Increasing malaria mortality in tropical countries has been linked with an increase in resistance to affordable antimalarial drugs.1 The use of artemisinin-based combinations is now accepted as the optimum chemotherapeutic approach for uncomplicated malaria. Atovaquone-proguanil (AP, Malarone®; GlaxoSmithKline, Research Triangle Park, NC) is a relatively new combination antimalarial with atovaquone inhibiting cytochrome b and proguanil inhibiting dihydrofolate reductase. The combination has excellent antimalarial activity and no serious toxicity.2 Its main shortcoming lies in the propensity for Plasmodium falciparum to develop rapid resistance to atovaquone via a point mutation in the gene encoding for cytochrome b. The combination of AP increases antimalarial activity through synergy, and reduces the rate of resistance to atovaquone. However, susceptibility to resistance remains. Combining AP with artesunate (AAP) allows mutual protection against resistance and confers the advantage of reducing gametocyte carriage and thus the transmission of resistant strains.2 Antimalarials such as quinidine, quinine,3 and halofantrine4 have been shown to alter cardiac conduction, while studies of lumefantrine (used in combination with artemether) and of mefloquine (alone or with artesunate) 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 published 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. falciparum 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 positive for P. falciparum and meeting World Health Organization criteria for uncomplicated disease were randomly assigned 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 Committee 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 cardiotoxicity.6 Informed consent was obtained from all participating adults and from the parents of children who participated. One electrocardiogram (ECG) was conducted at baseline 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. Electrocardiographic intervals (RR, PR, QRS, QT, and QTc as calculated by Bazett’s correction) were measured by the machine 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 summarizes 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 or with either treatment, AP, or the AAP triple combination (P = 0.48 and 0.81, respectively, by paired t-test). A mean increase in QTc of more than 25% has been used to define cardiotoxicity4 that could lead to clinically significant arrhythmias. Percentage changes in QTc in this study were all well below this level.
Combination antimalarial therapy is becoming the rule, and in particular, AP is an increasingly popular option for treatment and prophylaxis of uncomplicated P. falciparum malaria. Previous findings that some antimalarials can prolong the QTc interval suggest that it is important to evaluate the possible cardiac interactions of combinations as well as individual drugs. In this study, no prolongation of the QTc interval was found using AP either alone or in combination with artesunate, and there was no difference in QTc interval between these two treatment groups. Such cardiotoxicity studies will continue to be important as new antimalarials and combinations become available.
Summary of ECG results for the combined AP and AAP arms at baseline and after each dose at days 1, 2, and 3*
| HR 0 | HR 1 | HR 2 | HR 3 | PR 0 | PR 1 | PR 2 | PR 3 | QRS 0 | QRS 1 | QRS 2 | QRS 3 | QTc 0 | QTc 1 | QTc 2 | QTc 3 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| * ECG = electrocardiographic; AP = atovaquone-proguanil; AAP = atovaquone-proguanil and artesunate; HR = heart rate. Values in parentheses are percentage changes from baseline. | ||||||||||||||||
| Mean (%) | 89 | 86 (3) | 79 (11) | 76 (15) | 146 | 144 (1) | 146 (0) | 149 (2) | 96.0 | 92.4 (4) | 97.2 (1) | 97.4 (1) | 415 | 411 (1) | 416 (0.2) | 417 (0.4) |
| SD | 25.5 | 23.3 | 20.9 | 21 | 18.3 | 17.4 | 19.9 | 26.5 | 12.0 | 12.1 | 11.7 | 11.3 | 22.2 | 29.1 | 23.8 | 23.9 |
| Range | 55–144 | 63–138 | 66–131 | 50–129 | 126–206 | 130–189 | 110–193 | 120–194 | 75–116 | 76–108 | 80–112 | 84–112 | 369–453 | 359–478 | 366–460 | 360–451 |
Paired t-test analysis of differences in heart rate (HR) and ECG intervals (RR, PR, QRS, and QTc) between baseline (0) and days 1, 2, and 3 of treatment with atovaquone-proguanil (AP) alone or in combination with artesunate (AAP)*
| Paired differences | ||||||
|---|---|---|---|---|---|---|
| Pairs | Mean | SD | 95% confidence interval | t | Degrees of freedom (n − 1) | Two-tailed significance p |
| * The QTc interval pair for day 0 and 3 has been subdivided into treatment groups. | ||||||
| HR0−HR3 | 12.7 | 17.1 | 7.3–18.0 | 4.80 | 41 | < 0.001 |
| PR0−PR3 | −3.0 | 17.7 | −9.9–3.5 | −0.963 | 41 | 0.34 |
| QRS0−ORS3 | −1.4 | 11.1 | −4.7–2.2 | −0.726 | 41 | 0.47 |
| QTc0−QTc1 | 4.0 | 25.6 | −3.9–12.0 | 1.02 | 41 | 0.31 |
| QTc0−QTc2 | −1.0 | 16.7 | −6.4–4.4 | −0.37 | 41 | 0.71 |
| QTc0−QTc3 | −1.30 | 17.8 | −6.9–4.2 | −0.477 | 41 | 0.64 |
| QTc0−QTc3 AP only | −3.23 | 21.1 | −12.6–6.1 | −0.716 | 21 | 0.48 |
| QTc0−QTc3 AAP only | −0.75 | 13.4 | −7.0–5.5 | −0.25 | 19 | 0.81 |
Address correspondence to Dr. François Nosten, PO Box 46, Mae Sot 63110, Thailand. E-mail: SMRU@tropmedres.ac
Authors’ addresses: Ravindra K. Gupta, Shoklo Malaria Research Unit, PO Box 46, Mae Sot 63110, Thailand and Oxford University Medical School, Headington, Oxford OX3 9DU, United Kingdom. Michele van Vugt and Lucy Paiphun, Shoklo Malaria Research Unit, PO Box 46, Mae Sot 63110, Thailand and Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. Thra Slight, Shoklo Malaria Research Unit, PO Box 46, Mae Sot 63110, Thailand. Sornchai Looareesuwan, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. Nicholas J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand and Centre for Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Old Road, Headington, Oxford OX3 7LJ, United Kingdom. François Nosten, Shoklo Malaria Research Unit, PO Box 46, Mae Sot 63110, Thailand, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand, and Centre for Vaccinology and Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Old Road, Headington, Oxford OX3 7LJ, United Kingdom, E-mail: SMRU@tropmedres.ac.
Acknowledgments: We are grateful to the staff of the Shoklo Malaria Research Unit for their work and to the study participants.
Financial support: François Nosten and Nicholas J. White are supported by the Wellcome Trust of Great Britain. This investigation was part of the Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Program.
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