Fatal cardiac incident after use of halofantrine.

Halofantrine (HF) is a phenanthrene-methanol antimalarial which is effective against the asexual erythrocytic stage of malaria parasites, currently recommended at a dosage of 24 mg/kg given as 8 mg/kg 3 times at 6-hourly intervals, for the treatment of uncomplicated Plasmodium falciparum malaria in nonimmune patients. HF has been shown to be well tolerated and effective against multiple drug resistant P. falciparum.No heart toxicity was detected in animal studies, and no severe cardiac side effects were noted until 1993, when a few cases of severe, or fatal, cardiac complications were reported.1–4 Administration of HF can result in prolongation of the Q-Tc interval, and severe ventricular tachyarrythmias in susceptible individuals.5–8 These cases have occurred particularly under certain conditions, which include, the use of dosages higher than recommended, recent or concomitant treatment with mefloquine, the presence of preexisting prolongation of Q-Tc interval (Romano-Ward syndrome), or in patients with thiamine deficiency. We report a new fatal cardiac incident in a 31-year-old woman without previous electrocardiographic (ECG) anomaly, after halofantrine regimen. A previously healthy 31-year-old French woman, who had traveled to South Africa within the preceding 2 months, experienced a febrile attack, presumed to be malarial, in December 1993, 2 weeks after her trip. She had a 3 week trip, and had taken the prophylactic combination of 100 mg chloroquine and 200 mg proguanil daily, during and after traveling, until the occurrence of the febrile crisis. Before the result of the blood film examination was known, malaria was suspected clinically, and the patient was treated on a presumptive outpatient basis,using halofantrine given without food in fasting conditions, in a total dosage of 1.5 g divided into 3 doses of 500 mg at intervals of 6 hours. The blood film on admission, repeated 12 hours later, was negative. Electrolytes, and blood cell count were normal, and all serological tests were negative. Within 48 hours, she had a brief loss of consciousness, and malaise. No abnormality was found, despite a systolic blood pressure of 80 mm Hg. The blood film remained negative.Twelve hours later, she complained of malaise, rapidly followed by a cardiac arrest.A brief resuscitation following electroversion was obtained in the mobile intensive care unit, showing an supraventricular and ventricular tachycardia,with a prolonged Q-Tc interval (0.52 second for theoretical value of 0.36 second) leading to several bursts of torsades de pointes, finally followed by a fatal heart failure.Post mortem investigation revealed a macrocytic anemia (hemoglobinemia: 7.5 g/dL) and a thrombopenia (platelet count: 128,000/mm3). Cerebrospinal fluid analysis showed no cells, and the biochemistry was normal. Blood films were negative for Plasmodium.Plasma measurements for halofantrine and desbutylhalofantrine by high-performance liquid chromatography9 were 879 ng/mL (normal values,200–500) and 510 ng/mL (normal values,50-200),respectively.The main notable finding was heart post mortem path-anatomic examination, showing a right ventricular arrhythmogenic dysplasia, obviously undiscovered previously. Past medical history failed to reveal any familial history of heart disease or sudden death. Two previous baseline electrocardiograms (ECG) failed to show any electrical anomaly (Q-Tc interval, 0.35 second).