Diet Drugs and Cardiac Valvulopathy: A Survey of Dental Patients

The recent finding that several appetite suppressant drugs (fenfluramine and dexfenfluramine) were linked to cardiac valvular disease in a significant percentage of the population led to their voluntary withdrawal. The Centers for Disease Control and Prevention issued a series of recommendations in 1997 for evaluating dental patients who had taken these drugs. Since that time, several studies have further investigated the prevalence of valvular abnormalities. This information is crucial because of the problem of dentally associated bacterial endocarditis. This study surveyed more than 1,300 dental patients and determined the prevalence of patients taking these diet drugs and cardiac valvulopathy and the percentage of dental patients required to take antimicrobial endocarditis prophylaxis before "at risk" dental procedures. It remains important for dentists to query their patients for this information.

In 1997, fenfluramine and dexfenfluramine (Fen/Dex), components of several diet drugs (appetite suppressants), were linked with cardiac valvular disease in possibly 32.89 percent of patients.1 Because of this association, the companies producing the drugs voluntarily removed them from the market.2

When the public and profession were notified by the Centers for Disease Control and Prevention3 of the valvulopathology associated with diet drugs, the following recommendations and guidelines were stated:

1. All people exposed to Fen/Dex for any period of time, either alone or in combination with other agents, should undergo a medical history and cardiovascular examination by their physicians to determine the presence or absence of cardiopulmonary signs or symptoms.

2. An echocardiographic evaluation should be performed on all people who were exposed to Fen/Dex for any period of time, either alone or in combination with other agents, and who exhibit new cardiopulmonary signs (including a new murmur) or symptoms suggestive of valvular disease.

3. Although the clinical importance of a symptomatic valvular regurgitation in exposed patients and the risk for developing bacterial endocarditis in these patients are unknown, practitioners should strongly consider performing echocardiography on all people -- regardless of whether they have cardiopulmonary signs or symptoms -- who have been exposed to Fen/Dex for any period of time, either alone or in combination with other agents, before the patient undergoes any invasive procedure for which antimicrobial endocarditis prophylaxis is recommended by 1997 American Heart Association guidelines. Any echocardiographic finding that meets the AHA criteria for prophylaxis -- regardless of whether they are attributable to possible Fen/Dex use -- should be recognized as an indication for antimicrobial endocarditis prophylaxis. The invasive procedures, including certain medical or dental procedures where antimicrobial endocarditis prophylaxis is recommended, are defined in the 1997 AHA guidelines.4 For emergency procedures for which cardiac evaluation cannot be performed, empiric antimicrobial endocarditis prophylaxis should be administered according to the 1997 AHA guidelines.

4. Because of the prevalence of minimal degrees of regurgitation in the general population, the current case definition of drug-associated valvulopathy should include exposed patients with echocardiographically demonstrated aortic regurgitation of mild or greater severity and/or mitral regurgitation of moderate or greater severity, based on published criteria.5,6

Since the initial notification by the CDC, a number of studies have been published, and court cases have transpired.7 Studies have looked at the evidence of valvulopathy8-10 as well as the exact location of the pathoses8 and the mechanism by which the damage occurs.1,11-14 Several organizations have made recommendations relative to the need for antimicrobial endocarditis prophylaxis prior to invasive procedures.3,15-19,21

In the present study, the authors surveyed patients presenting to a dental school clinic to determine the incidence of diet drug utilization (Fen/Dex) and whether they had been evaluated for cardiac valvular damage.

Study Design

A health history questionnaire was designed to elicit from patients (1) whether they had ever taken diet drugs and (2) whether the diet drugs taken were ones that contained Fen/Dex. If answered in the affirmative, they were then asked whether they had seen their physicians for cardiovascular examinations (Table 1). Patients were then followed to determine the prevalence of a cardiac valvulopathy and the need for antimicrobial endocarditis prophylaxis.

The questionnaire was filled out by all new adult patients presenting to the dental school, as well as existing patients who were in the process of having their health history updated. The questionnaires were printed on duplicate forms; the original was placed into the patient's chart, and the copy was turned in at a central collecting station each day. Patients who responded positively to any of these questions were evaluated by a faculty member. If valvular damage was diagnosed and the physician recommended antimicrobial endocarditis prophylaxis, then, depending on the nature of the dental procedure, the current antimicrobial endocarditis prophylaxis was prescribed.

Results

A total of 1,373 questionnaires were tabulated. Forty patients (0.03 percent) had a history of diet drug use. Twenty eight of these patients (0.02 percent) met the criteria for the use of diet drugs containing fenfluramine (Pondimin), dexfenfluramine (Redux), or fenfluramine-phentermine (Fen-Phen). Twelve patients reported the diet drugs but not Fen-Phen, Pondimin or Redux.

Eighteen of these 28 patients (64 percent) were evaluated for cardiac damage. The other 10 were lost to follow-up. Four of these 18 patients (22 percent) were diagnosed with some degree of cardiac valvulopathy. In two of these cases, the physician recommended antimicrobial endocarditis prophylaxis to be used prior to invasive dental procedures. The other two were believed to have only a mild valve dysfunction, which did not require antimicrobial endocarditis prophylaxis.

Discussion

Much of the research related to cardiac disease following the use of Fen/Dex diet drugs has focused on the incidence of valvular pathosis.1,2,8,11-14 Much of this discussion centered around whether, in fact, the valvulopathy actually occurred secondary to the use of diet drugs, or whether the incidence of cardiac valvular damage found in this group was high due to other risk factors (e.g., obesity). Some investigators attributed the high incidence of valvular disease to the detail and intensity of the evaluation process.8,20 Studies also disclosed a relationship between valvulopathy and the length of time Fen/Dex was taken and the dosage.10 The two most common abnormalities discovered by echocardiogram were atrial and mitral regurgitation.

In a 1998 study by Jick and colleagues,9 equal numbers of patients had newly discovered valve disorders, with or without predisposing conditions (congenital or rheumatic heart disease). All idiopathic patients (those with no predisposing conditions) had received Fen/Dex for more than three months. Approximately 1 percent of patients receiving Fen/Dex were diagnosed with symptomatic valvulopathy.

A recent study by Gardin and colleagues10 demonstrates a significant prevalence of both primarily mild asymptomatic atrial regurgitation and mitral regurgitation in patients taking Fen/Dex. This study provides data on the relationship of duration and use. An 11.6 percent difference was noted between the groups taking the drugs for less than three months or more than three months. This percentage increases to 21.2 percent if the drugs were taken for more than 18 months. The majority of the echocardiographic studies in asymptomatic patients receiving Fen/Dex reveal that the most common abnormality is atrial regurgitation, which appears to be minor or benign.

Prior to 1997, Fen/Dex was commonly prescribed for diet control. The substantial majority of patients in the United States received the drugs for less than three months. For these patients, the risk of valvular disorders appears small. The increased risk of valvulopathy is real, symptomatic, and clinically significant in patients who have taken the drugs for longer than three months.

The prevalence of cardiac valvulopathy in the current study of dental patients taking Fen/Dex was 22 percent. However the current survey did not question duration and dosage of drug use. Detailed information was not received regarding the degree of valvulopathy. However antimicrobial endocarditis prophylaxis was recommended for 11 percent of the patients.

When a valvulopathy occurs it can range from mild and asymptomatic to severe and symptomatic. The decision as to what degree of valvulopathy requires antimicrobial endocarditis prophylaxis prior to invasive procedures remains a point of discussion.

Proper dental referral for patients at risk would be an examination by a physician. Depending on the risk or findings, a referral to a cardiologist may be indicated. If warranted, an echocardiographic evaluation should be done. However, the valvulopathy may progress; and a repeat cardiac evaluation should be performed in six to eight months. Once a diagnosis has been made and the severity evaluated with recommendations for antimicrobial endocarditis prophylaxis, the dentist has clear recommendations from the AHA and American Dental Association as to the types of dental procedures that are considered "at risk." This is a clinical decision made by the dentist predicated on guidelines published in 1997 by the AHA and ADA for prevention of infective endocarditis.3

Currently almost all dental health histories ask about heart problems or heart murmurs. While only a minority of American patients (4 to 5 million) took the specific diet drugs mentioned in this article for longer than 3 months and many have been evaluated by their physicians for valvular disease, it is still appropriate to ask patients about their diet drug history and consult their physicians regarding any resulting valvulopathy and need for antimicrobial endocarditis prophylaxis.

Authors

Richard Rudin, DDS, MA, is an assistant professor of diagnosis and management at the University of the Pacific School of Dentistry.
William M. Carpenter, DDS, MS, is professor and chairman in the Department of Pathology and Medicine at UOP School of Dentistry.

References

1. Connolly HM, Crary JL, et al, Valvular heart diseases associated with fenfluramine-phentermine. N Engl J Med 337:581-8, 1997.
2. Food and Drug Administration, FDA analysis of cardiac valvular dysfunction with the use of appetite suppressants. http://www.fda.gov/cder/news.
3. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997. MMWR 46:1066, 1997.
4. Dajani AS, Taubert KA, et al, Prevention of bacterial endocarditis: Recommendations by the American Heart Association. J Am Dent Assoc 128:1142-50, 1997.
5. Perry GJ, Helmcke F, et al, Evaluation of aortic insufficiency by doppler color flow mapping. J Am Coll Cardio 9:952-9, 1987.
6. Helmcke F, Nanda NC, et al, Color doppler assessment of mitral regurgitation with orthogonal planes. Circulation 75:175-83, 1987.
7. Nationwide class-action settlement agreement with American Home Products Corp. http://www.settlementdietdrugs.com/ Accessed July 17, 2000.
8. Kahn, M., Herzogg C, et al, The prevalence of cardiac valvular insufficiency assessed by transthoratic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 339:713-8, 1998.
9. Jick H, Vasilakis C, et al, A population-based study of appetite suppression drugs and the risk of cardiac valve regurgitation. N Engl J Med 339:719-24, 1998.
10. Gardin JM, Schumacher D, et al, Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine. J Am Med Assoc 283:1703-9.
11. Griffen L, Anchors M, Asymptomatic mitral and aortic valve disease is seen in 1/2 patients taking "Phen-Fen." Arch Intern Med 1998:158, 102.
12. Griffen L, Anchors M, The "Phen-Pro" drug combination is not associated with valvular heart disease. Arch Inter Med 158:1278-9, 1998.
13. Shivley BK, Roldan CA, et al. Prevalence and determinants of valvulopathology in patients treated with dexfenfluramine. Circulation 100:2161-7, 1999.
14. Hick J, Summary, editorial. J Am Med Assoc 283 No 13, April 5, 2000.
15. ACC/AHA Guidelines on Valvular Heart Disease.
16. ACC Oct. 18, 1997, Nov. 18, 1997. Available at http://www.acc.org/pubs/news/statement.html
17. The Dentists Insurance Company, Fen-Phen and Redux alert. TDIC memorandum to policy holders, May 5, 1998.
18. Loitz G, CDA Council on Dental Research and Developments. TDIC Risk Management Jan 28, 1998.
19. Pallasch TJ, An expert addresses Fen-Phen. CDA Update 9(12):1, 15.
20. Weisman N, Tighe J, Gottdiener J, An assessment of heart valve abnormalities in obese patients taking dexfenfluramine, sustained release dexfluramines or placebo. N Eng J Med 339:725-32, 1998.
21. Pallasch TJ, Current status of fenfluramine/dexfenfluramine-induced cardiac valvulopathology. J Cal Dent Assoc 27(5):400-4, 1999.

To request a printed copy of this article, please contact/Richard Rudin, DDS, MA, UOP School of Dentistry, 2155 Webster St., San Francisco, CA 94115.

Table 1. UOP Medical History (Supplemental Question)

YES NO Have you ever taken prescription medication for weight reduction (Diet Pills)?

If "YES," did you take any of the below listed drugs? (Please indicate with an X on line).

___Fen-Phen (fenfluramine - phentermine)
___Pondimin (fenfluramine)
___Redux (dexfenfluramine)

YES NO If you have taken any of the above drugs, have you had a medical exam to ensure that your heart valves were not affected?

Patient's Signature ______________________________ Date___________
Please Print Name ______________________________

Table 2. Study Results