Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hypertension
Lucien Abenhaim, M.D., Yola Moride, Ph.D., François Brenot, M.D., Stuart Rich, M.D., Jacques Benichou, M.D., Xavier Kurz, M.D., Tim Higenbottam, M.D., Celia Oakley, M.D., Emil Wouters, M.D., Michel Aubier, M.D., Gérald Simonneau, M.D., Bernard Bégaud, M.D., for The International Primary Pulmonary Hypertension Study Group
Background Recently in France, primary pulmonary hypertensiondeveloped in a cluster of patients exposed to derivatives offenfluramine in appetite suppressants (anorexic agents), whichare used for weight control. We investigated the potential roleof anorexic agents and other suspected risk factors for primarypulmonary hypertension.
Methods In a case–control study, we assessed 95 patientswith primary pulmonary hypertension from 35 centers in France,Belgium, the United Kingdom, and the Netherlands and 355 controlsrecruited 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 confidenceinterval, 3.0 to 13.2). For the use of anorexic agents in thepreceding year, the odds ratio was 10.1 (95 percent confidenceinterval, 3.4 to 29.9). When anorexic drugs were used for atotal of more than three months, the odds ratio was 23.1 (95percent confidence interval, 6.9 to 77.7). We also confirmedan association with several previously identified risk factors:a family history of pulmonary hypertension, infection with thehuman immunodeficiency virus, cirrhosis, and use of cocaineor intravenous drugs.
Conclusions The use of anorexic drugs was associated with thedevelopment of primary pulmonary hypertension. Active surveillancefor this disease should be considered, particularly since theuse of anorexic drugs is expected to increase in the near future.
Primary pulmonary hypertension is a rare, often fatal diseasethat tends to occur with particular frequency in women duringtheir third or fourth decade.1,2 The factors leading to itsdevelopment remain enigmatic. The occurrence of familial primarypulmonary hypertension suggests a genetic susceptibility.3 Reportshave also suggested that portal hypertension4,5 and recent pregnancy6may have causative roles. Exogenous factors have been suspectedas well, including cocaine use,7 infection with the human immunodeficiencyvirus (HIV),8 oral-contraceptive use,9,10 and the use of anorexicagents.11,12,13 In the 1960s, there was an epidemic of primarypulmonary hypertension in Switzerland, Germany, and Austriain association with a particular anorexic agent, aminorex fumarate.11In the early 1990s, French investigators reported a clusterof cases among patients who had used derivatives of fenfluramine.13Dexfenfluramine, the main drug thought to be involved, is usedto treat obesity.
We sought to assess the incidence of primary pulmonary hypertensionand investigate the causative roles of various suspected riskfactors, especially anorexic agents.14
Methods
This was a prospective case–control study conducted infour countries (France, Belgium, the United Kingdom, and theNetherlands). The study included men and women 18 to 70 yearsof age who had lived in the country where they were studiedfor more than six months, were able to participate in the interview,and did not have another chronic, active, life-threatening disease.
Three hundred six cardiology and pulmonary-medicine centersat large or university-based hospitals, public and private,were contacted in France, Belgium, the United Kingdom, and theNetherlands, and 220 of them agreed to participate. The centerswere provided with stamped, preaddressed postcards with whichto report cases of primary pulmonary hypertension to local researchteams. The centers were also contacted every two to three monthsby mail or telephone, or they were visited. The medical recordsof the patients identified were screened at each site by trainedspecialists who, in almost all instances, were not affiliatedwith the reporting centers. During the site visits, the diagnosticand reporting process at the centers was reviewed to identifypatients with primary pulmonary hypertension who might havebeen overlooked and assess potential biases in reporting. InBelgium, regular contact was established with each of 71 centerswhere primary pulmonary hypertension might have been diagnosed.This contact allowed us to calculate the annual incidence ofthe disease in the Belgian population.
Patients
We recruited patients with primary pulmonary hypertension diagnosedfrom September 1, 1992, through September 30, 1994, at the timeof the patient's first right-heart catheterization. The diagnosisrequired both that pulmonary hypertension be documented andthat the following secondary causes be absent: congenital abnormalitiesof the lungs, thorax, or diaphragm; congenital or acquired valvularor myocardial disease; pulmonary thromboembolism; obstructivelung disease; interstitial lung disease; pulmonary-artery orpulmonary-valve stenosis; pulmonary venous hypertension; centralhypoventilation with hypoxemia and hypercapnia; parasitic diseaseaffecting the lungs; sickle cell anemia; the acquired immunodeficiencysyndrome (AIDS); and collagen vascular diseases. An internationalpanel of reviewers assessed abstracted medical data, cardiac-catheterizationreports, chest radiographs, perfusion lung scans, and echocardiographicimages or reports for patients qualifying for the study. Thepanel, whose members had no knowledge of any patient's exposureto anorexic drugs, classified the patients in three groups:patients with definite primary pulmonary hypertension, thosewith probable primary pulmonary hypertension, and those whowere not considered appropriate for the study. The first twogroups were included in the case–control analysis. Thereproducibility of the classifications, as verified by a secondreview of 10 randomly selected files, was excellent (all thedecisions to include or exclude patients were confirmed). Theresults of autopsy or biopsy were obtained for nine patientswho underwent transplantation or died soon after their inclusionin the study, and they all had plexogenic pulmonary arteriopathy,regardless of their status with respect to anorexic-drug use.
Controls
Four control patients were sought for each patient with primarypulmonary hypertension. The controls were randomly selectedfrom lists of consecutive patients seen by the same generalpractitioner as the patient with primary pulmonary hypertension.The general practitioner was identified by the patient and definedas the physician the patient consulted for usual care. If thisphysician was unavailable (usually because he or she refusedto participate in the study), other general practitioners werecontacted who practiced in the region where the patient lived.One third of the controls were recruited in this manner. Thecontrols were individually matched to the case patients withrespect to age (within five years), sex, and the number of visitsto the physician per year (<2 or >2). The following datawere recorded for all the visits made during a one-week period:the patient's name, age, sex, and the number of visits madeby that patient per year. All visits of patients who met thematching criteria were identified, and four controls were randomlyselected by the local coordinating center. The general practitionerwas contacted again for the names and telephone numbers of thepatients selected. The same criteria for inclusion and exclusionwere used in selecting the controls that were used in selectingthe case patients, except for the diagnosis of primary pulmonaryhypertension.
Exposure to Anorexic Drugs
Each patient underwent a thorough, face-to-face interview conductedby a specially trained interviewer who had no medical backgroundand was unaware of the study's main hypotheses. The patientswere asked about demographic characteristics; their medical,surgical, and obstetrical histories; and exposure to drugs.Data on such exposures were recorded chronologically on a calendar-likedata sheet. The recording of exposures reported to have occurredafter August 1, 1989, was more detailed than that of earlierexposures. The presence of HIV infection and the diagnosis ofcirrhosis were determined by a review of the medical charts.Drug use was established by three methods: spontaneous reportingby the patient; the presentation to the patient of lists ofapproximately 80 trade names chosen from among the most commonlyprescribed drugs in 17 therapeutic classes (the individual productsvaried slightly from country to country); and the presentationto the patient of a visual display showing 35 selected packages,tablets, or both. Only exposure to antihypertensive drugs, oralcontraceptives, thyroid extracts, and anorexic agents (alsocalled appetite suppressants) was analyzed. The following anorexicagents were considered: derivatives of fenfluramine (fenfluramineand dexfenfluramine), amphetamine-like anorexic agents (diethylpropion[amfepramone], clobenzorex, fenproporex, mazindol, and phenmetrazine),and compound preparations of appetite-suppressant drugs andother drugs taken to lose weight. Special preparations usedin order to lose weight, with no reference to appetite suppression,were not considered anorexic agents. Each patient was givena special questionnaire assessing his or her use of illicitdrugs (intravenous drugs, cocaine, hashish, and marijuana).The data-collection process was identical in all the countriesstudied.
For each case patient and that patient's matched controls, theindex date used in the study of risk factors corresponded tothe date of onset of the case patient's symptoms (usually dyspnea).Patients were classified as having been exposed to a given riskfactor if the exposure occurred before the index date (a "definiteexposure"). Exposures reported to have occurred at an indeterminatetime or during the same month as the index date were classifiedas "possible exposures." Patients in whom the exposure beganafter the index date were considered unexposed to that riskfactor. Definite exposure to anorexic agents was categorizedfurther, depending on whether the exposure occurred in the 12months before the index date ("recent use") or had ended morethan 12 months earlier ("past use"). Because of the design ofthe calendar data sheet, this categorization could be used onlyfor 65 case patients and 234 matched controls whose index dateswere later than August 1, 1989.
Statistical Analysis
All the odds ratios presented here were obtained through conditionallogistic regression. All the models included exposure to appetitesuppressants (categorized as none, possible, or definite, asdefined above), weight-related confounding variables, and othervariables thought to be possible risk factors. The weight-relatedvariables consisted of the patient's highest lifetime body-massindex (calculated as the weight in kilograms divided by thesquare of the height in meters and dichotomized as <30 and>30, a cutoff point selected a priori); behavior aimed atlosing weight (categorized as present or absent, with the formerdefined as a report of unstable weight; the use of diuretics,laxatives, or phytotherapy for weight loss; or episodes of anorexia);and the use of thyroid extracts (yes or no). The other variablesthought to be risk factors were the use of cocaine, intravenousdrugs, or both (yes or no); treatment for systemic hypertension(present or absent); and smoking (yes or no). In separate analysesconducted of women, oral-contraceptive use (yes or no) and pregnancyduring the year before the index date (yes or no) were alsoconsidered, and adjustment was made for them. Variability insampling associated with the estimated odds ratios was assessedby two-sided 95 percent confidence intervals. All the analyseswere performed with the SAS statistical package, version 6.13(Unix), and Egret, version 026.6. P values of less than 0.05were considered to indicate statistical significance.
Results
One hundred thirty-five patients with primary pulmonary hypertensionmet the criteria for inclusion in the study. An additional 26patients were already dead or were too sick to be interviewed.Twenty-three of the 135 patients were considered by the reviewpanel not likely to have primary pulmonary hypertension, 2 werelost to follow-up, 2 declined to participate, and 13 could notbe interviewed, or their data reviewed, before the final analysis.The remaining 95 patients (80 with definite and 15 with probableprimary pulmonary hypertension), who were retained in the case–controlstudy, were identified at a total of 35 specialized centers(Table 1). A national referral center for primary pulmonaryhypertension in France (Antoine Béclère Hospital)15contributed 35 patients; the other centers each contributed1 to 6 patients (mean, 1.7). The mean (±SD) age of thecase patients was 44.7±12.3 years, and that of the controlswas 45.1±12.6 years. Among the case patients, the female:maleratio was 2.3:1 (Table 1). Among the controls, the rate of participationwas 85.3 percent in France, 92.1 percent in Belgium, 81.8 percentin the United Kingdom, and 100 percent in the Netherlands.
Table 1. Characteristics and Countries of the Study Population.
The clinical characteristics of the patients with primary pulmonaryhypertension are shown in Table 2. Dyspnea was the initial symptomin 91 percent, and it was severe (New York Heart Associationclass III or IV) in two thirds at the time of diagnosis. Inalmost two thirds of these patients, the diagnosis was not establisheduntil more than a year had passed after the appearance of symptoms.
Table 2. Clinical, Functional, and Pulmonary Hemodynamic Variables in the 95 Patients with Primary Pulmonary Hypertension.
The case patients and the controls were very similar with regardto both occupation and 24 broad classes of preexisting morbidity,as defined in the International Classification of Diseases,Ninth Revision. The case patients and the controls had takenan almost identical number of drugs (4.4±4.5 and 4.3±4.4,respectively). Two case patients reported a family history ofprimary pulmonary hypertension; three had HIV infection (eightwith AIDS were excluded from the study at the screening stage);more case patients than controls were alcohol drinkers (72.6percent vs. 64.0 percent), but not significantly more (P = 0.13);and seven case patients reported a history of cirrhosis, whichcould be confirmed in four from the medical chart. None of thesediseases were reported by any of the controls.
Table 3 shows the frequency of appetite-suppressant use andthe adjusted odds ratios for primary pulmonary hypertensionwith all the confounding variables and other risk factors. Thirtycase patients (31.6 percent) and 26 controls (7.3 percent) reportedusing appetite suppressants before their index date, yieldinga crude (matched) odds ratio of 7.1 (95 percent confidence interval,3.7 to 13.9) and an adjusted odds ratio of 6.3 (95 percent confidenceinterval, 3.0 to 13.2) (Table 3). The odds ratio associatedwith recent use (in the year before the index date) was 10.1(95 percent confidence interval, 3.4 to 29.9), and the oddsratio associated with past use was 2.4 (95 percent confidenceinterval, 0.7 to 8.2). The odds ratio increased sharply withthe duration of exposure (use for three months or less, 1.8;use for more than three months, 23.1). The total intake of anorexicdrugs was estimated by totaling the reported number of monthsof use. Figure 1 shows the distribution of such intake for thepatients with primary pulmonary hypertension and the controls.Very few controls (0.6 percent) used anorexic agents for a totalof 12 months or more, as compared with 12.6 percent of casepatients.
Figure 1. Duration of Exposure to Anorexic Drugs in the Study Patients before the Onset of Symptoms of Primary Pulmonary Hypertension.
When the case patients with cirrhosis, familial pulmonary hypertension,HIV infection, or intravenous drug use and their matched controlswere excluded from the analysis, the adjusted odds ratio associatedwith anorexic-drug use increased to 8.6 (95 percent confidenceinterval, 3.8 to 19.5). There was no change in the effects ofanorexic drugs or other risk factors for primary pulmonary hypertensionwhen alcohol intake was included in the logistic model (oddsratio, 6.3). Among female subjects, 27 patients with primarypulmonary hypertension (40.9 percent) and 25 controls (9.4 percent)had used anorexic drugs (adjusted odds ratio, 7.9; 95 percentconfidence interval, 3.5 to 17.5), as compared with 3 male patientswith primary pulmonary hypertension (10.3 percent) and 1 malecontrol (1.1 percent) (adjusted odds ratios were not definedfor men).
Table 3 also shows the individual drugs used by the case patientsand the controls. Dexfenfluramine and fenfluramine were themost commonly used: 22 patients (23.2 percent) and 23 controls(6.5 percent) had used at least one of them; of these subjects,16 patients (16.8 percent) and 18 controls (5.1 percent) reportednot using any other anorexic drug. Amphetamine-like anorexicagents (diethylpropion, clobenzorex, fenproporex, phenmetrazine,or a combination of these) had been used by eight case patients(8.4 percent) and eight controls (2.3 percent), among whom onlytwo case patients and three controls did not also report usinga fenfluramine derivative before the index date. Seven patientswith primary pulmonary hypertension (7.4 percent) and no controlsreported exposure to compound preparations. The content of thecompound preparations used by three patients was learned: onecontained dexfenfluramine, one contained an amphetamine-likeanorexic agent and possibly fenfluramine, and one containedboth an amphetamine-like anorexic agent and dexfenfluramine;the preparations also typically contained diuretics, phytotherapyproducts, thyroid extracts, or a combination of these. Mostof the exposure to appetite suppressants occurred in France(22 patients and 22 controls) and Belgium (6 patients and 4controls). One patient each from the United Kingdom and theNetherlands had used appetite suppressants. The matched crudeodds ratios associated with the use of appetite suppressantswere 10.7 in Belgium and 5.9 in France (these ratios could notbe calculated in the Netherlands or the United Kingdom). Allthe patients from the national referral center in France andseveral Belgian patients were followed, and there was no markedimprovement in the condition of those who had used anorexicagents after that use had stopped.
Table 4 shows the frequency of the weight-related confoundingvariables and the other variables thought to be risk factorsfor primary pulmonary hypertension, with their correspondingodds ratios (after adjustment for each other and for the useof anorexic agents). High body-mass index, treated systemichypertension, the use of cocaine or intravenous drugs (in patientswithout HIV infection), and pregnancy in the year before theonset of symptoms were more frequent in the patients with primarypulmonary hypertension than in the controls, but not significantlyso. The case patients used thyroid extracts less often thanthe controls, but not significantly so. Although smoking wasreported significantly more often by case patients than by controls,it was not associated with an increased risk of primary pulmonaryhypertension when other covariates were controlled for. Theuse of oral contraceptives, hashish, and marijuana (data notshown) did not differ between the patients and the controls.When the case patients with HIV, cirrhosis, familial pulmonaryhypertension, or intravenous drug use and their matched controlswere excluded from the analysis, the effect of the risk factorsshown in Table 4 did not differ notably between groups. Theadjusted odds ratio associated with obesity was 1.6 (95 percentconfidence interval, 0.7 to 3.7) in women.
Table 4. Frequency of Weight-Related and Other Variables and Adjusted Odds Ratios for the Risk of Primary Pulmonary Hypertension.
Incidence Study
In the study of the annual incidence of primary pulmonary hypertensionin Belgium, 24 patients were identified over a 24-month period(13 were included in the case–control study and 11 eitherhad died or were identified too late to be included). Therewere approximately 7 million inhabitants of Belgium 18 to 70years of age at the time of the study. The annual incidenceof primary pulmonary hypertension in this population was 1.7per million (95 percent confidence interval, 1.0 to 2.4).
Discussion
Our most striking findings concern the use of appetite suppressantsas a risk factor for primary pulmonary hypertension, especiallyuse lasting more than three months (odds ratio, 23.1). Thisis especially important because dexfenfluramine, the main druginvolved in this study, was recently approved by the Food andDrug Administration for the long-term treatment of obesity.The risk of primary pulmonary hypertension seems to increasesteadily with the quantity of appetite suppressants used, butthere has been very little experience with their long-term usein Europe.
We conducted additional analyses to identify potential sourcesof bias. We investigated whether patients exposed to anorexicagents could have been preferentially included in the study.This phenomenon may not be significant in the United Kingdomand the Netherlands, where anorexic agents were rarely used,or in Belgium, where the number of patients in the incidencestudy was very close to the number expected on the basis ofearlier figures.14 In France, only two thirds of the centerscontacted agreed to participate in the study. We think it veryunlikely that at these centers a significant number of patients,if any, with diagnosed primary pulmonary hypertension mightnot have been reported, considering all the verification procedureswe used. There is no reason to believe that the proportion ofpatients exposed to anorexic agents would differ in the centersthat did not participate. We have been informed that at leastfive cases of primary pulmonary hypertension diagnosed duringthe study period in patients who were exposed to derivativesof fenfluramine were reported to the manufacturer by nonparticipatingcenters. Among the participating centers, the exposure to anorexicagents was similar in the patients originally identified atthe national referral center (31 percent) and those identifiedat all the other French centers combined (37 percent). Also,we obtained data on exposure to anorexic drugs in the 13 patientsidentified too late to be included in the study and found thatit was 31 percent — close to the proportion reported forthe patients who were included. Sixty-two percent of the patientsdid not report any use of anorexic agents, as is consistentwith the fact that anorexic agents are obviously not the onlypossible cause of this disease.
There could be another selection bias if persons with primarypulmonary hypertension who used anorexic agents were more likelyto have their disease recognized than other patients. To explorethis potential bias, we examined the time between the appearanceof the first symptoms and the diagnosis and found that it didnot differ significantly between the case patients who usedanorexic agents and those who did not (16.8 and 17.6 months,respectively). We also compared the degree of dyspnea at thetime of diagnosis and found that it was more often severe (NewYork Heart Association class III or IV) in case patients whoused anorexic agents (89.7 percent) than in those who did not(56.6 percent), whereas the reverse would be expected if therewere a preferential bias based on the diagnosis. (This studywas done only among patients whose index dates were later thanAugust 1, 1989.)
We also examined potential sources of misclassification of theexposure to anorexic agents. Patients with primary pulmonaryhypertension might be more likely to remember using anorexicagents than controls (recall bias). On the basis of sales figures,we estimated a priori that 5 percent of the controls would haveexposure to a derivative of fenfluramine,14 and we found that6.2 percent actually had such exposure. The accuracy of theindex date was another source of concern, since the developmentof dyspnea is often insidious. To explore this matter, we recalculatedthe odds ratios with the index dates moved back to 12 monthsbefore the reported dates and found that the odds ratio associatedwith the use of anorexic agents was 7.4 — higher thanthe original odds ratio (6.3). Exposure after the original indexdate was slightly less frequent in the case patients than inthe controls. All this rules out a "protopathic" (reverse causality)bias. We could not verify the actual content of most of theso-called appetite-suppressant compound preparations, but inthe three instances in which we could do so, we found that theydid contain anorexic agents. "Possible exposure" to anorexicagents was more often found in case patients than in controls.
We considered whether the association between the use of appetitesuppressants and primary pulmonary hypertension could be explainedby the confounding effect of obesity or that of any hidden factorassociated with obesity. The odds ratio for anorexic agentswas similar whether or not the logistic-regression models wereadjusted for high body-mass index. The odds ratio for the interactionbetween obesity and appetite-suppressant use was 1.0 (95 percentconfidence interval, 0.2 to 3.5). Therefore, the effect of anorexicagents was the same whether patients had a high body-mass indexor not. Neither weight-loss behavior of another type nor theuse of thyroid extracts was positively associated with the riskof primary pulmonary hypertension, as would have been expectedif obesity accounted for the odds ratio observed for anorexicagents.
We believe that the association between anorexic agents andprimary pulmonary hypertension is due to neither bias nor chance.Our findings are consistent with observations in the 1960s ofan association of primary pulmonary hypertension with the useof aminorex fumarate11 and of more recent associations withfenfluramine derivatives, other anorexic agents, or relatedproducts.11,12,13,16,17,18 The consistency of our observationswith previous findings, the strength of the association, thefact that it increases with longer use, and the fact that itis stronger with recent use than with past use all favor a causalrelation. It is also worth noting that cases have been describedin which the disease regressed after exposure to fenfluramineended.17 Susceptibility factors are also likely to play a part,considering the rarity of primary pulmonary hypertension. Theresults apply mainly to derivatives of fenfluramine, which wereused by 90 percent of the subjects who named an individual anorexicagent and were contained in all the preparations whose actualcontent was determined. The role of other amphetamine-like anorexicagents is unclear, and such agents were rarely used alone.
How fenfluramine and dexfenfluramine may lead to pulmonary hypertensionis unknown. Hypotheses have been put forward that implicateserotonin,19 a pulmonary vasoconstrictor, a direct vasoconstrictoreffect through potassium-channel blockade20 (an effect thathas also been shown to occur with aminorex), and pulmonary vasoconstriction,21but these hypotheses remain speculative.
This international epidemiologic study of primary pulmonaryhypertension confirms the clinical features of the disease asdescribed in the National Registry of Primary Pulmonary Hypertension2and several case series.15,22 The severity of dyspnea at thetime of diagnosis was consistent with the long delay betweenthe first symptoms and diagnosis, a finding similar to thatobserved in the registry.2 Efforts to shorten the delay couldbe valuable, since treatment has recently been shown to be effectivein some patients.23,24
Our results also confirm the role of several previously describedrisk factors for pulmonary hypertension, including HIV infection8,25and cirrhosis.4,5 Because of simultaneous or multiple exposures,the role of intravenous drug use could not be examined separatelyfrom that of cocaine use, but both were used more frequentlyby the patients with primary pulmonary hypertension than bythe controls. Primary pulmonary hypertension has previouslybeen observed in infants born to mothers with a history of cocaineabuse7 and in users of related drugs.26,27 Pulmonary hypertensionassociated with intravenous drug use may also be due to theembolism of talc or other foreign substances. Recent pregnancies6and treated systemic hypertension appeared to be more frequentin the case patients than in the controls, but the study didnot have sufficient power to be conclusive in this regard. Wecould not confirm the previously reported suspicion of an associationwith oral-contraceptive use.9,10 Obesity, which was marginallyassociated with the risk of primary pulmonary hypertension inthis study, has not been previously reported as a risk factor.A subject's report of obesity may have been associated withuse of anorexic agents that the subject did not report. If so,the appearance of an effect of obesity on the risk of primarypulmonary hypertension simply reflects the harmful effects ofsmall amounts of unrecorded drug use.
In conclusion, the annual incidence of primary pulmonary hypertensionestimated from this study is very low — on the order of1 case per 500,000 inhabitants. The corresponding absolute riskfor obese persons who use anorexic agents for more than threemonths would be more than 30 times higher than for nonusers.It is not known to what extent the risk continues to increasewith longer use, because the experience with long-term use ofanorexic agents has been extremely limited. We recommend activesurveillance of the use of these drugs, especially if long-termuse is planned.
Supported by a grant (9404 UO 27203-UI-A) from the IndustryProgram of the Medical Research Council of Canada, by the Institutde Recherches Internationales Servier, and by the Ministry ofPublic Health and Environment of Belgium.
We are indebted to Drs. Michael Kramer and John Esdaile fortheir valuable comments; to Ms. Linda Carfagnini for her administrativeassistance throughout the project; to Dr. Bernadette Rains forreviewing the anatomical and pathological slides; and to Mr.Luc Lalonde for assistance with the statistical analysis.
* Other contributing authors and the participants in the InternationalPrimary Pulmonary Hypertension Study Group are listed in theAppendix.
Source Information
From the Centre for Clinical Epidemiology and Community Studies, McGill University and Sir Mortimer B. Davis–Jewish General Hospital, Montreal (L.A., Y.M.); the Pneumology Service, Antoine Béclère Hospital, Clamart, France (F.B., G.S.); the Section of Cardiology, University of Illinois, Chicago (S.R.); the National Cancer Institute, Rockville, Md. (J.B.); the Pharmacology Laboratory, Pathology Institute, Centre Hospitalier Universitaire de Liège, Liege, Belgium (X.K.); the Section of Respiratory Medicine, University of Sheffield, Sheffield, United Kingdom (T.H.); the Department of Cardiology, Hammersmith Hospital, London (C.O.); the Department of Pulmonology, University Hospital Maastricht, Maastricht, the Netherlands (E.W.); the Pneumology Service, Bichat Hospital, Paris (M.A.); and the Centre for Pharmacovigilance, Pellegrin Hospital, Bordeaux, France (B.B.).
Address reprint requests to Dr. Abenhaim at the Centre for Clinical Epidemiology and Community Studies, Sir Mortimer B. Davis–Jewish General Hospital and McGill University, 3755 Côte Sainte-Catherine, Montreal, QC H3T 1E2, Canada.
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Appendix
Robert Naeije, M.D., William Dab, M.D., David Langleben, M.D.,Anicet Chaslerie, M.D., Bruno Stricker, M.D., Thierry Ducruet,M.Sc., Cees Wagenvoort, M.D. (deceased), Maurits Demedts, M.D.,Emmanuel Weitzenblum, M.D., Marion Delcroix, M.D., Denise Walckiers,M.Sc., Claudine Peiffer, M.D., David Dutka, M.D., Ellen Pouw,M.D., Miriam Sturkenboom, Ph.D., Michael McGoon, M.D., and LewisRubin, M.D., were contributing authors of this paper.
Investigators at the participating centers: France — P.Achkar, S. Adnot, D. Anthoine, A. Arnaud, P. Assayag, P. Bareiss,J.-P. Bassand, A. Beardt, J. Beaume, P. Bernadet, Y. Bernard,B. Blaive, J.P. Bonhoure, M. Bory, J. Brune, I. Caubarrere,F. Chabot, A. Chavaillon, J. Clementy, L. Couraud, L. Desfossay,A. Didier, C. Dromer, G. Ducloux, P. Duroux, J.M. Fauvel, E.Ferrari, J.-L. Fincker, I. Gandjbakhch, G. Gebrac, P. Geslin,F. Guérin, A. Haloum, P. Hervé, A. Heulin, B.Housset, R. Kessler, P. Lemoigne, P. Leophonte, J. Lerousseau,P. Meyer, A. Michaud, A. Millaire, P. Morand, J.-F. Mornex,J.-F. Muir, M. Noirclerc, R. Pariente, S. Pham, J.-M. Polu,J.-C. Potier, M. Reynaud-Gaubert, J. Rochemaure, A. Sacrez,P. Scanu, M. Stern, A.B. Tonnel, E. Tuchais, P. Vacheron, P.-E.Valere, and C. Vinti; Belgium — E. Balthazar, Y. Bogaerts,R. Broux, P. Clement, J.-C. Debaisieux, S. Degre, L. Delaunois,M. DePauw, W. Elinck, M. Estenne, V. Legrand, M. Mairesse, P.Mengeot, M. Radermacker, J.-L. Vachiery, B. Van de Maele, P.Van Den Brande, J. Van Haecke, W. Van Mieghem, D. Van Renterghem,and J. Vanwelden; The Netherlands — F. Beaumont, G.J.Bosman, M. Cheriex, C. Jansveld, G.P.M. Mannes, M. van Rossum,J. van Stigt, F.J. Visser, and A. Welling; United Kingdom —A. Mitchell, A. Peacock, M. Ryan, and N. Uren.
Appetite-Suppressant Drugs and Primary Pulmonary Hypertension
Sobieraj J., Schembre D. B., Boynton K. K., Fishman A. P., Hoffman R. M., Upson D., Dhurandhar N. V., Atkinson R. L., Williamson D. F., Abenhaim L., Rich S., Bénichou J., Begaud B., The International Primary Pulmonary Hypertension Study Group
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Valvular Heart Disease Associated with Fenfluramine–Phentermine
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N Engl J Med 1997;
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