Table 1 Controlled prevalence studies. Each of the studies compared the prevalence of aortic (mild or greater) and mitral (moderate or greater) regurgitation in a series of patients exposed to either fenfluramine or dexfenfluramine. Only studies reporting duration of exposure to these drugs are included here. A single study excluded prior valve disease by baseline echocardiograms and is also included. Controls were generally recruited matching for age, gender, height and weight.

Khan, 1998

Exposed patients participated in one of 3 studies at a medical center. One study used 30–60 mg fenfluramine with phentermine 30 mg/day (exposure duration 26.5 months). The other two studies used dexfenfluramine 30 mg/day (one without phentermine, exposure duration 4.9 months; the other allowed phentermine 30 mg/day, exposure duration 9 months). Controls were recruited later, matched to sex, age, height, BMI.

Echocardiographers were apparently unblinded with regard to patient status. The first reader was blinded for all but potentially 60 exposed cases. All films were read by a second reader. A third reader was used if the 1^st and 2^nd reader did not agree. Good concordance reported

Weissman, 1998

Participants were in a randomized, placebo-controlled trial comparing dexfenfluramine, sustained-release dexfenfluramine, and placebo. Original protocol was for 16 weeks but was stopped prematurely due to withdrawal of fenfluramine and dexfenfluramine from market. Blinding maintained and echocardiography scheduled soon after stopped. Investigators and patients remained blinded to treatment.

Standardized protocol. Echocardiographers were unaware of patient status. Echocardiograms read at an independent reading center. Scans were-re-read if any valve abnormality seen. 5% of scans read by other readers to judge reproducibility. Excellent reproducibility.

Shively, 1999

26 sites were to supply 5 or more cases who had taken dexfenfluramine (no other anorexic) for at least 3 months and 5 or more controls (matched by age, gender, and BMI) who had used no anorexics for 5 or more years.

Echocardiographers (at centers near each site) were blinded to subject status. There were three blinded readers (2 of 3 readers had to agree or re-reading required). Good inter-reader agreement reported.

Hensrud, 1999

Participants of a small, double-blind, randomized trial assigned to either fen-phen or placebo. Echocardiograms read by a blinded reviewer.

Ryan, 1999

Patients were enrolled in a long-term research study with fenfluramine (and some with dexfenfluramine) with baseline echocardiograms. 86 patients were re-scanned after fenfluramine and dexfenfluramine were withdrawn. 7 of these (8.1%) had pre-existing regurgitation and are eliminated in this analysis.

Good inter- and intra-reader concordance was demonstrated for baseline and follow-up echocardiograms. Readings were blinded as to order (baseline versus follow-up) of echocardiograms.

Gardin, 2000

Investigators at 25 centers who had frequently prescribed dexfenfluramine or fen-phen and could enroll subjects were invited to participate. Initially, controls were matched on 4 criteria (age, sex, BMI, and geographical area), then less stringent geographic criteria were implemented.

Standardized protocol. Echocardiographers were blinded with regard to patient treatment status. Echocardiograms were read blind at a core lab. Good inter- and intra-reader concordance reported.

Jollis, 2000

33 practices with large numbers of prescriptions were invited to participate. Required 3 months+ treatment with fen-phen. Matched controls from same centers. Dyspnea on exertion more frequent in drug group. SSRI use was not associated with AR or MR.

Standardized protocol. Readers blinded to treatment status. Good agreement in 350 scans read by 2 or more cardiologists.

Davidoff, 2001

Female smokers who had participated in a double-blind placebo-controlled trial of fenfluramine for smoking cessation were contacted approximately 4.5 years after the study was completed to undergo echocardiography.

Standardized protocol. Echocardiographers were blinded to patient history. Tapes read at central lab. Re-reading performed when abnormalities present. Good inter-reader agreement reported.