Silver Lining to the Cloud over Anorexogen-Related Cardiac Valvulopathy?

Pharmacologic appetite suppression has been used as an alternative strategy in the treatment of obesity for four decades. Anorexogen therapy is a more attractive method of losing weight than prolonged, often unsuccessful dietary restriction or gastric bypass or stapling procedures that facilitate gastric emptying. The appetite-suppressing effect of anorexogens is mediated by altering serotonin kinetics; phentermine inhibits clearance of serotonin in the lungs, and fenfluramine stimulates its release and blocks its neuronal reuptake. The common aim of the different therapies, used singly or in combination, is to reduce the morbidity due to coronary heart disease, stroke, and hypertension associated with obesity. Initially, fenfluramine (introduced in 1959) and phentermine (introduced in 1973) were used individually for short-term therapy (<3 months). These agents were well tolerated and resulted in reduction in body weight without serious complications, except for rare reports of pulmonary hypertension (1). In 1992, a series of long-term studies of weight control (2) suggested that long-term combination therapy with fenfluramine and phentermine (fen-phen) was more effective in treatment of obesity. Subsequently, the number of prescriptions for dexfenfluramine (the dextro isomer of fenfluramine) and fenfluraminephentermine skyrocketed. By late 1995, approximately 15 million prescriptions had been filled, predominantly for young to middle-aged women. Unfortunately, societal condemnation of obesity fueled the explosion in use of anorexogen treatment, which extended to casual use for cosmetic weight loss, particularly in minimally overweight, nonobese women. Treatment of obesity with fenfluraminephentermine was abruptly halted in 1997, when both agents were voluntarily withdrawn from the market by the manufacturer. This withdrawal was prompted by a public health advisory from the U.S. Food and Drug Administration (3) in response to the report of 24 patients treated with fenfluraminephentermine for more than 6 months who had clinical and echocardiographic evidence of valvular regurgitation, predominantly involving the mitral and aortic valves (4). Five patients required surgical intervention and 8 developed pulmonary hypertension. Histologic findings of the explanted valves consisted of nondestructive encasement of the leaflets and subvalve apparatus that was indistinguishable from carcinoid or ergotamine-induced valve disease (4). The investigators suggested that the valvular lesions were related to elevated plasma serotonin levels with consequent fibroblast activation and proliferation, although serotonin levels were never measured. These findings aroused major concern about how large a proportion of the patients exposed to fenfluramine and phentermine had sustained or were likely to develop future valvular heart damage. A further disquieting feature was the certain knowledge that 18 million prescriptions for anorexogens had been filled by 1996. Provider-initiated reports to the Food and Drug Administration suggested that dexfenfluramine used alone or in combination with phentermine was also associated with increased incidence of valvular disease. Analysis of the initial reports to the Food and Drug Administration (5) indicated that the prevalence of valvulopathy ranged from 20% to 32%, on the basis of echocardiographic criteria for the presence of aortic regurgitation graded as mild or worse and mitral regurgitation graded as moderate or worse (3). These echocardiographic criteria are derived from the fact that mild mitral regurgitation is common in normal persons and mild aortic regurgitation occurs in fewer than 1% of normal persons. Three important studies all confirmed the association between use of anorexogens and newly diagnosed valvular heart disease (6-8). However, no correlation existed between valvulopathy and obesity per se or weight loss from dietary restriction. The incidence of newly diagnosed valvular disease associated with single or combination therapy varied from 7.1 per 10 000 in a large casecontrol study to 22.7% in an echocardiographic study (6, 7); however, unlike in the original report (4), the severity of valve disease in the majority of patients in these studies was mild. The disparity between reported frequencies of valvulopathy reflected differences in methods, including definition of valvulopathy, the means used to detect valve regurgitation (clinical examination or Doppler echocardiography), single-agent versus combination therapy, duration of drug exposure, and length of follow-up. The true prevalence of anorexogen-related valvulopathy has decreased from the early studies to less than 10% for dexfenfluramine (9) and for fenfluramine and phentermine (10-12). As experience with patients exposed to anorexogens increased, it became clear that although subtle mitral leaflet thickening and restriction may result in mitral regurgitation (8), there was a more convincing causal relationship between anorexogen use and aortic regurgitation. Two key factors emerged from subsequent population studies. First was the relation between duration of treatment with fenfluramine and phentermine and likelihood of valvulopathy (11). Aortic regurgitation developed mainly in patients who took the drugs for more than 6 months, and a sixfold greater prevalence of aortic regurgitation was observed in patients exposed to therapy for 2 years (11). Second, valvular regurgitation did not appear to progress in the 3 to 5 months after discontinuation of dexfenfluramine therapy in 1073 patients studied by Doppler echocardiography, although these patients had only short exposure (<3 months) (13). Whether progressive valvulopathy requiring surgical intervention is confined to patients with prolonged exposure, as indicated by the initial study (4), and whether the onset of valve disease may be delayed remain to be determined. Recent reports have suggested improvement in valvulopathy as assessed by Doppler echocardiography (14, 15). Hensrud and colleagues (15) described improvement in 8 of 15 patients who underwent echocardiographic studies after stopping therapy and 6 months later. In this issue of Annals, two studies bring potentially welcome news about the natural history of anorexogen-related valvulopathy after cessation of therapy. Weissman and colleagues (16) report a study of 1095 obese, predominantly white middle-aged women treated for 2 to 3 months with dexfenfluramine or placebo who had echocardiography 1 to 3 months after discontinuation of anorexogen treatment. Of these women, 914 had repeated echocardiograms 1 year after withdrawal of treatment to assess changes in valve structure and prevalence and severity of valvular regurgitation. Patients who declined follow-up were younger and heavier but had no difference in frequency and severity of valve regurgitation on their initial echocardiogram. Echocardiograms were interpreted side by side, and readers were blinded to treatment assignment and temporal sequence. In 95% of patients with paired studies, the aortic, mitral, and tricuspid valves could be evaluated for regurgitation by Doppler echocardiography. The exciting finding was the statistically significant decrease in the prevalence of aortic regurgitation in the dexfenfluramine group (6.4%) and the sustained-release dexfenfluramine group (5.1%) at 1 year; no change was seen in the placebo group. However, the prevalence of mitral regurgitation or mitral or aortic valve morphology remained the same. This study demonstrates that aortic regurgitation may regress within 1 year after short exposure to a single agent. Mast and colleagues (17) report the clinical and echocardiographic follow-up of 50 patients (some of whom were included in the original report [4]) exposed to prolonged treatment with fenfluramine (mean duration of therapy, 447 days). Patients had echocardiograms after termination of treatment and at 1 year of follow-up. In contrast to Weissman and colleagues' findings, the incidence of valvulopathy was high; 76% of patients had mild or worse mitral regurgitation and 86% had mild or worse aortic regurgitation. Serial echocardiograms obtained a mean of almost 1 year apart demonstrated reduction in severity of mitral regurgitation in 45% of patients and regression of aortic regurgitation by at least one grade in 44%. Severity of mitral or aortic regurgitation did not change in 50% of patients. Evidence of progressive worsening of valvular regurgitation occurred only in a minority of patients with mitral regurgitation (5%) or aortic regurgitation (5%). The observation in these studies that both mitral and aortic regurgitation may regress over time after discontinuation of therapy with anorexogens has important clinical implications for management of patients in whom surgical intervention might otherwise be considered. The natural history of anorexogen-induced valvulopathy has yet to be fully charted. Long-term studies of large cohorts of patients, particularly those with prolonged exposure, are awaited. The studies by Weissman and Mast and their colleagues clarify two important issues: that progressive valvulopathy is uncommon and that valvular regurgitation may spontaneously resolve in some patients after cessation of anorexogen therapy. These new findings may be a silver lining to the dark cloud of anorexogen-related valvulopathy.