- Email: [email protected]
Hydroxycarbamide for sickle-cell anaemia in infancy
Comment
Enough about endpoints. What we really want to know is: should we use hydrogel coils in our patients? For medium-sized ruptured aneurysms, if we want to avoid angiographic recurrence, HELPS offers evidence of benefit of hydrogel over platinum coils. Before extending that conclusion to all ruptured aneurysms, the still unanswered issue of hydrocephalus might need to be taken into account. What else can HELPS help with? The trialists have kindly provided us with several provocative analyses that can shape future trials. First, hydrogel-coil-associated hydrocephalus remains a victim of the statistics of rare events; even in this trial, the event rate was so low that no statistically significant difference between groups was recorded. Rates provided by HELPS can improve power estimates for future study of hydrocephalus and meningeal reaction. Second, the recorded benefit of hydrogel coils in medium-sized aneurysms suggests that future trials of endovascular aneurysm treatments might benefit from narrowed inclusion criteria. These medium-sized aneurysms seem to represent the statistical sweetspot (not too small, when all coils do well, and not too big, when no coil does well) for comparing coil technologies; investigators should be aware, though, that the feasibility and generalisability of trials with narrow inclusion criteria might be compromised. Finally, treatment targets, including the proportion of hydrogel coils used, could be worth investigating. These findings might provide support for mechanistic and biological
theories of why hydrogel-coated coils can be beneficial in the treatment of aneurysms. HELPS was a successful trial, providing us with some important answers and several questions to consider in the future. *David F Kallmes, Andrew J Molyneux Mayo Clinic, Rochester, MN 55905, USA (DFK) and Oxford Neurovascular and Neuroradiology Research Unit, Nuffield Department of Surgical Sciences, Oxford Radcliffe Hospital, Oxford, UK (AJM) [email protected] DFK has applied for grants to support preclinical research from eV3, MicroVention, Sequent, NFocus, Micrus, Cook, AthroCare, CareFusion; and his institution has received payment for development of educational presentations from eV3 and CareFusion. AJM has a consulting agreement with Micrus Endovascular Inc and Covidien Inc. 1
5
2
3 4
5
White PM, Lewis SC, Gholkar A, et al, for the HELPS trial collaborators. Hydrogel-coated coils versus bare platinum coils for the endovascular treatment of intracranial aneurysms (HELPS): a randomised controlled trial. Lancet 2011; 377: 1655–62. Molyneux AJ, Kerr RSC, Birks J, et al, for the ISAT Collaborators. Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up. Lancet Neurol 2009; 8: 427–33. Montori VM, Permanyer-Miralda G, Ferreira-González I, et al. Validity of composite end points in clinical trials. BMJ 2005; 330: 594–96. Molyneux AJ, Kerr RSC, Yu LM, et al, for the International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 2005; 366: 809–17. Im SH, Han MH, Kwon BJ, et al. Aseptic meningitis after embolization of cerebral aneurysms using hydrogel-coated coils: report of three cases. AJNR Am J Neuroradiol 2007; 28: 511–12.
Hydroxycarbamide for sickle-cell anaemia in infancy See Articles page 1663
1628
The inherited disorders of haemoglobin, sicklecell anaemia, its variants, and the thalassaemias, are by far the commonest monogenic diseases. An estimated 300 000 babies are born each year with these conditions, mainly in middle-income and lowincome countries.1 Last year, the US National Institutes of Health held a symposium to commemorate 100 years of research on sickle-cell disease since it was first described by the American physician James Herrick in 1910.2 It was the first disease to be characterised at the molecular level, as reported in Linus Pauling’s famous 1949 paper,3 and much has been learnt about its pathophysiology. However, much less progress has been made in prevention and management. Because
of the remarkable phenotypic variability, prenatal diagnosis has been applied less frequently than for the β thalassaemias. Although neonatal screening and the use of prophylactic antibiotics or vaccines has reduced associated mortality due to infection in early life in higher-income countries, and the symptomatic management of various complications, including stroke, has improved for many patients, sickle-cell anaemia remains a crippling disease. For reasons that are still not absolutely clear, patients with sickle-cell anaemia or β thalassaemia continue to produce variable amounts of fetal haemoglobin (HbF), throughout their lives. Many years ago, we observed that patients with higher concentrations of HbF tend www.thelancet.com Vol 377 May 14, 2011
to have milder forms of these diseases4 and thoughts turned to whether stimulation of HbF production in these conditions might be possible. Reports of a transient increase in HbF concentrations in patients recovering from bone-marrow suppression after chemotherapy hinted that increased HbF production might, at least partly, reflect accelerated erythroid-cell differentiation.5 Studies with hydroxycarbamide (previously hydroxyurea), an S-phase-specific chemotherapeutic drug, showed that the drug increased HbF production, both in phlebotomised monkeys6 and in people with sicklecell anaemia.7 A large randomised, placebo-controlled trial was set up to analyse the clinical effects of hydroxycarbamide therapy in sickle-cell disease, but it was terminated prematurely because interim analysis revealed a significant reduction in the frequency of painful crises and other complications in the treated group.8 On the basis of this trial, hydroxycarbamide became the first agent for stimulating HbF production to be approved by the US Food and Drug Administration for the treatment of sickle-cell anaemia. Although there was undoubtedly a variable increase in HbF production in the treated patients compared with controls, the production did not reach very high levels; and it was suggested later9 that at least some of the therapeutic effects of hydroxycarbamide might be mediated by an anti-inflammatory effect related to a reduction in the white-cell count. The precise therapeutic action of hydroxycarbamide is still uncertain, although its efficacy is undoubted. Although there has been wide experience of the use of hydroxycarbamide in adults, and to date no evidence for long-term toxicity or a tendency to malignant transformation of the bone marrow, its use in children has naturally been approached with extreme caution. Early studies10 and preliminary trials11,12 suggested that the drug had equal or greater efficacy in childhood and led to the larger controlled trial that is reported by Winfred Wang and colleagues in The Lancet.13 This blinded study compared hydroxycarbamide against placebo in patients with sickle-cell anaemia aged 9–18 months who were followed up for 2 years. As well as the clinical course, the study was designed to examine whether liquid hydroxycarbamide (20 mg/kg daily) had any effect on reducing the effects of sickle-cell anaemia on organ function, particularly the spleen and kidney. The outcome of this important study suggests that compared with the 97 patients in the placebo group, www.thelancet.com Vol 377 May 14, 2011
Science Photo Library
Comment
Electron micrograph showing sickle cell (left)
the 96 patients in the hydroxycarbamide group had substantial clinical benefits, including lower rates of pain and dactylitis, a common complication in early life. Requirements for hospital admission and transfusion were also lower, and haematological variables improved. The only significant adverse effect was mild-tomoderate neutropenia, but there was no increase in the number of infective episodes. Assessment of splenic, renal, and neurological function suggested some benefit but the results were not conclusive. These findings are extremely encouraging, especially in light of recent studies in Africa, which suggest that the pattern of infection in early life is similar to that in higherincome countries and therefore amenable to screening and appropriate prophylaxis.14 Hydroxycarbamide is inexpensive and could certainly be made available in low-income countries in which sickle-cell anaemia is so common. Although there is still a long way to go in the management of sickle-cell anaemia, enough can be achieved such that establishment of international partnerships between richer countries and low-income countries for the better management of sickle-cell anaemia is now vital.15 In view of the early deaths that result from this disease in sub-Saharan Africa, the success of this trial in early infancy is particularly encouraging. D J Weatherall Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK [email protected]
1629
Comment
I declare that I have no conflicts of interest. 1 2 3 4 5 6
7
8
9
Christianson A, Howson CP, Modell B. March of Dimes global report on birth defects. New York: March of Dimes Birth Defects Foundation, 2006. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch Intern Med 1910; 6: 517–21. Pauling L, Itano HA, Singer SJ, Wells IG. Sickle-cell anemia, a molecular disease. Science 1949; 110: 543–48. Weatherall DJ, Clegg JB. The thalassaemia syndromes, 4th edn. Oxford: Blackwell Science, 2001. Sheridan BL, Weatherall DJ, Clegg JB, et al. The patterns of fetal haemoglobin production in leukaemia. Br J Haematol 1976; 32: 487–506. Letvin NL, Linch DC, Beardsley GP, McIntyre KW, Nathan DG. Augmentation of fetal-hemoglobin production in anemic monkeys by hydroxyurea. N Engl J Med 1984; 310: 869–73. Platt O, Orkin S, Dover GJ, Beardsley GP, Miller B, Nathan DG. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest 1984; 74: 652–56. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995; 332: 1317–22. Saunthararajah Y, Atweh GF. Induction of fetal hemoglobin in the treatment
10
11
12
13
14
15
of sickle cell disease and beta thalassemia. In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ eds. Disorders of hemoglobin, 2nd edn. Cambridge: Cambridge University Press, 2009: 745–54. Ferster A, Tahriri P, Vermylen C, et al. Five years of experience with hydroxyurea in children and young adults with sickle cell disease. Blood 2001; 97: 3628–32. Thompson BW, Miller ST, Rogers ZR, et al. The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design. Pediatr Blood Cancer 2010; 54: 250–55. Wang WC, Wynn LW, Rogers ZR, Scott JP, Lane PA, Ware RE. A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia. J Pediatr 2001; 139: 790–96. Wang WC, Ware RE, Miller ST, et al, for the BABY HUG investigators. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011; 377: 1663–72. Williams TN, Uyoga S, Macharia A, et al. Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet 2009; 374: 1364–70. Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood 2010; 115: 4331–36.
The cost of dengue control Dengue is thought to be the most important vector-borne disease,1 with about 2·5 billion people (two-fifths of the world’s population) living in regions affected by dengue.2 There are 50–100 million new infections annually.3 According to WHO, the incidence is increasing because of human population growth and wider spread of vector mosquitoes due to climate change (figure).4,5 The total yearly cost of treatment in dengue-endemic areas can reach US$2 billion.3 Without an effective vaccine or specific antiviral treatment, control of the main mosquito vector, Aedes aegypti, is the
Published Online May 3, 2011 DOI:10.1016/S01406736(11)60470-4
SASI Group (University of Sheffield) and Mark Newman (University of Michigan)
See Articles page 1673
only option for the prevention and control of dengue,6 at a cost of between $0·207 and $1·008 a head. In The Lancet, Paula Luz and colleagues9 present a dynamic model of dengue transmission that includes the evolution of insecticide resistance together with human immunity. They also did a cost-effectiveness analysis of 43 insecticide-based control strategies, and concluded that high-efficacy larval control reduced dengue burden for up to 2 years, whereas control of adult mosquitoes reduced dengue burden for up to 4 years. The investigators assessed the use of high-efficacy, intermediate-efficacy,
Figure: Deaths from dengue worldwide Territories are sized in proportion to number of people who died from dengue in 2002.
1630
www.thelancet.com Vol 377 May 14, 2011
Enough about endpoints. What we really want to know is: should we use hydrogel coils in our patients? For medium-sized ruptured aneurysms, if we want to avoid angiographic recurrence, HELPS offers evidence of benefit of hydrogel over platinum coils. Before extending that conclusion to all ruptured aneurysms, the still unanswered issue of hydrocephalus might need to be taken into account. What else can HELPS help with? The trialists have kindly provided us with several provocative analyses that can shape future trials. First, hydrogel-coil-associated hydrocephalus remains a victim of the statistics of rare events; even in this trial, the event rate was so low that no statistically significant difference between groups was recorded. Rates provided by HELPS can improve power estimates for future study of hydrocephalus and meningeal reaction. Second, the recorded benefit of hydrogel coils in medium-sized aneurysms suggests that future trials of endovascular aneurysm treatments might benefit from narrowed inclusion criteria. These medium-sized aneurysms seem to represent the statistical sweetspot (not too small, when all coils do well, and not too big, when no coil does well) for comparing coil technologies; investigators should be aware, though, that the feasibility and generalisability of trials with narrow inclusion criteria might be compromised. Finally, treatment targets, including the proportion of hydrogel coils used, could be worth investigating. These findings might provide support for mechanistic and biological
theories of why hydrogel-coated coils can be beneficial in the treatment of aneurysms. HELPS was a successful trial, providing us with some important answers and several questions to consider in the future. *David F Kallmes, Andrew J Molyneux Mayo Clinic, Rochester, MN 55905, USA (DFK) and Oxford Neurovascular and Neuroradiology Research Unit, Nuffield Department of Surgical Sciences, Oxford Radcliffe Hospital, Oxford, UK (AJM) [email protected] DFK has applied for grants to support preclinical research from eV3, MicroVention, Sequent, NFocus, Micrus, Cook, AthroCare, CareFusion; and his institution has received payment for development of educational presentations from eV3 and CareFusion. AJM has a consulting agreement with Micrus Endovascular Inc and Covidien Inc. 1
5
2
3 4
5
White PM, Lewis SC, Gholkar A, et al, for the HELPS trial collaborators. Hydrogel-coated coils versus bare platinum coils for the endovascular treatment of intracranial aneurysms (HELPS): a randomised controlled trial. Lancet 2011; 377: 1655–62. Molyneux AJ, Kerr RSC, Birks J, et al, for the ISAT Collaborators. Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up. Lancet Neurol 2009; 8: 427–33. Montori VM, Permanyer-Miralda G, Ferreira-González I, et al. Validity of composite end points in clinical trials. BMJ 2005; 330: 594–96. Molyneux AJ, Kerr RSC, Yu LM, et al, for the International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 2005; 366: 809–17. Im SH, Han MH, Kwon BJ, et al. Aseptic meningitis after embolization of cerebral aneurysms using hydrogel-coated coils: report of three cases. AJNR Am J Neuroradiol 2007; 28: 511–12.
Hydroxycarbamide for sickle-cell anaemia in infancy See Articles page 1663
1628
The inherited disorders of haemoglobin, sicklecell anaemia, its variants, and the thalassaemias, are by far the commonest monogenic diseases. An estimated 300 000 babies are born each year with these conditions, mainly in middle-income and lowincome countries.1 Last year, the US National Institutes of Health held a symposium to commemorate 100 years of research on sickle-cell disease since it was first described by the American physician James Herrick in 1910.2 It was the first disease to be characterised at the molecular level, as reported in Linus Pauling’s famous 1949 paper,3 and much has been learnt about its pathophysiology. However, much less progress has been made in prevention and management. Because
of the remarkable phenotypic variability, prenatal diagnosis has been applied less frequently than for the β thalassaemias. Although neonatal screening and the use of prophylactic antibiotics or vaccines has reduced associated mortality due to infection in early life in higher-income countries, and the symptomatic management of various complications, including stroke, has improved for many patients, sickle-cell anaemia remains a crippling disease. For reasons that are still not absolutely clear, patients with sickle-cell anaemia or β thalassaemia continue to produce variable amounts of fetal haemoglobin (HbF), throughout their lives. Many years ago, we observed that patients with higher concentrations of HbF tend www.thelancet.com Vol 377 May 14, 2011
to have milder forms of these diseases4 and thoughts turned to whether stimulation of HbF production in these conditions might be possible. Reports of a transient increase in HbF concentrations in patients recovering from bone-marrow suppression after chemotherapy hinted that increased HbF production might, at least partly, reflect accelerated erythroid-cell differentiation.5 Studies with hydroxycarbamide (previously hydroxyurea), an S-phase-specific chemotherapeutic drug, showed that the drug increased HbF production, both in phlebotomised monkeys6 and in people with sicklecell anaemia.7 A large randomised, placebo-controlled trial was set up to analyse the clinical effects of hydroxycarbamide therapy in sickle-cell disease, but it was terminated prematurely because interim analysis revealed a significant reduction in the frequency of painful crises and other complications in the treated group.8 On the basis of this trial, hydroxycarbamide became the first agent for stimulating HbF production to be approved by the US Food and Drug Administration for the treatment of sickle-cell anaemia. Although there was undoubtedly a variable increase in HbF production in the treated patients compared with controls, the production did not reach very high levels; and it was suggested later9 that at least some of the therapeutic effects of hydroxycarbamide might be mediated by an anti-inflammatory effect related to a reduction in the white-cell count. The precise therapeutic action of hydroxycarbamide is still uncertain, although its efficacy is undoubted. Although there has been wide experience of the use of hydroxycarbamide in adults, and to date no evidence for long-term toxicity or a tendency to malignant transformation of the bone marrow, its use in children has naturally been approached with extreme caution. Early studies10 and preliminary trials11,12 suggested that the drug had equal or greater efficacy in childhood and led to the larger controlled trial that is reported by Winfred Wang and colleagues in The Lancet.13 This blinded study compared hydroxycarbamide against placebo in patients with sickle-cell anaemia aged 9–18 months who were followed up for 2 years. As well as the clinical course, the study was designed to examine whether liquid hydroxycarbamide (20 mg/kg daily) had any effect on reducing the effects of sickle-cell anaemia on organ function, particularly the spleen and kidney. The outcome of this important study suggests that compared with the 97 patients in the placebo group, www.thelancet.com Vol 377 May 14, 2011
Science Photo Library
Comment
Electron micrograph showing sickle cell (left)
the 96 patients in the hydroxycarbamide group had substantial clinical benefits, including lower rates of pain and dactylitis, a common complication in early life. Requirements for hospital admission and transfusion were also lower, and haematological variables improved. The only significant adverse effect was mild-tomoderate neutropenia, but there was no increase in the number of infective episodes. Assessment of splenic, renal, and neurological function suggested some benefit but the results were not conclusive. These findings are extremely encouraging, especially in light of recent studies in Africa, which suggest that the pattern of infection in early life is similar to that in higherincome countries and therefore amenable to screening and appropriate prophylaxis.14 Hydroxycarbamide is inexpensive and could certainly be made available in low-income countries in which sickle-cell anaemia is so common. Although there is still a long way to go in the management of sickle-cell anaemia, enough can be achieved such that establishment of international partnerships between richer countries and low-income countries for the better management of sickle-cell anaemia is now vital.15 In view of the early deaths that result from this disease in sub-Saharan Africa, the success of this trial in early infancy is particularly encouraging. D J Weatherall Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK [email protected]
1629
Comment
I declare that I have no conflicts of interest. 1 2 3 4 5 6
7
8
9
Christianson A, Howson CP, Modell B. March of Dimes global report on birth defects. New York: March of Dimes Birth Defects Foundation, 2006. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch Intern Med 1910; 6: 517–21. Pauling L, Itano HA, Singer SJ, Wells IG. Sickle-cell anemia, a molecular disease. Science 1949; 110: 543–48. Weatherall DJ, Clegg JB. The thalassaemia syndromes, 4th edn. Oxford: Blackwell Science, 2001. Sheridan BL, Weatherall DJ, Clegg JB, et al. The patterns of fetal haemoglobin production in leukaemia. Br J Haematol 1976; 32: 487–506. Letvin NL, Linch DC, Beardsley GP, McIntyre KW, Nathan DG. Augmentation of fetal-hemoglobin production in anemic monkeys by hydroxyurea. N Engl J Med 1984; 310: 869–73. Platt O, Orkin S, Dover GJ, Beardsley GP, Miller B, Nathan DG. Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia. J Clin Invest 1984; 74: 652–56. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med 1995; 332: 1317–22. Saunthararajah Y, Atweh GF. Induction of fetal hemoglobin in the treatment
10
11
12
13
14
15
of sickle cell disease and beta thalassemia. In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ eds. Disorders of hemoglobin, 2nd edn. Cambridge: Cambridge University Press, 2009: 745–54. Ferster A, Tahriri P, Vermylen C, et al. Five years of experience with hydroxyurea in children and young adults with sickle cell disease. Blood 2001; 97: 3628–32. Thompson BW, Miller ST, Rogers ZR, et al. The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design. Pediatr Blood Cancer 2010; 54: 250–55. Wang WC, Wynn LW, Rogers ZR, Scott JP, Lane PA, Ware RE. A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia. J Pediatr 2001; 139: 790–96. Wang WC, Ware RE, Miller ST, et al, for the BABY HUG investigators. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet 2011; 377: 1663–72. Williams TN, Uyoga S, Macharia A, et al. Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet 2009; 374: 1364–70. Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood 2010; 115: 4331–36.
The cost of dengue control Dengue is thought to be the most important vector-borne disease,1 with about 2·5 billion people (two-fifths of the world’s population) living in regions affected by dengue.2 There are 50–100 million new infections annually.3 According to WHO, the incidence is increasing because of human population growth and wider spread of vector mosquitoes due to climate change (figure).4,5 The total yearly cost of treatment in dengue-endemic areas can reach US$2 billion.3 Without an effective vaccine or specific antiviral treatment, control of the main mosquito vector, Aedes aegypti, is the
Published Online May 3, 2011 DOI:10.1016/S01406736(11)60470-4
SASI Group (University of Sheffield) and Mark Newman (University of Michigan)
See Articles page 1673
only option for the prevention and control of dengue,6 at a cost of between $0·207 and $1·008 a head. In The Lancet, Paula Luz and colleagues9 present a dynamic model of dengue transmission that includes the evolution of insecticide resistance together with human immunity. They also did a cost-effectiveness analysis of 43 insecticide-based control strategies, and concluded that high-efficacy larval control reduced dengue burden for up to 2 years, whereas control of adult mosquitoes reduced dengue burden for up to 4 years. The investigators assessed the use of high-efficacy, intermediate-efficacy,
Figure: Deaths from dengue worldwide Territories are sized in proportion to number of people who died from dengue in 2002.
1630
www.thelancet.com Vol 377 May 14, 2011