Fen-Phen and Redux, References and Abstracts, Medical Litigation News

Article References & Abstracts
Fen-Phen and Redux

1.Author Langleben D
Institution Division of Cardiology, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Title Relearning the lessons of history: anorexigens and pulmonary hypertension.
Source Chest 1998 Jul;114(1 Suppl):55S-57S
ISSN 0012-3692

2. Author Simonneau G; Fartoukh M; Sitbon O; Humbert M; Jagot JL; Herve P
Institution Center for Pulmonary Vascular Disease, Paris-Sud University, Antoine Beclere Hospital, Clamart, France.
Title Primary pulmonary hypertension associated with the use of fenfluramine derivatives.
Source Chest 1998 Sep;114(3 Suppl): p195S-199S
ISSN 0012-3692
Abstract

Fenfluramine derivatives (Fds) are a well-established risk factor for primary pulmonary hypertension (PPH). We compared 62 Fd-PPH patients (61 women) evaluated in our center between 1986 and 1997 with 125 sex-matched PPH patients nonexposed to Fd referred during the same period (control PPH). In the Fd-PPH group, 33 patients (53%) used dexfenfluramine alone, 7 patients (11%) used fenfluramine alone, and 5 patients (8%) used both drugs. In 17 cases (27%), Fd use was associated with that of amphetamines. Most of the exposed patients used Fd for at least 3 months (81%). The interval between the onset of dyspnea and that of drug intake was 49+/-68 months (27 days to 23 years). At the time of diagnosis, Fd-PPH and control PPH were similar in terms of New York Heart Association functional class and symptoms. The two groups significantly differed only in terms of age (50+/-12 vs 40+/-14 years) and body mass (28+/-6 vs 23+/-4). The two groups displayed similar severe baseline hemodynamics (total pulmonary vascular resistance: 32+/-12 vs 31+/-12 IU/m2), but the percentage of responders to acute vasodilator testing was higher in control PPH (27% vs 10%, p < 0.01). As a result, more patients were treated with oral vasodilators in the control PPH group (36% vs 16%, p < 0.01) and long-term epoprostenol infusion was more frequently used in the Fd-PPH group (52% vs 31%, p < 0.01). Overall survival was similar in the two groups with a 3-year survival rate of 50%.

3. Author Gurtner HP
Title [Chronic pulmonary hypertension of vascular etiology, plexogenic pulmonary arteriopathy and the appetite depressant Aminorex: lessons from an epidemic]
Vernacular Title [Chronische pulmonale Hypertonie vaskularen Ursprungs, plexogene pulmonale Arteriopathie und der Appetitzugler Aminorex: Nachlese zu einer Epidemie.]
Source Schweiz Med Wochenschr 1985 Jun 15;115(24): p818-27
ISSN 0036-7672

4. Author Douglas JG; Munro JF; Kitchin AH; Muir AL; Proudfoot AT
Title Pulmonary hypertension and fenfluramine.
Source Br Med J (Clin Res Ed 1981 Oct 3;283(6296): p881-3
ISSN 0267-0623

5. Author Brenot F; Herve P; Petitpretz P; Parent F; Duroux P; Simonneau G
Institution Service de Pneumologie-Reanimation, Hopital Antoine Beclere, Paris, France.
Title Primary pulmonary hypertension and fenfluramine use [see comments]
Source Br Heart J 1993 Dec;70(6): p537-41
ISSN 0007-0769
Abstract

Not all the risk factors for primary pulmonary hypertension (PPH) are known. Appetite suppressants, including fenfluramine derivatives, are strongly suspected aetiological agents. In a 5 year retrospective study fenfluramine use was evaluated among patients referred to a medical centre specialising in the management of PPH. Fifteen (20%) of 73 patients with PPH had used fenfluramine: all of them were women and in 10 (67%) there was a close temporal relation between fenfluramine use and the development of exertional dyspnoea. Initial right heart catheterisation in the 15 women showed severe resting pulmonary hypertension (mean (SD)) with pulmonary artery pressure (PAP) 57 (9) mm Hg, cardiac 2.1 (0.5) l/min/m2, and pulmonary vascular resistance (PVR) 29 (10) U/m2. Short-term epoprostenol infusion produced a significant vasodilator response in 10 patients (mean fall in PVR 24 (15%) compared with control values). Three fenfluramine users with PPH showed spontaneous clinical and haemodynamic improvement 3, 6 and 12 months after drug withdrawal but there was no significant difference in overall survival (transplant recipients excluded) between fenfluramine users and controls. Histological examination of lung tissue from five women who had used fenfluramine and 22 controls, with PPH showed features typical of advanced plexogenic pulmonary arteriopathy in all. These results do not accord with earlier reports that PPH associated with fenfluramine is less severe and has a better outcome. Fenfluramine may be one aetiological agent that can precipitate or hasten the development of PPH. The results of a European case-control study should give new insights into risk factors for PPH and the cause and effect relation with fenfluramine.

6. Author Abenhaim L; Moride Y; Brenot F; Rich S; Benichou J; Kurz X; Higenbottam T; Oakley C; Wouters E; Aubier M; Simonneau G; Begaud B
Institution Centre for Clinical Epidemiology and Community Studies, McGill University, Montreal, Canada.
Title Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group [see comments]
Source N Engl J Med 1996 Aug 29;335(9):609-16
ISSN 0028-4793
Abstract

BACKGROUND: Recently, a cluster of patients was observed in France in whom primary pulmonary hypertension developed in patients exposed to derivatives of fenfluramine in appetite suppressants (anorexic agents), which are used for weight control. We investigated the potential role of anorexic agents and other suspected risk factors for primary pulmonary hypertension. METHODS: In a case-control study, we assessed 95 patients with primary pulmonary hypertension from 35 centers in France, Belgium, the United Kingdom, and the Netherlands and 355 controls recruited from general practices and matched to the patients' sex and age. RESULTS: The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension (odds ratio with any anorexic-drug use, 6.3; 95 percent confidence interval, 3.0 to 13.2). For the use of anorexic agents in the preceding year, the odds ratio was 10.1 (95 percent confidence interval, 3.4 to 29.9). When anorexic drugs were used to a total of more than three months, the odds ratio was 23.1 (95 percent confidence interval, 6.9 to 77.7). We also confirmed an association with several previously identified risk factors: a family history of pulmonary hypertension, infection with the human immunodeficiency virus, cirrhosis, and use of cocaine or intravenous drugs. CONCLUSIONS: The use of anorexic drugs was associated with the development of primary pulmonary hypertension. Active surveillance for this disease should be considered, particularly since their use is expected to increase in the near future

7. Author Connolly HM; Crary JL; McGoon MD; Hensrud DD; Edwards BS; Edwards WD; Schaff HV
Institution Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA.
Title Valvular heart disease associated with fenfluramine-phentermine [see comments] [published erratum appears in N Engl J Med 1997 Dec 11; 337(24):1783]
Source N Engl J Med 1997 Aug 28;337(9): p581-8
ISSN 0028-4793
Abstract

BACKGROUND: Fenfluramine and phentermine have been individually approved as anorectic agents by the Food and Drug Administration (FDA). When used in combination the drugs may be just as effective as either drug alone, with the added advantages of the need for lower doses of each agent and perhaps fewer side effects. Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million. METHODS: We identified valvular heart disease in 24 women treated with fenfluramine-phentermine who had no history of cardiac disease. The women presented with cardiovascular symptoms or a heart murmur. As increasing numbers of these patients with similar clinical features were identified, there appeared to be an association between these features and fenfluramine-phentermine therapy. RESULTS: Twenty-four women (mean [+/-SD] age, 44+/-8 years) were evaluated 12.3+/-7.1 months after the initiation of fenfluramine-phentermine therapy. Echocardiography demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved. Eight women also had newly documented pulmonary hypertension. To date, cardiac surgical intervention has been required in five patients. The heart valves had a glistening white appearance. Histopathological findings included plaque-like encasement of the leaflets and chordal structures with intact valve architecture. The histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease. CONCLUSIONS: These cases arouse concern that fenfluramine-phentermine therapy may be associated with valvular heart disease. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease.