDA de®nition of valvulopathy. After excluding 14 Although the most recent studies provide further patients without complete information on drug expo- support to the association of appetite-suppressant sure and covariates, the ®nal study sample consisted 4±6 medications with valvulopathy, none of them of 74 fen-phen patients with valvulopathy. Patients with severe valvulopathy were classi®ed as those either undergoing valve replacement surgery or *Correspondence: Ruowei Li, Division of Nutrition and Physical Activity (Mailstop K26), Centers for Disease Control and having severe AR or severe MR; all other patients Prevention, 4770 Buford Hwy, N.E., Atlanta, were considered to have less-severe valvulopathy. GA 30341-3717, USA. w2 test was used to examine the difference in the E-mail: [email protected] Received 23 November 1998; revised 5 February 1999; accepted proportion of severe valvulopathy. Logistic regression 31 March 1999 analysis was used to determine whether the severity of Severity of valvulopathy and fen¯oramine use R Li et al 927 valvulopathy was related to the drug use, after adjust- Table 2 Odds ratios (OR) for severe valvulopathy ing for age, body weight at report, and the duration of Crude OR Adjusted OR a drug use. No interaction terms between duration and (95% CI) (95% CI) drug use were included in the model, because of their Age (10 y) 1.2 (0.7 ± 1.9) 1.3 (0.7 ± 2.4) statistical insigni®cance (P > 0.01). All statistical ana- Weight at Report (10 kg) 1.2 (1.0 ± 1.4) 1.1 (0.8 ± 1.4) lyses were done using SAS version 6.12.7 Duration (1 month) 1.0 (1.0 ± 1.1) 1.0 (1.0 ± 1.1) Fen¯uramine (mg=d) <40 1.0 (ref) 1.0 (ref) 40 1.4 (0.2 ± 8.4) 1.5 (0.2 ± 10.2) Results 60 9.0 (2.2 ± 36.4) 9.2 (2.1 ± 40.8) 95% CI 95% con®dence interval. aAdjusted for all other variables. Thirty-®ve out of 74 fen-phen patients (47%) were classi®ed as having severe valvulopathy, whereas 39 (53%) were classi®ed as having less severe valvulo- Discussion pathy. Among patients with severe valvulopathy, 17 underwent value replacement surgery, ®ve had severe AR, and 13 had severe MR. In all patients, the median This is the ®rst study to suggest that the severity of dosage for fen¯uramine and phentermine was cardiac valvulopathy was associated with fen¯ura- 60 mg=d (range 10 ± 220 mg=d) and 30 mg=d mine dosage, but not with phentermine dosage. (range 15 ± 60 mg=d) respectively, whereas the Among patients with valvulopathy, those with median duration of fen-phen use was 11 months severe valvulopathy were substantially more likely (range 1 ± 39 months). Table 1 shows that patients to have taken a higher dose of fen¯uramine with severe valvulopathy tended to use higher fen- (60 mg=d) than those with less severe valvulopathy. ¯uramine doses than those with less-severe valvulo- The mechanism of the drug-associated valvulo- pathy (82% of severe vs 38% of less-severe patients pathy is unclear. It has been speculated that serotonin took 60 mg=d, w2 15.08, P 0.0001). The propor- might be the link, because the injured valves look tion with severe valvulopathy increased from 20% identical to those observed in carcinoid-induced valv- (6=30) to 66% (29=44), as fen¯uramine dosage ular disease.1 An additional hypothesis is that phen- increased from 40 mg=d to 60 mg=d. Compared termine may impair the clearance of serotonin by the with patients taking <40 mg=d fen¯uramine, patients lung, which would allow abnormally high concentra- taking 60 mg=d had an adjusted or of 9.2 (95% tions of serotonin to reach the left side of the heart, con®dence interval 2.1 ± 40.8) for severe valvulopa- when it is taken together with fen¯uramine.9,10 thy (Table 2). The Hosmer and Lemeshow goodness- Because all the subjects in this study were treated of-®t tests indicated that the logistic model ®ts the with both fen¯uramine and phentermine, we cannot data well with goodness-of-®t statistic 1.3 reject the possibility that the dose-effect of fen¯ur- (P 0.9961).8 In contrast, both phentermine dosage amine on the severity of valvulopathy may have a and duration of drug use did not appear to be related phentermine-related threshold. to the severity of valvulopathy. Because data on initial body weight were not provided, weight at the time of report was used as a proxy. Patients with severe valvulopathy had a sig- Table 1 Description of cases of severe and less-severe ni®cantly higher weight at the time of report than valvulopathy those with less-severe valvulopathy, which may Severe Less-severe re¯ect differences in initial weight. Nevertheless, the valvulopathy vavulopathy effect of fen¯uramine dosage on severity of valvulo- (n 35) (n 39) pathy cannot be ascribed to differential body weight, Female 35.(100%) 38.(98%) because weight was not signi®cantly related to sever- Age (y) 44.3 (s.d. 9.6) 43.1 (s.d. 8.5) Weight at report (kg) 95.0 (s.d. 28.3) 87.1 (s.d. 18.6)* ity of valvulopathy in the logistic models. Fen¯uramine (mg=d) Although a previous study showed an association of <40 3.(9%) 14.(36%) valvulopathy with the duration of drug use,5 duration 40 3.(9%) 10.(26%) 60 24.(68%) 13.(33%) of drug use did not appear to be related to the severity > 60 5.(14%) 2.(5%) of valvulopathy in this MEDWATCH data. There are Phentermine (mg=d) several explanations. First, the duration of exposure <30 11.(32%) 13.(33%) 30 18.(51%) 21.(54%) depended upon the reporting physician's recall and > 30 6.(17%) 5.(13%) may have been underestimated for those patients who Duration of drug use (months) had previously used appetite-suppressants under the 6 9.(26%) 12.(31%) > 6 ± 12 15.(43%) 14.(36%) care of other physicians. Second, cardiac disorders > 12 ± 24 6.(17%) 10.(26%) may occur as early as a few weeks after drug expo- > 24 ± 5.(14%) 3.(8%) sure,6 whereas 93% of all patients in this study had Percentage may not add up to 100 because of rounding-off.