Anorexigens and Pulmonary Hypertension in the United States

Stuart Rich, MD, FCCP; Lewis Rubin, MD, FCCP; Alexander M. Walker, MD, DrPH; Sebastian Schneeweiss, MD and Lucien Abenhaim, MD From the Section of Cardiology (Dr. Rich), Rush Medical College, Chicago, IL; the Section of Pulmonary and Critical Care Medicine (Dr. Rubin), University of California San Diego, School of Medicine, San Diego, CA; the Department of Epidemiology (Drs. Walker and Schneeweiss), Harvard School of Public Health, Cambridge, MA; and the Department of Epidemiology and Biostatistics (Dr. Abenhaim), Jewish General Hospital, McGill University, Montreal, Canada.


CHEST. 2000;117(3) 

In This Article

Abstract and Introduction

Background: The use of appetite suppressants in Europe has been associated with the development of primary pulmonary hypertension (PPH). Recently, fenfluramine appetite suppressants became widely used in the United States but were withdrawn in September 1997 because of concerns over adverse effects.
Materials and methods: We conducted a prospective surveillance study on patients diagnosed with pulmonary hypertension at 12 large referral centers in North America. Data collected on patients seen from September 1, 1996, to December 31, 1997, included the cause of the pulmonary hypertension and its severity. Patients with no identifiable cause of pulmonary hypertension were classed as PPH. A history of drug exposure also was taken with special attention on the use of antidepressants, anorexigens, and amphetamines.
Results: Five hundred seventy-nine patients were studied, 205 with PPH and 374 with pulmonary hypertension from other causes (secondary pulmonary hypertension [SPH]). The use of anorexigens was common in both groups. However, of the medications surveyed, only the fenfluramines had a significant preferential association with PPH as compared with SPH (adjusted odds ratio for use > 6 months, 7.5; 95% confidence interval, 1.7 to 32.4). The association was stronger with longer duration of use when compared to shorter duration of use and was more pronounced in recent users than in remote users. An unexpectedly high (11.4%) number of patients with SPH had used anorexigens.
Conclusion: The magnitude of the association with PPH, the increase of association with increasing duration of use, and the specificity for fenfluramines are consistent with previous studies indicating that fenfluramines are causally related to PPH. The high prevalence of anorexigen use in patients with SPH also raises the possibility that these drugs precipitate pulmonary hypertension in patients with underlying conditions associated with SPH.

Primary pulmonary hypertension (PPH), although a rare disease, has gained attention recently due to its association with the use of anorexigens. An epidemic of PPH occurred in the 1960s in association with the use of the anorexigen aminorex fumarate in Switzerland, Austria, and Germany.[1,2] More recently, cases of PPH have been linked to the use of fenfluramine derivatives in the United Kingdom, France, and Belgium.[3,4,5,6,7,8] The International Primary Pulmonary Hypertension Study (IPPHS) showed a strong association between PPH and the use of appetite suppressants, primarily the fenfluramine derivatives.[9]

In April 1996, the US Food and Drug Administration approved dexfenfluramine for extended use as an anorexigen in the United States. At the same time, the use of fenfluramine and phentermine together ("fen-phen") was gaining in popularity, and cases of PPH associated with these drugs soon appeared.[10] Although the IPPHS had shown that the risk of developing PPH increased with the duration of use of appetite suppressants, the experience with long duration of use in Europe was limited since the indicated use of these drugs had been restricted to 3 months. Approval in the United States, however, did not carry any limitation on the duration of use of dexfenfluramine.

Given the extraordinary prevalence of obesity in the United States, and the widespread and growing use of anorexigens without a limit on their length of use, a significant increase in the number of cases of PPH seemed likely.[9] Consequently, a group of pulmonary hypertension specialists initiated a voluntary collaborative survey entitled Surveillance of North American Pulmonary Hypertension (SNAP). The goal of the project was to collect clinical information on patients with pulmonary hypertension who had been referred to their institutions and to document their exposure to commonly used medications, with special emphasis on anorexigens and chemically related substances. By doing so, we would be able to compare the association between anorexigen use and the development of PPH using patients with secondary pulmonary hypertension (SPH) as a comparison group.