- Email: [email protected]
Statins for multiple sclerosis
Correspondence
Fawad Aslam [email protected] Male Hostel, Aga Khan University Medical College, Stadium Road, Karachi 74800, Pakistan 1
2
3
4
5
The Lancet. OTC statins: a bad decision for public health. Lancet 2004; 363: 1659. Topol EJ. Intensive statin therapy: a sea change in cardiovascular prevention. N Engl J Med 2004; 350: 1562–64. Sen K, Bonita R. Global health status: two steps forward, one step back. Lancet 2000; 356: 577–82. Nishtar S. Prevention of coronary heart disease in South Asia. Lancet 2002; 360: 1015–18. National Heart Foundation of Pakistan. SAARC Region Prevention Guidelines. http:// heartfile.org/ (accessed June 24, 2004).
Statins for multiple sclerosis Timothy Vollmer and colleagues (May 15, p 1007)1 provide evidence that treatment with 80 mg of simvastatin inhibits the inflammatory components of multiple sclerosis. Their study is not, however, “the first to provide some evidence of an effect with a statin in multiple sclerosis”, as stated by Chris Polman and Joep Killestein in their Commentary.2 In 2003, we reported3 the results of an observational study of seven female patients who had relapsing-remitting disease after 1 year of monotherapy with 40 mg of lovastatin. In agreement with Vollmer and colleagues’ findings, we noted a reduction in the mean number of gadolinium (Gd)-enhancing lesions and no great differences between pretreatment and treatment expanded disability status scores. Three patients remained free of relapses, and the mean annual relapse rate decreased during the year. However, we did detect new lesions on T2-weighted images in five patients at the end of the study. Six people have now completed 2 years of lovastatin monotherapy; three patients had relapses and developed new T2-weighted lesions during the second year of treatment. Our results suggest that the reduction in Gd-enhancing lesions observed by Vollmer and colleagues after 6 months of treatment cannot ensure an inhibitory effect on the progression of the disease, 412
which is only testable with longer periods of follow up. As Polman and Killestein note,2 the differential anti-inflammatory potency of statins should be considered in this context, since they can also be dosedependent. However, experimental evidence 4 suggests that high doses of statins, which pass the blood-brain barrier, could interfere with neural repair mechanisms. Hence, we feel that the widespread use of these drugs in patients with multiple sclerosis cannot be recommended until randomised controlled trials have been done to address these issues.
*Armando Sena, Rui Pedrosa, M Graça Morais [email protected] *Serviço de Neurologia, Hospital dos Capuchos, Centro Hospitalar de Lisboa, Alameda de Santo António dos Capuchos, 1169-050 Lisboa, Portugal (AS, RP); and Departamento de Bioquímica, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria, Lisboa, Portugal (AS, MGM) 1
2
3
4
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsingremitting multiple sclerosis. Lancet 2004; 363: 1607–08. Polman CH, Killestein J. Statins for the treatment of multiple sclerosis: cautious hope. Lancet 2004; 363: 1570. Sena A, Pedrosa R, Morais MG. Therapeutic potential of lovastatin in multiple sclerosis. J Neurol 2003; 250: 754–55. Schulz JG, Bösel J, Stoeckel M, Megow D, Dirnagl U, Endres M. HMG-CoA reductase inhibition causes neurite loss by interfering with geranylgeranyl pyrophosphate synthesis. J Neurochem 2004; 89: 24–32.
Timothy Vollmer and colleagues1 report the effective use of a drug that is generally considered safe in the treatment of relapsing-remitting multiple sclerosis, which is very promising. Although no serious adverse drug effects arose during the study, three patients complained of muscle weakness, one had an increased creatinine phosphokinase concentration, and two had abnormal liverfunction test results. This high proportion of adverse effects could be a direct consequence of the fairly high daily dose of simvastatin used. We caution against the chronic administration of such a high dose. In 2000 and 2001 (before the cerivastatin withdrawal episode), our Regional
Centre of Pharmacovigilance recorded 13 cases of raised creatinine phosphokinase concentrations in individuals prescribed simvastatin (n=2), atorvastatin (n=6), cerivastatin (n=2), fluvastatin (n=1), or pravastatin (n=2). In all cases, doses complied with the marketing authorisations, but the highest creatinine phosphokinase values arose in those patients given the highest doses. Median treatment duration was equivalent to that reported by Vollmer and colleagues. The French National Pharmacovigilance Data Base includes more than 20 cases of rhabdomyolysis, occurring during simvastatin use at recommended dose. Although simvastatin, lovastatin, and mevastatin inhibit proliferation of peripheral blood mononuclear cells in a dose-dependent manner they should be regarded as potentially myotoxic, and high doses should be used cautiously in the long term. 2 We acknowledge the treatment breakthrough, but think muscle enzyme values should be closely monitored so as to avoid any inappropriate and unwanted interruption of treatment. As statins begin to be available without prescription in some countries, this issue is likely to become a greater concern.
Marie-Laure Laroche, *Louis Merle [email protected] Centre Régional de Pharmacovigilance, Hôpital Dupuytren, 87042 Limoges, France 1
2
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004; 363: 1607–08. Neuhaus O, Strasser-Fuchs S, Fazekas F, et al. Statins as immunomodulators: comparison with interferon-beta1b in MS. Neurology 2002; 59: 990–97.
Authors’ reply We appreciate the comments of Armando Sena, Rui Pedrosa, and Graça Morais. Our study was an exploratory study and is suggestive of benefit from oral simavastatin therapy in patients with relapsing forms of multiple sclerosis by an MRI surrogate measure. Their data seem similar to ours. We agree that neither of these studies provides adequate support for the use of statins as a treatment for multiple sclerosis outside of welldesigned clinical trials. We also agree that www.thelancet.com Vol 364 July 31, 2004
Correspondence
data from these two studies indicate a need for randomised, parallel designed, controlled trials. Although, we are aware of the article by Schulz and colleagues, there is also evidence that doses of 3-hydroxy3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors that can cross the blood-brain barrier might be able to inhibit the production of tumour necrosis factor (TNF) and nitric oxide through inducible nitric oxide synthase induction in astrocytes and microglia.1,2 Since these molecules have been postulated to play a part in the neurodegenerative phase of multiple sclerosis, their inhibition could be beneficial in slowing the progression of disability and axonal or neuronal loss that characterises many patients with the disease. Therefore, we believe this issue will need to be resolved by long-term randomised trials designed to detect an effect of statin therapy on disability and brain MRI markers of axonal and neuronal loss. We also appreciate the comments of Marie-Laure Laroche and Louis Merle. We were keenly aware of the potential risks of high-dose simvastatin therapy, including the risk of rhabdomyolysis. We selected our dose on the basis of the results of preclinical and clinical trials, which suggested at approximately 1 mg/kg dose for simvastatin some penetration of the blood-brain barrier is possible. Again, based on studies from the laboratory of Inderjit Singh, 1,3 we believe a treatment effect on microglia and astrocytes, in addition to the potential effect of statin therapy on regulatory T-cell subsets and antigen presentation, could be important for maximising efficacy in patients with multiple sclerosis. Although safety data from clinical studies of individuals treated with 80 mg of simvastatin per day indicated adequate safety to proceed with our study, we agree whole heartedly that the myotoxic potential of high-dose statin therapy deserves close monitoring of muscle enzymes in serum of treated patients.
*Timothy Vollmer, Inderjit Singh [email protected] Division of Neurology, Barrow Neurological Institute, Phoenix, AZ 85013, USA
www.thelancet.com Vol 364 July 31, 2004
1
2
3
Pahan K, Sheikh F, Namboodiri AMS, Singh I. Lovastatin and phenylacetate inhibit the induction of inducible nitric oxide synthase and cytokines in primary astrocytes, microglia and macrophages. J Clin Invest 1997; 100: 2671–79. Stanislaus R, Pahan K, Singh AK, Singh I. Amelioration of experimental allergic encephalomyelitis in Lewis rats by lovastatin. NeuroSci Let 1999; 269: 71–74. Stanislaus R, Singh AK, Singh I. Lovastatin treatment blocks the infiltration of mononuclear cells and induction of inflammatory process in experimental allergic encephalomyelitis. J NeuroSci Res 2001; 66: 155–62.
Diuretics in the LIFE study In 2002, Björn Dahlöf and colleagues reported that the angiotensin-receptor blocker losartan was superior to the blocker atenolol in the prevention of stroke in hypertensive patients with leftventricular hypertrophy. 1 We write to raise a concern about whether a difference in the number of patients taking diuretics influenced the results. Referring to table 2 of their report, Dahlöf and colleagues described that there was no difference in the distribution of additional drugs between the study groups. However, hydrochlorothiazide was used as an additional drug, solely or in combination with others, in 2027 (829 plus 1198) of 4605 patients on losartan (44%) and 1729 (713 plus 1016) of 4588 patients on atenolol (38%). A 2 test reveals that the proportion taking hydrochlorothiazide in each group is significantly different (p<0·0001). In a substudy published afterwards,2 a similar efficacy of losartan was reported for primary prevention of stroke in isolated systolic hypertension. As shown in table 2 of that report, the distribution of additional treatment was not significantly different between groups. However, if the total numbers of patients taking hydrochlorothiazide are included in the same way as above, a significant difference is also found between the groups: 253 of 660 (38%) patients on losartan versus 220 of 666 (33%) on atenolol (p=0·045). In PROGRESS,3 a single treatment with perindopril had no significant effect on
the secondary prevention of stroke, but combination with the diuretic indapamide reduced recurrence of the disorder. The preventive effect of diuretics on stroke have been well documented in several clinical trials, and the large-scale, randomised study ALLHAT showed that chlorthalidone was superior to lisinopril in the primary prevention of the disorder.4 In the LIFE study, the more frequent use of the diuretic hydrochlorothiazide might have partly contributed to the lower incidence of stroke in the losartan group. Therefore, conclusions from the LIFE study on the preventive effect of angiotensin-receptor blockers on stroke should be interpreted with caution.
*Johji Kato, Tanenao Eto [email protected] First Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan 1
2
3
4
Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003. Kjeldsen SE, Dahlöf B, Devereux RB, et al. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. JAMA 2002; 288: 1491–98. PROGRESS Collaborative Group. Randomised trial of a perindopril-based bloodpressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: 1033–41. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–97.
Authors’ reply Johji Kato and Tanenao Eto question whether the difference in use of the diuretic hydrochlorothiazide between the treatment groups accounts for the advantage of losartan seen in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. According to the design of the study, investigators were to add hydrochlorothiazide, increase the 413
Fawad Aslam [email protected] Male Hostel, Aga Khan University Medical College, Stadium Road, Karachi 74800, Pakistan 1
2
3
4
5
The Lancet. OTC statins: a bad decision for public health. Lancet 2004; 363: 1659. Topol EJ. Intensive statin therapy: a sea change in cardiovascular prevention. N Engl J Med 2004; 350: 1562–64. Sen K, Bonita R. Global health status: two steps forward, one step back. Lancet 2000; 356: 577–82. Nishtar S. Prevention of coronary heart disease in South Asia. Lancet 2002; 360: 1015–18. National Heart Foundation of Pakistan. SAARC Region Prevention Guidelines. http:// heartfile.org/ (accessed June 24, 2004).
Statins for multiple sclerosis Timothy Vollmer and colleagues (May 15, p 1007)1 provide evidence that treatment with 80 mg of simvastatin inhibits the inflammatory components of multiple sclerosis. Their study is not, however, “the first to provide some evidence of an effect with a statin in multiple sclerosis”, as stated by Chris Polman and Joep Killestein in their Commentary.2 In 2003, we reported3 the results of an observational study of seven female patients who had relapsing-remitting disease after 1 year of monotherapy with 40 mg of lovastatin. In agreement with Vollmer and colleagues’ findings, we noted a reduction in the mean number of gadolinium (Gd)-enhancing lesions and no great differences between pretreatment and treatment expanded disability status scores. Three patients remained free of relapses, and the mean annual relapse rate decreased during the year. However, we did detect new lesions on T2-weighted images in five patients at the end of the study. Six people have now completed 2 years of lovastatin monotherapy; three patients had relapses and developed new T2-weighted lesions during the second year of treatment. Our results suggest that the reduction in Gd-enhancing lesions observed by Vollmer and colleagues after 6 months of treatment cannot ensure an inhibitory effect on the progression of the disease, 412
which is only testable with longer periods of follow up. As Polman and Killestein note,2 the differential anti-inflammatory potency of statins should be considered in this context, since they can also be dosedependent. However, experimental evidence 4 suggests that high doses of statins, which pass the blood-brain barrier, could interfere with neural repair mechanisms. Hence, we feel that the widespread use of these drugs in patients with multiple sclerosis cannot be recommended until randomised controlled trials have been done to address these issues.
*Armando Sena, Rui Pedrosa, M Graça Morais [email protected] *Serviço de Neurologia, Hospital dos Capuchos, Centro Hospitalar de Lisboa, Alameda de Santo António dos Capuchos, 1169-050 Lisboa, Portugal (AS, RP); and Departamento de Bioquímica, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria, Lisboa, Portugal (AS, MGM) 1
2
3
4
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsingremitting multiple sclerosis. Lancet 2004; 363: 1607–08. Polman CH, Killestein J. Statins for the treatment of multiple sclerosis: cautious hope. Lancet 2004; 363: 1570. Sena A, Pedrosa R, Morais MG. Therapeutic potential of lovastatin in multiple sclerosis. J Neurol 2003; 250: 754–55. Schulz JG, Bösel J, Stoeckel M, Megow D, Dirnagl U, Endres M. HMG-CoA reductase inhibition causes neurite loss by interfering with geranylgeranyl pyrophosphate synthesis. J Neurochem 2004; 89: 24–32.
Timothy Vollmer and colleagues1 report the effective use of a drug that is generally considered safe in the treatment of relapsing-remitting multiple sclerosis, which is very promising. Although no serious adverse drug effects arose during the study, three patients complained of muscle weakness, one had an increased creatinine phosphokinase concentration, and two had abnormal liverfunction test results. This high proportion of adverse effects could be a direct consequence of the fairly high daily dose of simvastatin used. We caution against the chronic administration of such a high dose. In 2000 and 2001 (before the cerivastatin withdrawal episode), our Regional
Centre of Pharmacovigilance recorded 13 cases of raised creatinine phosphokinase concentrations in individuals prescribed simvastatin (n=2), atorvastatin (n=6), cerivastatin (n=2), fluvastatin (n=1), or pravastatin (n=2). In all cases, doses complied with the marketing authorisations, but the highest creatinine phosphokinase values arose in those patients given the highest doses. Median treatment duration was equivalent to that reported by Vollmer and colleagues. The French National Pharmacovigilance Data Base includes more than 20 cases of rhabdomyolysis, occurring during simvastatin use at recommended dose. Although simvastatin, lovastatin, and mevastatin inhibit proliferation of peripheral blood mononuclear cells in a dose-dependent manner they should be regarded as potentially myotoxic, and high doses should be used cautiously in the long term. 2 We acknowledge the treatment breakthrough, but think muscle enzyme values should be closely monitored so as to avoid any inappropriate and unwanted interruption of treatment. As statins begin to be available without prescription in some countries, this issue is likely to become a greater concern.
Marie-Laure Laroche, *Louis Merle [email protected] Centre Régional de Pharmacovigilance, Hôpital Dupuytren, 87042 Limoges, France 1
2
Vollmer T, Key L, Durkalski V, et al. Oral simvastatin treatment in relapsing-remitting multiple sclerosis. Lancet 2004; 363: 1607–08. Neuhaus O, Strasser-Fuchs S, Fazekas F, et al. Statins as immunomodulators: comparison with interferon-beta1b in MS. Neurology 2002; 59: 990–97.
Authors’ reply We appreciate the comments of Armando Sena, Rui Pedrosa, and Graça Morais. Our study was an exploratory study and is suggestive of benefit from oral simavastatin therapy in patients with relapsing forms of multiple sclerosis by an MRI surrogate measure. Their data seem similar to ours. We agree that neither of these studies provides adequate support for the use of statins as a treatment for multiple sclerosis outside of welldesigned clinical trials. We also agree that www.thelancet.com Vol 364 July 31, 2004
Correspondence
data from these two studies indicate a need for randomised, parallel designed, controlled trials. Although, we are aware of the article by Schulz and colleagues, there is also evidence that doses of 3-hydroxy3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors that can cross the blood-brain barrier might be able to inhibit the production of tumour necrosis factor (TNF) and nitric oxide through inducible nitric oxide synthase induction in astrocytes and microglia.1,2 Since these molecules have been postulated to play a part in the neurodegenerative phase of multiple sclerosis, their inhibition could be beneficial in slowing the progression of disability and axonal or neuronal loss that characterises many patients with the disease. Therefore, we believe this issue will need to be resolved by long-term randomised trials designed to detect an effect of statin therapy on disability and brain MRI markers of axonal and neuronal loss. We also appreciate the comments of Marie-Laure Laroche and Louis Merle. We were keenly aware of the potential risks of high-dose simvastatin therapy, including the risk of rhabdomyolysis. We selected our dose on the basis of the results of preclinical and clinical trials, which suggested at approximately 1 mg/kg dose for simvastatin some penetration of the blood-brain barrier is possible. Again, based on studies from the laboratory of Inderjit Singh, 1,3 we believe a treatment effect on microglia and astrocytes, in addition to the potential effect of statin therapy on regulatory T-cell subsets and antigen presentation, could be important for maximising efficacy in patients with multiple sclerosis. Although safety data from clinical studies of individuals treated with 80 mg of simvastatin per day indicated adequate safety to proceed with our study, we agree whole heartedly that the myotoxic potential of high-dose statin therapy deserves close monitoring of muscle enzymes in serum of treated patients.
*Timothy Vollmer, Inderjit Singh [email protected] Division of Neurology, Barrow Neurological Institute, Phoenix, AZ 85013, USA
www.thelancet.com Vol 364 July 31, 2004
1
2
3
Pahan K, Sheikh F, Namboodiri AMS, Singh I. Lovastatin and phenylacetate inhibit the induction of inducible nitric oxide synthase and cytokines in primary astrocytes, microglia and macrophages. J Clin Invest 1997; 100: 2671–79. Stanislaus R, Pahan K, Singh AK, Singh I. Amelioration of experimental allergic encephalomyelitis in Lewis rats by lovastatin. NeuroSci Let 1999; 269: 71–74. Stanislaus R, Singh AK, Singh I. Lovastatin treatment blocks the infiltration of mononuclear cells and induction of inflammatory process in experimental allergic encephalomyelitis. J NeuroSci Res 2001; 66: 155–62.
Diuretics in the LIFE study In 2002, Björn Dahlöf and colleagues reported that the angiotensin-receptor blocker losartan was superior to the blocker atenolol in the prevention of stroke in hypertensive patients with leftventricular hypertrophy. 1 We write to raise a concern about whether a difference in the number of patients taking diuretics influenced the results. Referring to table 2 of their report, Dahlöf and colleagues described that there was no difference in the distribution of additional drugs between the study groups. However, hydrochlorothiazide was used as an additional drug, solely or in combination with others, in 2027 (829 plus 1198) of 4605 patients on losartan (44%) and 1729 (713 plus 1016) of 4588 patients on atenolol (38%). A 2 test reveals that the proportion taking hydrochlorothiazide in each group is significantly different (p<0·0001). In a substudy published afterwards,2 a similar efficacy of losartan was reported for primary prevention of stroke in isolated systolic hypertension. As shown in table 2 of that report, the distribution of additional treatment was not significantly different between groups. However, if the total numbers of patients taking hydrochlorothiazide are included in the same way as above, a significant difference is also found between the groups: 253 of 660 (38%) patients on losartan versus 220 of 666 (33%) on atenolol (p=0·045). In PROGRESS,3 a single treatment with perindopril had no significant effect on
the secondary prevention of stroke, but combination with the diuretic indapamide reduced recurrence of the disorder. The preventive effect of diuretics on stroke have been well documented in several clinical trials, and the large-scale, randomised study ALLHAT showed that chlorthalidone was superior to lisinopril in the primary prevention of the disorder.4 In the LIFE study, the more frequent use of the diuretic hydrochlorothiazide might have partly contributed to the lower incidence of stroke in the losartan group. Therefore, conclusions from the LIFE study on the preventive effect of angiotensin-receptor blockers on stroke should be interpreted with caution.
*Johji Kato, Tanenao Eto [email protected] First Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan 1
2
3
4
Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995–1003. Kjeldsen SE, Dahlöf B, Devereux RB, et al. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. JAMA 2002; 288: 1491–98. PROGRESS Collaborative Group. Randomised trial of a perindopril-based bloodpressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358: 1033–41. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–97.
Authors’ reply Johji Kato and Tanenao Eto question whether the difference in use of the diuretic hydrochlorothiazide between the treatment groups accounts for the advantage of losartan seen in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. According to the design of the study, investigators were to add hydrochlorothiazide, increase the 413