Fen-phen heart valve damage in 24 women triggered FDA advisory in July 1997

On July 8, 1997, 24 cases of valvular heart disease in women treated with the appetite suppressants fenfluramine and phentermine were publicly reported ^[1]. The Food and Drug Administration issued a public health advisory the same day and sent letters to 700,000 U.S. health-care practitioners and institutions asking whether they had seen similar patients ^[1].

The 24 women had used the two-drug combination known as fen-phen. Valve lesions appeared on both sides of the heart, but a left-sided valve was affected in every case. Under the microscope, the tissue changes resembled carcinoid-induced valvular disease, a pattern linked to serotonin ^[1].

More reports followed. As of September 30, the FDA had received 144 individual, provider-initiated reports involving fenfluramine or dexfenfluramine, with or without phentermine, a total that included the original 24 cases ^[1]. Of the 132 reports with complete information, 113 (86%) met the agency's case definition: aortic regurgitation of mild or greater severity and/or mitral regurgitation of moderate or greater severity ^[1]. Trace or mild mitral regurgitation and trace aortic regurgitation are common in the general population and are not generally considered abnormal, which is why the definition used higher thresholds ^[1].

Of those 113 cases, 111 (98%) were in women. The median age was 44, with a range of 22 to 68. Median duration of drug use was 9 months, with a range of 1 to 39 months. Eighty-seven (77%) people were symptomatic, 27 (24%) required cardiac valve-replacement surgery, and three died after surgery ^[1]. Eighty-nine (79%) had taken fenfluramine plus phentermine, 16 (14%) dexfenfluramine alone, two (2%) fenfluramine alone, and six (5%) all three drugs. None had used phentermine alone ^[1].

Five independent echocardiographic surveys looked at people exposed to these drugs who had no obvious history of cardiac disease or cardiac symptoms. The prevalence of valvular disease meeting the case definition ranged from 30.0% to 38.3%, with an overall figure of 32.8% (95% confidence interval 27.7% to 38.9%) ^[1]. The report put the expected prevalence of regurgitation meeting the same definition in the general adult population at an estimated 5% or less, and said it may be lower among obese people ^[1]. Among survey patients with valvulopathy, 86% had aortic regurgitation, 19% had mitral regurgitation alone or in combination, and a heart murmur could be heard in 17% ^[1].

Prevalence appeared higher with longer exposure: 22% (five of 23) for less than 3 months, 22% (five of 23) for 3 to 5 months, and 35% (83 of 236) for 6 months or more ^[1].

Based on the five surveys, the FDA requested voluntary withdrawal of fenfluramine and dexfenfluramine, and manufacturers and the agency announced the withdrawal on September 15 ^[1]. Fenfluramine (Pondimin) had been approved in 1973 and dexfenfluramine (Redux) in 1996, both as single-drug appetite suppressants ^[1]. Since 1995, about 14 million prescriptions had been written for either drug, and an estimated 1.2 million to 4.7 million people in the United States had been exposed ^[1].

Why it matters for patients

Fenfluramine and dexfenfluramine are no longer on the U.S. market. Phentermine (sold as Adipex, Fastin and Ionamin) was approved in 1959 for single-drug, short-term use and was not part of the withdrawal ^[1].

History and physical examination alone do not appear sensitive enough to detect this valvulopathy in all exposed patients, particularly when obesity makes murmurs hard to hear. The Department of Health and Human Services recommended that everyone exposed to fenfluramine or dexfenfluramine, for any period and alone or in combination with other drugs, have a medical history and cardiovascular examination, and it issued further guidance on echocardiographic evaluation ^[1].

Several key questions were unresolved at the time. The natural history of the lesions was not determined, including whether they resolve, progress or stay unchanged after the drug is stopped. The clinical importance of mild valvulopathy in people without symptoms or audible murmurs was also not determined, nor were any characteristics that might make a person more likely to develop valve abnormalities ^[1]. Studies designed specifically to estimate the prevalence of regurgitant valve lesions among obese adults who lost weight or were never exposed to these drugs had not yet been reported ^[1].

What happens next

The department said its interim recommendations may be revised as more definitive data about the natural history of the disease become available ^[1]. The report also cited 1997 American Heart Association guidance on preventing bacterial endocarditis, noting one patient with the valve condition who had fever, signs of cardiac failure, aortic and mitral regurgitation and a large endocarditic vegetation, with blood cultures positive for streptococci. How much risk these patients face for endocarditis had not yet been determined ^[1].