SHORT REPORT: NO EVIDENCE OF CARDIOTOXICITY OF ATOVAQUONE-PROGUANIL ALONE OR IN COMBINATION WITH ARTESUNATE RAVINDRA K. GUPTA, MICHELE VAN VUGT, LUCY PAIPHUN, THRA SLIGHT, SORNCHAI LOOAREESUWAN, NICHOLAS J. WHITE, AND FRANÇOIS NOSTEN* Department of Infection, St. Thomas’ Hospital, London, United Kingdom; Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; Shoklo Malaria Research Unit, Mae Sot, Thailand; Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom Abstract. Combinations are set to become the mainstay in treatment and prophylaxis of malaria due to Plasmodium falciparum. Various antimalarials have been implicated in cardiotoxicity via prolongation of the QTc interval. Atova- quone-proguanil is an effective and increasingly popular antimalarial choice when used alone or with artesunate in areas of drug resistance. We report the results of an investigation carried out on the Thai-Burmese border in 42 patients randomized to receive either atovaquone-proguanil or atovaquone-proguanil-artesunate for three days. Electrocardio- graphic recordings were made at baseline and one hour after each dose. There was no statistically significant change in QTc interval between baseline and any subsequent readings in either treatment group or the cohort as a whole. We conclude that atovaquone-proguanil shows no evidence of cardiotoxicity either alone or when combined with artesunate. Increasing malaria mortality in tropical countries has been linked with an increase in resistance to affordable antima- larial drugs. 1 The use of artemisinin-based combinations is now accepted as the optimum chemotherapeutic approach for uncomplicated malaria. Atovaquone-proguanil (AP, Ma- larone; GlaxoSmithKline, Research Triangle Park, NC) is a relatively new combination antimalarial with atovaquone in- hibiting cytochrome b and proguanil inhibiting dihydrofolate reductase. The combination has excellent antimalarial activity and no serious toxicity. 2 Its main shortcoming lies in the pro- pensity for Plasmodium falciparum to develop rapid resis- tance to atovaquone via a point mutation in the gene encod- ing for cytochrome b. The combination of AP increases an- timalarial activity through synergy, and reduces the rate of resistance to atovaquone. However, susceptibility to resis- tance remains. Combining AP with artesunate (AAP) allows mutual protection against resistance and confers the advan- tage of reducing gametocyte carriage and thus the transmis- sion of resistant strains. 2 Antimalarials such as quinidine, qui- nine, 3 and halofantrine 4 have been shown to alter cardiac conduction, while studies of lumefantrine (used in combina- tion with artemether) and of mefloquine (alone or with arte- sunate) have not demonstrated cardiotoxicity in humans. 5 However, this does not rule out the possibility of rare cardiac effects with lumefantrine or mefloquine. We found no pub- lished electrocardiographic studies on Malarone. Neither component of this combination has structural similarities with antimalarials known to cause cardiotoxicity. We report the results of an evaluation of the cardiotoxicity of AP alone and in combination with artesunate. This study was part of a large randomized trial in 1999 comparing AAP with AP alone and with artesunate- mefloquine (AM) in the treatment of uncomplicated P. falci- parum malaria. The study population consisted of children and adults in a refugee camp as well as migrant workers from Burma and living along the Thai-Burmese border. Patients presenting to one of the camp clinics with a blood film posi- tive for P. falciparum and meeting World Health Organiza- tion criteria for uncomplicated disease were randomly as- signed to receive AP, AAP, or AM. The details of this study and its results have been published; the triple combination was more effective than AP alone and was well tolerated. 2 The study was reviewed and approved by the Ethics Commit- tee of the Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. Electrocardiographic monitoring (Autocardiner FCP-2155; Fukuda Denshi Co., Ltd., Tokyo, Japan) was conducted in 42 consecutive patients who were randomly assigned to receive either AP (15 mg/kg/day and 8 mg/kg/day, respectively, for 3 days) or AAP (artesunate at a dose of 4 mg/kg/day for 3 days). Patients assigned to the AM arm were not enrolled because this combination has already been evaluated for car- diotoxicity. 6 Informed consent was obtained from all partici- pating adults and from the parents of children who partici- pated. One electrocardiogram (ECG) was conducted at base- line and an additional ECG was conducted on each patient one hour after each dose. This interval between the dose and the ECG was chosen for practical reasons because patients were treated mainly on an outpatient basis. Four ECGs were conducted from each patient over a three-day period. Elec- trocardiographic intervals (RR, PR, QRS, QT, and QTc as calculated by Bazett’s correction) were measured by the ma- chine and verified manually. Forty-two patients were enrolled in the study (26 males and 16 females). The mean age was 24.4 years (range  6–61 years) and the mean weight 38.7 kg (range  14–60 kg). Twenty-two were randomly assigned to receive AAP and 20 to receive AP alone. A paired t-test was performed to analyze differences in QTc interval in each treatment group. Table 1 summarizes the ECG findings and Table 2 summa- rizes the paired t-tests comparing intervals before and after three days of treatment. There was no difference in mean ± SD QTc intervals between the two treatment groups either at baseline (419 ± 22.0 and 412 ± 22.0 milliseconds, respectively; P  0.75) or three days following treatment (413 ± 24.0 and 423 ± 23.7 milliseconds, respectively; P  0.60). There was a statistically significant decrease in heart rate (increase in RR interval) between baseline and day 3 in both groups (AAP and AP); this is postulated to be due to the defervescence with treatment and has been observed previously. 5 There was no statistically significant change in QTc interval between the baseline and any subsequent readings in the cohort as a whole * Address correspondence to Dr. François Nosten, PO Box 46, Mae Sot 63110, Thailand. E-mail: SMRU@tropmedres.ac Am. J. Trop. Med. Hyg., 73(2), 2005, pp. 267–268 Copyright © 2005 by The American Society of Tropical Medicine and Hygiene 267