Correspondence
General Hospital Braunau, Cardiology and Intensive Care, Braunau A-5280, Austria 1
2
3
4
5
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21. SEARCH Study Collaborative Group. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J 2007; 154: 815–23. Auer J, Lamm G, Eber B. Intensive lipid lowering with atorvastatin in coronary disease. N Engl J Med 2005; 353: 93–96. FDA Drug Safety Communication. New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. http://www.fda. gov/Drugs/DrugSafety/ucm256581.htm (accessed July 3, 2014). Schulz KF, Grimes DA. Sample size calculations in randomised trials: mandatory and mystical. Lancet 2005; 365: 1348–53.
We wish to congratulate Jeremy Chataway and colleagues for successfully completing the high-dose simvastatin in secondary progressive multiple sclerosis (MS-STAT) trial.1 The detected delay in disease progression in this phase 2 study now calls for phase 3 trial evidence. However, we are concerned such evidence will never be produced, simply because simvastatin costs about £0·06 per day in the UK. Which industrial partner will be prepared to fund a phase 3 development programme, let alone the costs to apply for (and maintain) a license should further trials confirm the efficacy of simvastatin in progressive multiple sclerosis? Or is there an alternative pathway to repurposing beyond the stage at which MS-STAT has arrived—ie, to the point where the drugs can be made available to patients with secondary progressive multiple sclerosis? If it is not feasible to develop licensed drugs to the stage they can actually be prescribed for a new indication, can we justify, ethically and economically, proof-of-concept studies such as MS-STAT? One might argue such trials become little more than academic exercises creating false hopes for people in desperate need of treatments. 952
We declare no competing interests.
*Gavin Giovannoni, David Baker, Klaus Schmierer [email protected] Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK 1
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21.
Authors’ reply We thank Johann Auer and Robert Berent for their Correspondence regarding our phase 2 trial of simvastatin in secondary progressive multiple sclerosis (MS-STAT). 1 In this trial, simvastatin (80 mg) was well-tolerated with no difference in adverse events between the two groups. The same dose was also used in the largest trial in relapsing-remitting multiple sclerosis (SIMCOMBIN), 2 which included 307 patients, and also in the Danish acute optic neuritis trial (64 patients);3 again, there was no difference in serious adverse events between placebo and active arms, in either trial.2,3 As Auer and Berent state, the US FDA has recommended that this dose is to be used with particular care in the treatment of vascular disease. We agree with that. However, the risk–benefit ratio is different in secondary progressive multiple sclerosis, for which no treatment exists for a devastating, progressively disabling disease. Although we recognise that infrequent adverse effects might require a larger sample size, we believe that if monitored carefully, as in our study,1 this dose of simvastatin can be safely used perhaps with additional pharmacogenomic information (eg, the SLCO1B1 risk allele for simvastatin-induced myopathy4). Indeed, in multiple sclerosis, we are familiar with using drugs such natalizumab and alemtuzumab, which have their own uncommon, but serious safety issues. For example, the risk of progressive multifocal
leukoencephalopathy (a potentially fatal viral disease) approaches 0·5% after 2 years of treatment with natalizumab in JC virus positive patients. Regarding the use of other statins, we were originally excited by the potential of simvastatin in multiple sclerosis by the study of Vollmer and colleagues,5 which again used simvastatin at a dose of 80 mg. One of our central reasons for using simvastatin was that we considered it to have a favourable combination of brain penetrance and potency. Gavin Giovannoni and colleagues raise the general issue of off-patent repurposed drugs and the subsequent licensing process. This is a crucial issue, which is a challenge for the current regulatory structure and one where guidance is evolving with the authorities. An effective resolution is needed, as there are an increasing number of compounds for which this process might apply—eg, the use of aspirin in cancer prevention.6 However without positive (investigator-led) phase 2 data such as ours, the opportunity or the grounds will not exist to challenge what is clearly an unsatisfactory and increasingly problematic situation. We declare no competing interests.
Jeremy Chataway on behalf of the MS-STAT investigators1 [email protected] National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK 1
2
3
4
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21. Sorensen P, Lycke J, Eralinna JP, et al. Simvastatin as add-on to interferon beta-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol 2011; 10: 691–701. Tsakiri A, Kallenbach K, Fuglo D, Wanscher B, Larsson H, Frederiksen J. Simvastatin improves final visual outcome in acute optic neuritis: a randomized study. Mult Scler J 2012; 18: 72–81. Ramsey LB, Johnson SG, Caudle KE, et al. The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 update. Clin Pharmacol Ther 2014; published online June 11. DOI:10.1038/clpt.2014.125.
www.thelancet.com Vol 384 September 13, 2014
Correspondence
6
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004; 363: 1607–08. Cuzick J, Thorat M, Bosetti C, et al. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Ann Oncol 2014; published online Aug 5. DOI:10.1093/annonc/ mdu225.
3
4
5
Can dementia be lessened by statins? The Lancet Editorial of June 281 states that Prime Minister David Cameron has taken the lead in the attempt to lessen the global epidemic of dementia by identifying a cure or disease modifying therapy by 2025. 1 Yet in the same issue of The Lancet, we read that statins have anti-inflammatory properties and inhibit leucocyte migration through the blood–brain barrier, thereby lessening atrophy of the brain. 2 Possible additional brain protective mechanisms are endothelial protection via action on the nitric oxide synthase system and as well as antioxidant and anti-inflammatory and anti-platelet effects.3–5 Thus there are several pointers that together make a case for the wider use of statins with the aim of lessening the effect of dementia. Although we will undoubtedly have more information by 2025, the currently available data suggest the use of high-dose statins as relatively simple therapy to lessen the severity of developing dementia. Ultimately a large-scale definitive study would be required fully to prove this concept. I declare no competing interests.
Lionel H Opie [email protected] Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town 7925, South Africa 1 2
The Lancet. Addressing global dementia. Lancet 2014; 383: 2185. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21.
www.thelancet.com Vol 384 September 13, 2014
Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke 1999; 30: 1969–73. Ma M, Uekawa K, Hasegawa Y, et al. Pretreatment with rosuvastatin protects against focal cerebral ischemia/reperfusion injury in rats through attenuation of oxidative stress and inflammation. Brain Res 2013; 1519: 87–94. Moon GJ, Kim SJ, Cho YH, Ryoo S, Bang OY. Antioxidant effects of statins in patients with atherosclerotic cerebrovascular disease. J Clin Neurol 2014; 10: 140–47.
The US Centers for Disease Control: a crucial actor in global health The Lancet’s Health of Americans Series rightly acknowledges the contribution made by US Centers for Disease Control and Prevention to global health.1 Yet, all great leadership should allow space to reflect on challenges. A great success in public health— the Presidential Emergency Plan for AIDS Relief (PEPFAR) evolved. Initially it was criticised for the health systems effect of vertical programming and for its conditionalities. 2 For example, organisations receiving funding were required to adhere to the Global Gag Rule. No funding could be given to organisations providing comprehensive sexual and reproductive health (SRH) services, which included safe abortion or information on abortion. 3 It also required recipients of funding to sign an anti-prostitution pledge. This requirement was rejected by human rights and sex worker activists as demonising activities and ignoring principles of empowerment and autonomy, which have been shown as essential to addressing the health needs of these communities. Similarly, the programmes’ initial emphasis of abstinence over condoms was criticised as a so-called moral agenda flying in the face of evidence-based HIV prevention.4 At the heart of US engagement is a tension between an agency accountable to domestic policy audiences—the US Congress and
through it the people of the USA— while shaping the health and services of people abroad with little say in setting these agendas. Overcoming this tension holds the most important lesson of US engagement in global health: the need for more open and crucial dialogue about what works, to adapt, to evolve, and allow learning from implementation rather than a one-size-fits-all approach to reaching targets.
James King-Holmes/Science Photo Library
5
I declare no competing interests.
Johanna Hanefeld [email protected] London School of Hygiene and Tropical Medicine, London WC1H 9SH, UK 1
2
3
4
Schuchat A, Tappero J, Blandford J. Global health and the US Centers for Disease Control and Prevention. Lancet 2014; 384: 98–101. Hanefeld J. The impact of Global Health Initiatives at national and sub-national level—a policy analysis of their role in implementation processes of antiretroviral treatment (ART) roll-out in Zambia and South Africa. AIDS Care 2010; 22: 93–102. Ghanotakis E, Mayhew S, Watts C. Tackling HIV and gender-based violence in South Africa: how has PEPFAR responded and what are the implications for implementing organizations? Health Policy Plann 2009; 24: 357–66. Cohen J, Schleifer R, Tate T. AIDS in Uganda: the human-rights dimension. Lancet 2005; 365: 2075–76.
For the Series see http://www. thelancet.com/series/health-ofamericans-2014
Health of Americans I commend Ursula Bauer and colleagues1 for drawing attention to the need to address the non-communicable disease (NCD) burden as part of a series on the health of Americans.2 However, their work has three vital limitations. First, a deeper analysis of why only 3% of public spend on health care and less than 2% of employer spend goes to prevention is needed for sustained change. Underinvestment in prevention science—including the use of behavioral economics and innovative personalised technologies —is one key reason.3 This funding gap, starting with the National Institutes of Health, has led to less actionable knowledge by health authorities and the Congressional Budget Office. Sceptical attitudes 953
General Hospital Braunau, Cardiology and Intensive Care, Braunau A-5280, Austria 1
2
3
4
5
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21. SEARCH Study Collaborative Group. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J 2007; 154: 815–23. Auer J, Lamm G, Eber B. Intensive lipid lowering with atorvastatin in coronary disease. N Engl J Med 2005; 353: 93–96. FDA Drug Safety Communication. New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. http://www.fda. gov/Drugs/DrugSafety/ucm256581.htm (accessed July 3, 2014). Schulz KF, Grimes DA. Sample size calculations in randomised trials: mandatory and mystical. Lancet 2005; 365: 1348–53.
We wish to congratulate Jeremy Chataway and colleagues for successfully completing the high-dose simvastatin in secondary progressive multiple sclerosis (MS-STAT) trial.1 The detected delay in disease progression in this phase 2 study now calls for phase 3 trial evidence. However, we are concerned such evidence will never be produced, simply because simvastatin costs about £0·06 per day in the UK. Which industrial partner will be prepared to fund a phase 3 development programme, let alone the costs to apply for (and maintain) a license should further trials confirm the efficacy of simvastatin in progressive multiple sclerosis? Or is there an alternative pathway to repurposing beyond the stage at which MS-STAT has arrived—ie, to the point where the drugs can be made available to patients with secondary progressive multiple sclerosis? If it is not feasible to develop licensed drugs to the stage they can actually be prescribed for a new indication, can we justify, ethically and economically, proof-of-concept studies such as MS-STAT? One might argue such trials become little more than academic exercises creating false hopes for people in desperate need of treatments. 952
We declare no competing interests.
*Gavin Giovannoni, David Baker, Klaus Schmierer [email protected] Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK 1
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21.
Authors’ reply We thank Johann Auer and Robert Berent for their Correspondence regarding our phase 2 trial of simvastatin in secondary progressive multiple sclerosis (MS-STAT). 1 In this trial, simvastatin (80 mg) was well-tolerated with no difference in adverse events between the two groups. The same dose was also used in the largest trial in relapsing-remitting multiple sclerosis (SIMCOMBIN), 2 which included 307 patients, and also in the Danish acute optic neuritis trial (64 patients);3 again, there was no difference in serious adverse events between placebo and active arms, in either trial.2,3 As Auer and Berent state, the US FDA has recommended that this dose is to be used with particular care in the treatment of vascular disease. We agree with that. However, the risk–benefit ratio is different in secondary progressive multiple sclerosis, for which no treatment exists for a devastating, progressively disabling disease. Although we recognise that infrequent adverse effects might require a larger sample size, we believe that if monitored carefully, as in our study,1 this dose of simvastatin can be safely used perhaps with additional pharmacogenomic information (eg, the SLCO1B1 risk allele for simvastatin-induced myopathy4). Indeed, in multiple sclerosis, we are familiar with using drugs such natalizumab and alemtuzumab, which have their own uncommon, but serious safety issues. For example, the risk of progressive multifocal
leukoencephalopathy (a potentially fatal viral disease) approaches 0·5% after 2 years of treatment with natalizumab in JC virus positive patients. Regarding the use of other statins, we were originally excited by the potential of simvastatin in multiple sclerosis by the study of Vollmer and colleagues,5 which again used simvastatin at a dose of 80 mg. One of our central reasons for using simvastatin was that we considered it to have a favourable combination of brain penetrance and potency. Gavin Giovannoni and colleagues raise the general issue of off-patent repurposed drugs and the subsequent licensing process. This is a crucial issue, which is a challenge for the current regulatory structure and one where guidance is evolving with the authorities. An effective resolution is needed, as there are an increasing number of compounds for which this process might apply—eg, the use of aspirin in cancer prevention.6 However without positive (investigator-led) phase 2 data such as ours, the opportunity or the grounds will not exist to challenge what is clearly an unsatisfactory and increasingly problematic situation. We declare no competing interests.
Jeremy Chataway on behalf of the MS-STAT investigators1 [email protected] National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK 1
2
3
4
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21. Sorensen P, Lycke J, Eralinna JP, et al. Simvastatin as add-on to interferon beta-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol 2011; 10: 691–701. Tsakiri A, Kallenbach K, Fuglo D, Wanscher B, Larsson H, Frederiksen J. Simvastatin improves final visual outcome in acute optic neuritis: a randomized study. Mult Scler J 2012; 18: 72–81. Ramsey LB, Johnson SG, Caudle KE, et al. The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 update. Clin Pharmacol Ther 2014; published online June 11. DOI:10.1038/clpt.2014.125.
www.thelancet.com Vol 384 September 13, 2014
Correspondence
6
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004; 363: 1607–08. Cuzick J, Thorat M, Bosetti C, et al. Estimates of benefits and harms of prophylactic use of aspirin in the general population. Ann Oncol 2014; published online Aug 5. DOI:10.1093/annonc/ mdu225.
3
4
5
Can dementia be lessened by statins? The Lancet Editorial of June 281 states that Prime Minister David Cameron has taken the lead in the attempt to lessen the global epidemic of dementia by identifying a cure or disease modifying therapy by 2025. 1 Yet in the same issue of The Lancet, we read that statins have anti-inflammatory properties and inhibit leucocyte migration through the blood–brain barrier, thereby lessening atrophy of the brain. 2 Possible additional brain protective mechanisms are endothelial protection via action on the nitric oxide synthase system and as well as antioxidant and anti-inflammatory and anti-platelet effects.3–5 Thus there are several pointers that together make a case for the wider use of statins with the aim of lessening the effect of dementia. Although we will undoubtedly have more information by 2025, the currently available data suggest the use of high-dose statins as relatively simple therapy to lessen the severity of developing dementia. Ultimately a large-scale definitive study would be required fully to prove this concept. I declare no competing interests.
Lionel H Opie [email protected] Hatter Institute for Cardiovascular Research in Africa, Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town 7925, South Africa 1 2
The Lancet. Addressing global dementia. Lancet 2014; 383: 2185. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21.
www.thelancet.com Vol 384 September 13, 2014
Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke 1999; 30: 1969–73. Ma M, Uekawa K, Hasegawa Y, et al. Pretreatment with rosuvastatin protects against focal cerebral ischemia/reperfusion injury in rats through attenuation of oxidative stress and inflammation. Brain Res 2013; 1519: 87–94. Moon GJ, Kim SJ, Cho YH, Ryoo S, Bang OY. Antioxidant effects of statins in patients with atherosclerotic cerebrovascular disease. J Clin Neurol 2014; 10: 140–47.
The US Centers for Disease Control: a crucial actor in global health The Lancet’s Health of Americans Series rightly acknowledges the contribution made by US Centers for Disease Control and Prevention to global health.1 Yet, all great leadership should allow space to reflect on challenges. A great success in public health— the Presidential Emergency Plan for AIDS Relief (PEPFAR) evolved. Initially it was criticised for the health systems effect of vertical programming and for its conditionalities. 2 For example, organisations receiving funding were required to adhere to the Global Gag Rule. No funding could be given to organisations providing comprehensive sexual and reproductive health (SRH) services, which included safe abortion or information on abortion. 3 It also required recipients of funding to sign an anti-prostitution pledge. This requirement was rejected by human rights and sex worker activists as demonising activities and ignoring principles of empowerment and autonomy, which have been shown as essential to addressing the health needs of these communities. Similarly, the programmes’ initial emphasis of abstinence over condoms was criticised as a so-called moral agenda flying in the face of evidence-based HIV prevention.4 At the heart of US engagement is a tension between an agency accountable to domestic policy audiences—the US Congress and
through it the people of the USA— while shaping the health and services of people abroad with little say in setting these agendas. Overcoming this tension holds the most important lesson of US engagement in global health: the need for more open and crucial dialogue about what works, to adapt, to evolve, and allow learning from implementation rather than a one-size-fits-all approach to reaching targets.
James King-Holmes/Science Photo Library
5
I declare no competing interests.
Johanna Hanefeld [email protected] London School of Hygiene and Tropical Medicine, London WC1H 9SH, UK 1
2
3
4
Schuchat A, Tappero J, Blandford J. Global health and the US Centers for Disease Control and Prevention. Lancet 2014; 384: 98–101. Hanefeld J. The impact of Global Health Initiatives at national and sub-national level—a policy analysis of their role in implementation processes of antiretroviral treatment (ART) roll-out in Zambia and South Africa. AIDS Care 2010; 22: 93–102. Ghanotakis E, Mayhew S, Watts C. Tackling HIV and gender-based violence in South Africa: how has PEPFAR responded and what are the implications for implementing organizations? Health Policy Plann 2009; 24: 357–66. Cohen J, Schleifer R, Tate T. AIDS in Uganda: the human-rights dimension. Lancet 2005; 365: 2075–76.
For the Series see http://www. thelancet.com/series/health-ofamericans-2014
Health of Americans I commend Ursula Bauer and colleagues1 for drawing attention to the need to address the non-communicable disease (NCD) burden as part of a series on the health of Americans.2 However, their work has three vital limitations. First, a deeper analysis of why only 3% of public spend on health care and less than 2% of employer spend goes to prevention is needed for sustained change. Underinvestment in prevention science—including the use of behavioral economics and innovative personalised technologies —is one key reason.3 This funding gap, starting with the National Institutes of Health, has led to less actionable knowledge by health authorities and the Congressional Budget Office. Sceptical attitudes 953
