Correspondence

Digital Necrosis Associated with Dexfenfluramine

N Engl J Med 1997; 337:1776-1777December 11, 1997

Article

To the Editor:

A growing body of evidence implicates the anorectic drug fenfluramine and its d-isomer, dexfenfluramine, in the development of pulmonary hypertension and valvular heart disease.1,2 Pulmonary hypertension is thought to occur because of the vasoconstrictive effects of serotonin,2 which may also lead to cardiac valvular lesions that appear morphologically similar to those found in the carcinoid syndrome.2,3 We report on a patient in whom ischemic necrosis of the fingers developed shortly after the start of therapy with dexfenfluramine.

A 44-year-old man with non-insulin-dependent diabetes mellitus presented with a four-week history of pain and discoloration of the left index and small fingers. He reported no serious trauma, systemic symptoms, Raynaud's phenomenon, or any history of complications related to diabetes. Three months earlier, he had begun to take dexfenfluramine (15 mg twice daily) for mild obesity. He took no medications known to cause vasospasticity and did not smoke. There was no family history of collagen–vascular or hematologic disease. A physical examination was notable for a finding of purple discoloration and decreased sensation of the distal phalanges of the left index and small fingers (Figure 1Figure 1Left Hand of a Patient with Digital Necrosis after Three Months of Therapy with Dexfenfluramine.); the radial and ulnar pulses were palpable. An angiogram of the aortic arch and left upper extremity revealed normal vasculature to the level of the digital arteries. Both digital arteries of the index and small fingers were occluded; one digital artery was occluded in each of the other fingers. Vasospasm was noted in the carpal arch, which abated with an injection of tolazoline. An echocardiogram and a chest radiograph were normal. A complete blood count, liver-function studies, prothrombin and partial-thromboplastin times, thyroid-function studies, and urinalysis were normal, as were the urea nitrogen and creatinine levels. The erythrocyte sedimentation rate was 37 mm per hour. Tests for rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibody, lupus anticoagulant, anticardiolipin antibody, cryoglobulins, and hepatitis B and C and a rapid plasma reagin assay were negative. The levels of homocysteine, antithrombin III, protein C, protein S, and activated protein C resistance were normal. Blood cultures were sterile.

Dexfenfluramine was discontinued, but despite therapy with local transcutaneous nitrates, local sympathetic blockade with bupivacaine, and oral nifedipine, the lesions progressed to necrosis, and amputation of the involved distal phalanges was required. Pathological examination revealed thrombosis of the digital arteries with gangrenous necrosis; no vasculitis or emboli were present. The patient was discharged with instructions to avoid dexfenfluramine. However, several weeks later, there was mild discoloration of several fingers of the right hand after he started taking dexfenfluramine again. The discoloration has not progressed since the cessation of the drug.

Serotonin induces arterial spasm and has been implicated in Raynaud's phenomenon and increased vasoreactivity in patients with anorexia nervosa.4 Dexfenfluramine and fenfluramine may promote the release of endogenous serotonin and alter its reuptake, as well as enhance central serotonergic activity, which probably mediates the anorectic activity of the drugs.2 Lower-extremity arterial ischemia was reported in a patient treated concurrently with dexfenfluramine and minocycline.5 A young female taking dexfenfluramine, who had a myocardial infarction, was noted to have normal coronary arteries on angiography, which led the authors to conclude that coronary vasospasm was the likely cause.6 In addition to pulmonary hypertension, abnormal peripheral vascular reactivity may occur with the use of dexfenfluramine, which, as this report demonstrates, may lead to irreversible ischemic damage.

Mark A. Marinella, M.D.
Beth Anne Berrettoni, M.D.
Wright State University School of Medicine, Dayton, OH 45409

6 References

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Citing Articles (4)

Citing Articles

1. 1

   Evangelos Michelakis. (2002) Anorectic drugs and vascular disease:. Vascular Pharmacology 38:1, 51-59
   CrossRef

2. 2

   Evangelos D. Michelakis, E. Kenneth Weir. (2001) Anorectic Drugs and Pulmonary Hypertension from the Bedside to the Bench. The American Journal of the Medical Sciences 321:4, 292-299
   CrossRef

3. 3

   P. Egermayer. (2000) Epidemics of vascular toxicity and pulmonary hypertension: what can be learned?. Journal of Internal Medicine 247:1, 11-17
   CrossRef

4. 4

   &NA;. (1997) Dexfenfluramine. Reactions Weekly &NA;:682, 7
   CrossRef