Fenfluramine

Current Status of Fenfluramine/Dexfenfluramine-Induced Cardiac Valvulopathy

Since publication of the U.S. Department of Human and Health Services' interim recommendations in November 1997 for the management of patients having taken certain appetite suppressants, a number of studies evaluating the prevalence of cardiac valvular pathology in such individuals have been published. These studies generally support the association of fenfluramine/dexfenfluramine with cardiac valvulopathy but with significant differences in risk assessment. The analysis of these studies has produced two new guidelines for the management of such patients, including the appropriate use of antibiotic prophylaxis in these individuals. These studies are presented along with a comparison of the three present recommendations and their impact on dental practice.

An interim public health recommendation for individuals having taken certain appetite suppressants (fenfluramine, dexfenfluramine) was issued on Nov. 14, 1997, by the U.S. Department of Human and Health Services (DHHS)1 and was summarized in the CDA Update on Dec. 17, 1997.² The preliminary data gathered by the Centers for Disease Control and Prevention and the Food and Drug Administration indicated a possible 32.89 percent overall prevalence of cardiac valvulopathy in people exposed to fenfluramine (Pondimin) or dexfenfluramine (Redux). Phentermine (Apidex, Fastin, Ionamin), often combined with fenfluramine in "fen-phen," was itself not implicated. All four valves of the heart had been affected, with a definite predilection for the left side of the heart (aortic and mitral valves). The influence of dose or duration of therapy on this valvulopathy was unknown.

The DHHS then made the following recommendations:

* All people exposed to these drugs should undergo a medical history and cardiovascular examination.

* An echocardiogram should be performed on all people who exhibited cardiopulmonary signs and symptoms of cardiac valvular disease.

* An echocardiogram was to be strongly considered on all people exposed to these drugs for any period of time regardless of whether cardiopulmonary signs and symptoms were detected if the patient was to have an invasive procedure for which antimicrobial prophylaxis is recommended by the 1997 American Heart Association (AHA) guidelines for the prevention of bacterial endocarditis.

* For emergency procedures for which a cardiac evaluation cannot be performed,
empiric antibiotic prophylaxis should be administered according to the 1997 AHA guidelines. Dentists were then advised to:

* Identify such patients via a dialogue medical history;

* Advise the patient that an appropriate cardiovascular examination should be performed by the patient's physician;

* Avoid all elective dental procedures associated with significant bleeding from hard and soft tissues and meriting antibiotic prophylaxis for endocarditis prevention as delineated in the 1997 AHA guidelines until the patient's cardiac status could be determined;

* Provide antibiotic prophylaxis according to the 1997 AHA guidelines if valvulopathy meeting the current AHA guidelines is detected by the physician; and

* Use the 1997 AHA prevention of bacterial endocarditis guidelines if an emergency dental procedure must be performed and the cardiac status of the patient is yet undetermined.²

Since these guidelines were issued, a number of reports have appeared regarding the incidence of cardiac valvulopathy in patients taking these two drugs that range from letters to the editor to meeting abstracts to fully published well-conducted studies. They vary substantially in patient populations; dosage and length of time the drugs were taken; and, most importantly, the methodology of assessment and the skill of the physician assessor. These studies may also suffer from referral bias (the most affected patients were referred to major teaching hospitals); lack of baseline cardiac evaluations before the drugs were taken; lack of knowledge of the natural history of valve disease due to anorectic drugs; and, importantly, the lack of agreed criteria for systematic echocardiographic evaluation and general medical practitioner insensitivity to mild-moderate valvular regurgitation.^3,4

A recent study of 541 physicians in training or medical students indicated that an average of only 20 percent of them recognized 12 important and commonly encountered cardiac events by auscultation.⁵ It is probable, then, that cardiac valvulopathy would more likely be detected by a cardiologist than an internist/primary care physician and by sophisticated echocardiography rather than by auscultation.

In three major studies recently published in the New England Journal of Medicine, the incidence of cardiac valvulopathy in patients taking fenfluramine or dexfenfluramine ranged from 13 percent to 25 percent (12 percent to 24 percent above the expected value)⁶ to 6.9 percent vs. 4.5 percent of controls (a 2.4 percent difference)⁷ to a risk ratio of 0.14 per 1,000 patient years with up to three months of drug use to 0.7 per 1,000 patient years with greater than three months of use.⁸ In one of these studies, the incidence of moderate to severe valvular regurgitation was 8 percent as opposed to 0 percent in controls.⁶ In an evaluation of these studies, it was determined that each support the association between fenfluramine and dexfenfluramine and heart valve regurgitation but differ with regard to the strength and clinical significance of that association.³ Also, it appears that obesity itself is not responsible for the valve irregularities, that the use of these drugs for less than three months was a lower risk for valve abnormalities, and that prolonged use and/or exposure to higher doses appeared to confer greater risk for cardiac valve irregularities.³ It is important for consistency that all studies to be compared use the same diagnostic FDA criteria for valvulopathy: at least mild aortic regurgitation and at least moderate mitral insufficiency.³

In six abstracts presented at the 1998 Scientific Session of the American Heart Association, the prevalence of significant valvular regurgitation ranged from a statistically insignificant 2 percent to a highly significant 28 percent (2 percent, 3.6 percent, 6.6 percent, 10 percent, 14.4 percent, and 28 percent).^9-14 In 28 cases additional to the originally reported 24 cases,¹⁵ 24 had mitral valve, 19 aortic valve, 11 tricuspid valve, and 1 pulmonary valve insufficiency with no resolution upon drug withdrawal and again emphasizing the problem of multiply affected valves.¹⁶ One report has appeared of regression of the valve lesions over a period of years.¹⁷

From October 1994 to July 1997, the Belgian Center for Pharmacovigilance reported
43 cases of valvular heart disease in women using anorectic drugs.¹⁸ In other reports, 15 of 23 cases had abnormal valves on color flow Doppler echocardiography and six of 20 cases had valvular heart disease but with no baseline echocardiogram taken before medication onset.²⁰ At valve replacement or repair, the affected valves have a characteristic glistening white appearance with a plaque-like encasement of the leaflets and chordae and focal surface proliferation or fibrosis.²¹ These valvular lesions may produce a characteristic echocardiogram.²¹

Seemingly lost in all the concern about cardiac valvulopathy is the other major clinical problem associated with anorectic drugs: primary pulmonary hypertension, which is an ordinarily rare disorder occurring at a rate of 1 to 2 per million in the general population but which rises tenfold with the use of any anorectic drug and 20-fold with greater than three months' use.²² This disorder occurs primarily in young women (median age 36 years) with early signs and symptoms of shortness of breath on exertion, syncope, tiredness, chest pain, and peripheral edema.²³ Its diagnosis is commonly delayed one to two years after onset of symptoms, and people so afflicted have a median survival time of two to three years from onset of symptoms.²³ The first report of primary pulmonary hypertension associated with fenfluramine appeared in West Africa in 1975.²⁴ Fenfluramine has been associated with damage to brain serotonergic neurons in animals²⁵ and endocardial fibrosis in humans.²⁶

Since the publication of the DHHS guidelines in 1997,1 two other recommendations have appeared regarding the management of patients who have taken fenfluramine or dexfenfluramine, one by Devereux³ and the other by the joint Task Force of the American College of Cardiology (ACC) and the American Heart Association.⁴ These are summarized in Table 1.

In an editorial response to the three studies published in the New England Journal of
Medicine,^6-8 Devereux³ proposed the following management strategy of these patients:

* All patients are to be examined clinically.

* An echocardiogram should be recommended for those who have a heart murmur or other evidence of valvular disease as well as those who have received the drugs for three or more months or at high doses.

* The standard AHA antibiotic prophylaxis is recommended for patients with a heart murmur, those with "silent" moderate or severe regurgitation on Doppler echocardiography, and those with mild regurgitation associated with defined structural valvular lesions. Further studies will be required to determine if these patients need follow-up evaluations, and caution is indicated with the use of other serotonergic agents.³

The ACC/AHA statement⁴ recommends that:

* All patients with a history of fenfluramine or dexfenfluramine use undergo a careful history and thorough cardiovascular physical examination to include auscultation with the patient in the upright position at the end expiration to detect aortic regurgitation and in the left lateral decubitus position to detect mitral regurgitation.

* 2-D and Doppler echocardiography should be performed in those patients with symptoms, cardiac murmurs, or other signs of cardiac involvement (e.g., widened pulse pressure or regurgitant c or v waves in the jugular venous pulse).

* Patients whose body habitus prevents adequate cardiac auscultation should also undergo 2-D and Doppler echocardiography.

* Patients with clinical and echocardiographic evidence of valvular heart disease should then undergo treatment and/or further testing according to the recommendations developed for the specific valve lesions addressed earlier in these guidelines.

* Modification of these recommendations may be necessary as more information on the natural history of these specific valve lesions becomes available.⁴

Additionally the ACC/AHA guidelines contain the following caveats:

* Considering unknown variables, it is not possible to derive definitive diagnostic and treatment guidelines for patients who have received these anorectic drugs.

* Hence, clinical judgment is important.

* In the light of current evidence, echocardiographic screening of all patients with a history of fenfluramine or dexfenfluramine use, especially asymptomatic patients without murmurs or associated findings, is not recommended

* However, because of possible progression of subclinical valvular disease, asymptomatic patients without murmurs should undergo repeat physical examination in six to eight months.

Conclusions

The vast majority of the current clinical studies on cardiac valvulopathy associated with the use of fenfluramine or dexfenfluramine support such an association. However, these studies detect significant differences in risk with some supporting the original estimate of the DHHS and others assessing considerably less risk with the use of these anorectic agents. Methodology and expertise are likely significant factors in these discrepancies, as are dosage and the length of time the drugs were taken (valvular damage increased with both higher dose and longer duration). The dentist should continue to refer these patients to their physicians for a cardiovascular examination according to the recommendations of the DHHS, Devereux, or the ACC/AHA with the expectation that the physician will follow one of these guidelines. It would be appropriate to share this information with the physician for the purposes of consultation and proceed accordingly. If valvulopathy is detected, the 1997 AHA endocarditis prophylaxis guidelines regarding the management of dental patients with cardiac valvular disorders should be followed. For emergency dental procedures before a cardiac evaluation can be performed, empiric antibiotic prophylaxis should be administered according to the 1997 AHA guidelines.

Author

Thomas J. Pallasch, DDS, MS, is a professor of pharmacology and periodontics at the University of Southern California School of Dentistry.

References

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To request a printed copy of this article, please contact: Thomas J. Pallasch, DDS, MS, USC School of Dentistry, University Park MC-0641, Los Angeles, CA 90089-0641.