Published: July 2000

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Update on Valvular Abnormalities with Dexfenfluramine and Fenfluramine

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Prescriber Update 20: 48-52
July 2000

Medsafe Editorial Team

In June 1999, Medsafe issued an alert on valvular abnormalities with dexfenfluramine and fenfluramine. The alert advised that those who at any time in the past had received either agent for ≥ 3 months should be investigated for valvular abnormalities.
Since release of this advice, ACC has received > 400 claims for investigation. Two claims of medical mishap due to valvular damage associated with use of dexfenfluramine or fenfluramine have been accepted. The Centre for Adverse Reactions Monitoring has received eight reports of abnormalities, possibly associated with use of fenfluramines. In two cases there were some echocardiographic or histological features consistent with those described in the literature for these agents. One of these patients required valve replacement and the other had evidence of disease more than 20 years after exposure to fenfluramine.
Recent evidence suggests that those with mild disease may improve after withdrawal of fenfluramine, and that the incidence of valvular abnormalities may be dependent on the duration of treatment.
Individuals who have received dexfenfluramine or fenfluramine for ≥ 3 months at any time in the past and who have not yet been investigated should be evaluated for evidence of heart murmur or other abnormal cardiac signs, and referred to a cardiologist for echocardiography if any abnormality is identified. Until a cardiologist is able to advise on the risk of endocarditis, appropriate prophylactic antibiotics should be given to those requiring dental or surgical procedures putting them at risk of endocarditis. General practitioners should fill out an ACC claim for medical misadventure to cover the cost of investigation, detailing the patient’s exposure to the medication.

ACC has received > 400 claims for investigation for valvular disorders

In June 1999, Medsafe issued an alert¹ about heart valve abnormalities occurring in association with the anorexiants, dexfenfluramine (Adifax) and fenfluramine (Ponderax). Dexfenfluramine and fenfluramine were removed from the market worldwide in September 1997, but there was a possibility that people who had taken either agent in the past for ≥ 3 months may have symptomatic or asymptomatic valvular abnormalities. Those with any abnormality are at risk of endocarditis when undergoing dental and certain surgical procedures unless appropriate antibiotic prophylaxis is administered.

The alert recommended that all those who had taken dexfenfluramine or fenfluramine in the past for ≥ 3 months should be examined for evidence of a heart murmur or abnormal cardiac signs. Those in whom an abnormality has been detected should be referred to a cardiologist for further investigation including echocardiography.

The ACC made an undertaking before publication of the alert to cover the cost of the visits to general practitioners and cardiologists for investigation. At the time the advice was issued, Medsafe estimated that more than 25,000 people may have used dexfenfluramine or fenfluramine, but it had no information on duration of use.

At the beginning of June 2000, ACC had received 435 claims for visits to general practitioners in former users of either anorexiant.² The ACC did not have data on the number of cases who required investigation by a cardiologist, but it advised that 80% of claims were for more than $100. In addition, two cases of medical mishap for valvular heart disease occurring as a result of administration of dexfenfluramine or fenfluramine had been accepted and 3 cases were being processed.

CARM has received 8 reports of valvular disorders with fenfluramines

By the middle of March 2000, the Centre for Adverse Reactions Monitoring (CARM) had received eight reports of valvular disorders in individuals who had taken fenfluramine or dexfenfluramine. All cases were reported following the alert and for all the causal association with use of these agents was thought to be possible. However, four were of valvular stenosis which has not been described in the published cases, one appeared to be a result of rheumatic heart disease and one was not sufficiently well documented to permit detailed analysis. The remaining two cases were more consistent with what has been described in the literature.³ In both cases the patient had taken fenfluramine for more than a year in the 1970s and a heart murmur was diagnosed 1-4 years after commencing therapy. A full physical examination of one patient two years prior to use of fenfluramine had found no abnormalities. In one case an echocardiogram taken in 1995 showed thickened aortic valve leaflets and mild aortic incompetence. The other case required aortic valve replacement in 1997. The valve was thickened with 5mm fibrotic walls, and in the opinion of the surgeon, the damage had not been caused by rheumatic fever or other infection. Histologically the valve was too fibrotic to make a specific diagnosis, but there were some features in keeping with a fenfluramine effect.

Improvement may follow withdrawal in mild disease

Since release of the Medsafe advice, further studies have been published on heart valve abnormalities with dexfenfluramine and fenfluramine. Unfortunately, most have been very small, and suffered from the fact that it is not ethical to conduct a well-controlled prospective randomised trial to examine the issue.

One such study⁴ involved 19 recipients of fenfluramine and phentermine and 11 recipients of placebo who had been treated as part of a randomised trial which was terminated when dexfenfluramine and fenfluramine were removed from the market. Active treatment had been for 8-73 weeks (mean 41). Echocardiography at the end of treatment revealed that five of those who had received active treatment (vs 1 placebo recipient) had mild aortic regurgitation, and met published criteria for drug-related valvular disease. Follow-up echocardiography six months later showed improvement in all five cases, with three no longer meeting the criteria. This study provides the best evidence to date that recovery or improvement may follow valvular damage by fenfluramines at least in some patients.

Incidence appears to be related to treatment duration

A further study⁵ involved individuals from 25 centres in the United States treated with dexfenfluramine (479) or fenfluramine and phentermine (455) and untreated matched controls (539). The mean duration of therapy for the dexfenfluramine group was 6.0 (1-18) months and for the fenfluramine and phentermine group it was 11.9 (1-63) months. Significantly, increased rates of aortic regurgitation were found in the treated groups: 8.9% for dexfenfluramine, 13.7% for fenfluramine and phentermine and 4.1% for placebo. There was no increase in the respective rates in those who had been treated for ≤ 3 months, but treatment with fenfluramine and phentermine for > 18 months was associated with a rate of 21%. Only nine of the treated cases were of moderate or moderate to severe disease compared with 95 cases of mild disease. The physical findings and prevalence of serious cardiac events were not significantly different between the three groups. Considering all grades, there was no significant difference in the prevalence of mitral regurgitation between the three groups, but the treated groups had significantly higher rates of mild mitral regurgitation.

Serious valvular damage appears to be rare

This study is the first⁶ to provide data to support the suspicion that the incidence of heart valve disease may be dependent on treatment duration. It is also reassuring because severe disease was uncommon and physical findings and number of serious cardiac events did not differ significantly between the placebo group and the treated groups.

To date controlled studies have largely found only mild cases of valvular damage. Severe cases and/or those with long term consequences, such as those described in the original case series³ and seen in the 2 CARM reports highlighted in this article appear to be extremely rare.

Those treated ≥ 3 months should be investigated for valvular disorders

The advice issued in June 1999 still stands and should be observed.

• Patients who took dexfenfluramine or fenfluramine for < 3 months need not be examined.
• Those who took either or both agents for ≥ 3 months should be examined by a general practitioner for evidence of a heart murmur or other abnormal cardiac signs.
• If a murmur or other abnormality is found, or the heart cannot be examined due to obesity, refer the patient to a cardiologist for echocardiography.
• Until a cardiologist is able to advise on the risk of endocarditis, appropriate prophylactic antibiotics should be given to patients requiring dental or other surgical procedures that put them at risk of endocarditis.
• Practitioners should send an adverse reaction report for valve abnormalities requiring antibiotic prophylaxis in patients exposed to these medicines to CARM.

At the time of initial assessment, general practitioners should fill out a claim form clearly labelled "medical misadventure" which details the patient’s exposure to the medication. The ACC will make a minimum contribution of $26 towards the cost of the initial visit. The patient should forward the claim to ACC (The Special Claims Unit, P O Box 1426, Wellington) to seek prior approval before proceeding with further investigations, such as echocardiography.

A fuller version of this advice is in the article in Prescriber Update No.18, June 1999, and can be found on this web site.
A consumer information leaflet is also available on the web site, and it can be ordered from 04-496-2277 (phone), 03-479-0979 (fax), email pubs@health.govt.nz or post an order to the Ministry of Health, C/- Wickliffe Ltd. P O Box 932, Dunedin.

References

1. Valvular abnormalities with dexfenfluramine and fenfluramine. Prescriber Update No.18, June 1999, p.13-18
2. Matthews R. The Special Claims Unit, ACC, P O Box 1426, Wellington, personal communication, 1 May 2000.
3. Connolly HM, Crary JL, McGoon, et al. Valvular heart disease associated with fenfluramine-phentermine. NEJM 1997;337:581-8.
4. Hensrud DD, Connolly HM, Grogan M, et al. Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine. Mayo Clin Proc 1999;74:1191-7.
5. Gardin JM, Schumacher D, Constantine G, et al. Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine. JAMA 2000;283:1703-9.
6. Jick H. Heart valve disorders and appetite-suppressant drugs. JAMA 2000;283:1738-40.