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Pre-referral rectal artesunate in severe malaria
Comment
Pre-referral rectal artesunate in severe malaria The sun is setting in an east African village. The mother returns home to find her child still febrile despite the crushed tablets given earlier. To find appropriate parenteral treatment, the mother needs to take her child to the district hospital but that is 3 h away and difficult to reach especially at night. Early next morning, the mother takes her child to the hospital, where the child has another seizure. The doctor does his best but the child dies. This is a common occurrence in rural African settings. These deaths from severe malaria could be prevented by prompt intervention but such services are often not available. In The Lancet today, Melba Gomes and co-workers (the Study 13 Research Group) show that pre-referral administration of artesunate suppositories can reduce mortality from malaria.1 They conclude that, if patients with severe malaria cannot be treated orally and transfer to hospital is likely to take several hours, an immediate rectal dose of artesunate substantially reduces the risk of death or permanent disability. Their findings come from a large multicentre trial in Ghana, Tanzania, and Bangladesh (over 17 000 participants in total). Gomes and co-workers’ trial has provided clear answers to several questions. First, there is no significant
Published Online December 8, 2008 DOI:10.1016/S01406736(08)61735-3
Science Photo Library
See Articles page 557
Young child with malaria in Tanzanian hospital
522
survival benefit from receiving rectal suppositories when the definitive parenteral treatment could be administered reasonably promptly (the researchers used an arbitrary cut-off of within 6 h). Second, in patients who needed a longer period to receive parenteral treatment, mortality was halved from 3·8% to 1·9% (risk ratio 0·49, 95% CI 0·32–0·77, p=0·0013). This finding has important implications for many settings in Africa and elsewhere where access to hospitals is difficult. During the past decade, there have been substantial developments in malaria treatment. Antimalarial combination therapy is replacing the less effective singledrug treatments of uncomplicated malaria.2 In-hospital mortality from severe malaria in Asia and South America has fallen as a result of use of parenteral artesunate instead of parenteral quinine.3 About 40 earlier studies have shown the safety, efficacy, and pharmacokinetics of rectally administered artemisinin or one of its derivatives in small and diverse groups of patients.4,5 Gomes and co-workers’ study advances knowledge further and provides a strategy for patients with severe malaria who cannot access parenteral drugs quickly. If there are a handful of important papers every decade that will influence the way malaria is treated, this study is one of them. Dispensing of artesunate suppositories and referral of patients was done under clinical trial conditions. A substantial minority of patients did not subsequently attend hospital. How effective will the strategy be in real-life settings? A subgroup analysis of adult patients in Bangladesh showed that 22 of the artesunate recipients and nine of the placebo recipients died. However, this result is probably a chance finding, in view of the clear benefit of parenteral artesunate in adults with severe malaria seen in another trial at the same site,3 but should perhaps be monitored. How can artesunate suppositories be distributed to achieve maximum benefit? Remote communities that will benefit most from this intervention are likely to be the most difficult to access, engage with, and support. One way would be to distribute comprehensive kits of rapid diagnostic tests, emergency packs of oral antimalarials, and rectal suppositories to village health workers. How should such health workers www.thelancet.com Vol 373 February 14, 2009
Comment
be trained and supported to do this? What is the effectiveness and safety of near-home management of severe malaria in the real-life setting? What is the cost–benefit ratio? Will patients or their parents and guardians feel that hospitalisation can be deferred after a patient has received a suppository? And what about the treatable bacterial infections that also claim millions of lives each year? There are no obvious answers, and studies which show how best to use this important intervention most efficiently are urgently needed. The next important step is to develop widescale deployment strategies, through research, and to assess the effectiveness of artesunate suppositories under various real-life settings.
*Lorenz von Seidlein, Jacqueline L Deen Joint Malaria Project, Tanga, Tanzania (LvS, JLD); and International Vaccine Institute, Kwanak-gu, Seoul, Korea (JLD) [email protected] We declare that we have no conflict of interest. 1
2 3
4
5
Gomes MF, Faiz MA, Gyapong JO, et al, for the Study 13 Research Group. Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial. Lancet 2008; published online Dec 8. DOI:10.1016/S0140-6736(08)61734-1. International Artemisinin Study Group. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 2004; 363: 9–17. South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366: 717–25. Karunajeewa HA, Manning L, Mueller I, Ilett KF, Davis TM. Rectal administration of artemisinin derivatives for the treatment of malaria. JAMA 2007; 297: 2381–90. Gomes M, Ribeiro I, Warsame M, Karunajeewa H, Petzold M. Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies. BMC Infect Dis 2008; 8: 39.
Prophylaxis of catheter-related thrombosis in cancer patients
www.thelancet.com Vol 373 February 14, 2009
in patients with cancer. However, the most recent prospective clinical trials, which randomly assigned a wide series of patients with cancer to receive active thromboprophylaxis (low-molecular-weight heparin or low-dose vitamin K antagonists) or placebo after the insertion of a central venous catheter, failed to show appreciable benefits from the use of pharmacological prophylaxis.4,5,7 These findings have been confirmed by meta-analyses.8,9 Accordingly, the most recent international guidelines no longer recommend systematic prophylaxis in patients with cancer who have a central venous line.10
See Articles page 567
The printed journal includes an image merely for illustration
CGSTOCK
Long-term central venous catheters have greatly improved the management of patients with cancer. However, their use has been associated with upper-limb deep-vein thrombosis (DVT), especially in those patients who need chemotherapy.1 The true incidence of upper-limb DVT in patients with central venous lines is difficult to estimate, because published data are conflicting. When thromboprophylaxis was not used, Bern and colleagues2 found an incidence of 37%, as shown by phlebography. Monreal and co-workers3 reported an even higher incidence. Conversely, in recent case series and randomised studies that used ultrasonography or other non-invasive methods to detect upper-limb DVT, the rate of thrombotic disorder was lower.4–6 Along with the decreased sensitivity of objective non-invasive methods compared with phlebography, the introduction of new texture and coating of catheters (as well as new procedures to reduce invasiveness) probably accounts for these discrepancies. Whether the positioning of an indwelling central venous catheter in patients with cancer needs thromboprophylaxis is debated. Previous studies showed that the use of prophylactic doses of low-molecular-weight heparin or fixed low-dose vitamin K antagonists could greatly reduce the rate of this complication.2,3 Accordingly, at the end of the 1990s, nearly all international guidelines recommended the adoption of either prophylactic strategy for prevention of catheter-induced DVT
523
Pre-referral rectal artesunate in severe malaria The sun is setting in an east African village. The mother returns home to find her child still febrile despite the crushed tablets given earlier. To find appropriate parenteral treatment, the mother needs to take her child to the district hospital but that is 3 h away and difficult to reach especially at night. Early next morning, the mother takes her child to the hospital, where the child has another seizure. The doctor does his best but the child dies. This is a common occurrence in rural African settings. These deaths from severe malaria could be prevented by prompt intervention but such services are often not available. In The Lancet today, Melba Gomes and co-workers (the Study 13 Research Group) show that pre-referral administration of artesunate suppositories can reduce mortality from malaria.1 They conclude that, if patients with severe malaria cannot be treated orally and transfer to hospital is likely to take several hours, an immediate rectal dose of artesunate substantially reduces the risk of death or permanent disability. Their findings come from a large multicentre trial in Ghana, Tanzania, and Bangladesh (over 17 000 participants in total). Gomes and co-workers’ trial has provided clear answers to several questions. First, there is no significant
Published Online December 8, 2008 DOI:10.1016/S01406736(08)61735-3
Science Photo Library
See Articles page 557
Young child with malaria in Tanzanian hospital
522
survival benefit from receiving rectal suppositories when the definitive parenteral treatment could be administered reasonably promptly (the researchers used an arbitrary cut-off of within 6 h). Second, in patients who needed a longer period to receive parenteral treatment, mortality was halved from 3·8% to 1·9% (risk ratio 0·49, 95% CI 0·32–0·77, p=0·0013). This finding has important implications for many settings in Africa and elsewhere where access to hospitals is difficult. During the past decade, there have been substantial developments in malaria treatment. Antimalarial combination therapy is replacing the less effective singledrug treatments of uncomplicated malaria.2 In-hospital mortality from severe malaria in Asia and South America has fallen as a result of use of parenteral artesunate instead of parenteral quinine.3 About 40 earlier studies have shown the safety, efficacy, and pharmacokinetics of rectally administered artemisinin or one of its derivatives in small and diverse groups of patients.4,5 Gomes and co-workers’ study advances knowledge further and provides a strategy for patients with severe malaria who cannot access parenteral drugs quickly. If there are a handful of important papers every decade that will influence the way malaria is treated, this study is one of them. Dispensing of artesunate suppositories and referral of patients was done under clinical trial conditions. A substantial minority of patients did not subsequently attend hospital. How effective will the strategy be in real-life settings? A subgroup analysis of adult patients in Bangladesh showed that 22 of the artesunate recipients and nine of the placebo recipients died. However, this result is probably a chance finding, in view of the clear benefit of parenteral artesunate in adults with severe malaria seen in another trial at the same site,3 but should perhaps be monitored. How can artesunate suppositories be distributed to achieve maximum benefit? Remote communities that will benefit most from this intervention are likely to be the most difficult to access, engage with, and support. One way would be to distribute comprehensive kits of rapid diagnostic tests, emergency packs of oral antimalarials, and rectal suppositories to village health workers. How should such health workers www.thelancet.com Vol 373 February 14, 2009
Comment
be trained and supported to do this? What is the effectiveness and safety of near-home management of severe malaria in the real-life setting? What is the cost–benefit ratio? Will patients or their parents and guardians feel that hospitalisation can be deferred after a patient has received a suppository? And what about the treatable bacterial infections that also claim millions of lives each year? There are no obvious answers, and studies which show how best to use this important intervention most efficiently are urgently needed. The next important step is to develop widescale deployment strategies, through research, and to assess the effectiveness of artesunate suppositories under various real-life settings.
*Lorenz von Seidlein, Jacqueline L Deen Joint Malaria Project, Tanga, Tanzania (LvS, JLD); and International Vaccine Institute, Kwanak-gu, Seoul, Korea (JLD) [email protected] We declare that we have no conflict of interest. 1
2 3
4
5
Gomes MF, Faiz MA, Gyapong JO, et al, for the Study 13 Research Group. Pre-referral rectal artesunate to prevent death and disability in severe malaria: a placebo-controlled trial. Lancet 2008; published online Dec 8. DOI:10.1016/S0140-6736(08)61734-1. International Artemisinin Study Group. Artesunate combinations for treatment of malaria: meta-analysis. Lancet 2004; 363: 9–17. South East Asian Quinine Artesunate Malaria Trial (SEAQUAMAT) group. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 2005; 366: 717–25. Karunajeewa HA, Manning L, Mueller I, Ilett KF, Davis TM. Rectal administration of artemisinin derivatives for the treatment of malaria. JAMA 2007; 297: 2381–90. Gomes M, Ribeiro I, Warsame M, Karunajeewa H, Petzold M. Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies. BMC Infect Dis 2008; 8: 39.
Prophylaxis of catheter-related thrombosis in cancer patients
www.thelancet.com Vol 373 February 14, 2009
in patients with cancer. However, the most recent prospective clinical trials, which randomly assigned a wide series of patients with cancer to receive active thromboprophylaxis (low-molecular-weight heparin or low-dose vitamin K antagonists) or placebo after the insertion of a central venous catheter, failed to show appreciable benefits from the use of pharmacological prophylaxis.4,5,7 These findings have been confirmed by meta-analyses.8,9 Accordingly, the most recent international guidelines no longer recommend systematic prophylaxis in patients with cancer who have a central venous line.10
See Articles page 567
The printed journal includes an image merely for illustration
CGSTOCK
Long-term central venous catheters have greatly improved the management of patients with cancer. However, their use has been associated with upper-limb deep-vein thrombosis (DVT), especially in those patients who need chemotherapy.1 The true incidence of upper-limb DVT in patients with central venous lines is difficult to estimate, because published data are conflicting. When thromboprophylaxis was not used, Bern and colleagues2 found an incidence of 37%, as shown by phlebography. Monreal and co-workers3 reported an even higher incidence. Conversely, in recent case series and randomised studies that used ultrasonography or other non-invasive methods to detect upper-limb DVT, the rate of thrombotic disorder was lower.4–6 Along with the decreased sensitivity of objective non-invasive methods compared with phlebography, the introduction of new texture and coating of catheters (as well as new procedures to reduce invasiveness) probably accounts for these discrepancies. Whether the positioning of an indwelling central venous catheter in patients with cancer needs thromboprophylaxis is debated. Previous studies showed that the use of prophylactic doses of low-molecular-weight heparin or fixed low-dose vitamin K antagonists could greatly reduce the rate of this complication.2,3 Accordingly, at the end of the 1990s, nearly all international guidelines recommended the adoption of either prophylactic strategy for prevention of catheter-induced DVT
523