The efficacy and safety of nimodipine in acute ischemic stroke patients with mild cognitive impairment: a double-blind, randomized,placebo-controlled trial
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摘要
Nimodipine might be effective in subcortical vascular dementia(VaD). Its benefit in preventing further cognitive decline in patients with acute ischemic stroke(AIS) and vascular mild cognitive impairment(VaMCI) remains to be established. In this multicenter, double-blind trial, we randomly assigned 654 eligible patients to nimodipine 30 mg three times a day or placebo. The primary outcome was any cognitive decline defined by the changes on the Mini-Mental State Examination(DMMSE à3) or vascular AD assessment scale cognitive subscale(DADAS-cog ! 4) at 6 months. Secondary outcomes included any distribution shift of DADAS-cog, DMMSE or cognitive improvement defined by DADAS-cog à2, or DMMSE ! 0. The primary outcome in the nimodipine group and placebo group were similar for DMMSE à3(4.18% and 7.22%, respectively, P = 0.15) and DADAS-cog ! 4(8.36% and 8.93% respectively,P = 0.88). The distribution shift of DADAS-cog and DMMSE differed significantly between the two groups(P = 0.03 and P = 0.05 respectively). Cognitive improvement occurred in 55.4% in the nimodipine group and 43.6% in the placebo group measured by DADAS-cog à2(Odds Ratio, 1.54; 95% confidence interval[CI] 1.10–2.14, P < 0.01) or 84.0% and 74.6% respectively by DMMSE ! 0(Odds Ratio, 1.79; 95% CI 1.18–2.70, P < 0.01). Nimodipine was associated with better cognitive function in the memory domain. The adverse events rate was similar in two groups. This study is registered with ClinicalTrials.gov,NCT01220622. Nimodipine did not show benefit to prevent cognitive decline in AIS patients with VaMCI, but improved cognition moderately, especially measured in the memory domain.
Nimodipine might be effective in subcortical vascular dementia(VaD). Its benefit in preventing further cognitive decline in patients with acute ischemic stroke(AIS) and vascular mild cognitive impairment(VaMCI) remains to be established. In this multicenter, double-blind trial, we randomly assigned 654 eligible patients to nimodipine 30 mg three times a day or placebo. The primary outcome was any cognitive decline defined by the changes on the Mini-Mental State Examination(DMMSE à3) or vascular AD assessment scale cognitive subscale(DADAS-cog ! 4) at 6 months. Secondary outcomes included any distribution shift of DADAS-cog, DMMSE or cognitive improvement defined by DADAS-cog à2, or DMMSE ! 0. The primary outcome in the nimodipine group and placebo group were similar for DMMSE à3(4.18% and 7.22%, respectively, P = 0.15) and DADAS-cog ! 4(8.36% and 8.93% respectively,P = 0.88). The distribution shift of DADAS-cog and DMMSE differed significantly between the two groups(P = 0.03 and P = 0.05 respectively). Cognitive improvement occurred in 55.4% in the nimodipine group and 43.6% in the placebo group measured by DADAS-cog à2(Odds Ratio, 1.54; 95% confidence interval[CI] 1.10–2.14, P < 0.01) or 84.0% and 74.6% respectively by DMMSE ! 0(Odds Ratio, 1.79; 95% CI 1.18–2.70, P < 0.01). Nimodipine was associated with better cognitive function in the memory domain. The adverse events rate was similar in two groups. This study is registered with ClinicalTrials.gov,NCT01220622. Nimodipine did not show benefit to prevent cognitive decline in AIS patients with VaMCI, but improved cognition moderately, especially measured in the memory domain.
Nimodipine might be effective in subcortical vascular dementia(VaD). Its benefit in preventing further cognitive decline in patients with acute ischemic stroke(AIS) and vascular mild cognitive impairment(VaMCI) remains to be established. In this multicenter, double-blind trial, we randomly assigned 654 eligible patients to nimodipine 30 mg three times a day or placebo. The primary outcome was any cognitive decline defined by the changes on the Mini-Mental State Examination(DMMSE à3) or vascular AD assessment scale cognitive subscale(DADAS-cog ! 4) at 6 months. Secondary outcomes included any distribution shift of DADAS-cog, DMMSE or cognitive improvement defined by DADAS-cog à2, or DMMSE ! 0. The primary outcome in the nimodipine group and placebo group were similar for DMMSE à3(4.18% and 7.22%, respectively, P = 0.15) and DADAS-cog ! 4(8.36% and 8.93% respectively,P = 0.88). The distribution shift of DADAS-cog and DMMSE differed significantly between the two groups(P = 0.03 and P = 0.05 respectively). Cognitive improvement occurred in 55.4% in the nimodipine group and 43.6% in the placebo group measured by DADAS-cog à2(Odds Ratio, 1.54; 95% confidence interval[CI] 1.10–2.14, P < 0.01) or 84.0% and 74.6% respectively by DMMSE ! 0(Odds Ratio, 1.79; 95% CI 1.18–2.70, P < 0.01). Nimodipine was associated with better cognitive function in the memory domain. The adverse events rate was similar in two groups. This study is registered with ClinicalTrials.gov,NCT01220622. Nimodipine did not show benefit to prevent cognitive decline in AIS patients with VaMCI, but improved cognition moderately, especially measured in the memory domain.
引文
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[2] Blackburn DJ, Bafadhel L, Randall M, et al. Cognitive screening in the acute stroke setting. Age Ageing 2013;42:113–6.
[3] Wentzel C, Rockwood K, MacKnight C, et al. Progression of impairment in patients with vascular cognitive impairment without dementia. Neurology2001;57:714–6.
[4] Park JH, Kim BJ, Bae HJ, et al. Impact of post-stroke cognitive impairment with no dementia on health-related quality of life. J Stroke 2013;15:49–56.
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[6] Desmond DW, Moroney JT, Sano M, et al. Mortality in patients with dementia after ischemic stroke. Neurology 2002;59:537–43.
[7] Oksala NK, Jokinen H, Melkas S, et al. Cognitive impairment predicts poststroke death in long-term follow-up. J Neurol Neurosurg Psychiatry 2009;80:1230–5.
[8] Shah H, Albanese E, Duggan C, et al. Research priorities to reduce the global burden of dementia by 2025. Lancet Neurol 2016;15:1285–94.
[9] Langa KM, Levine DA. The diagnosis and management of mild cognitive impairment:a clinical review. JAMA 2014;312:2551–61.
[10] O’Brien JT, Thomas A. Vascular dementia. Lancet 2015;386:1698–706.
[11] Sachdev PS, Lo JW, Crawford JD, et al. STROKOG(stroke and cognition consortium):an international consortium to examine the epidemiology,diagnosis, and treatment of neurocognitive disorders in relation to cerebrovascular disease. Alzheimers Dement 2017;7:11–23.
[12] Bergantin LB, Caricati-Neto A. Challenges for the pharmacological treatment of neurological and psychiatric disorders:implications of the Ca2+/cAMP intracellular signalling interaction. Eur J Pharmacol 2016;788:255–60.
[13] Lopez-Arrieta JM, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev 2002:Cd000147.
[14] Pantoni L, Bianchi C, Beneke M, et al. The Scandinavian Multi-Infarct Dementia Trial:a double-blind, placebo-controlled trial on nimodipine in multi-infarct dementia. J Neurol Sci 2000;175:116–23.
[15] Pantoni L, Rossi R, Inzitari D, et al. Efficacy and safety of nimodipine in subcortical vascular dementia:a subgroup analysis of the Scandinavian MultiInfarct Dementia Trial. J Neurol Sci 2000;175:124–34.
[16] Pantoni L, del Ser T, Soglian AG, et al. Efficacy and safety of nimodipine in subcortical vascular dementia:a randomized placebo-controlled trial. Stroke2005;36:619–24.
[17] Wang P, Wang Y, Feng T, et al. Rationale and design of a double-blind, placebocontrolled, randomized trial to evaluate the safety and efficacy of nimodipine in preventing cognitive impairment in ischemic cerebrovascular events(NICE).BMC Neurol 2012;12:88.
[18] Sacco RL, Kasner SE, Broderick JP, et al. An updated definition of stroke for the21st century:a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:2064–89.
[19] Kokotailo RA, Hill MD. Coding of stroke and stroke risk factors using international classification of diseases, revisions 9 and 10. Stroke2005;36:1776–81.
[20] Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA:a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695–9.
[21] Folstein MF, Folstein SE, McHugh PR.‘‘Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res1975;12:189–98.
[22] Zhang MY, Katzman R, Salmon D, et al. The prevalence of dementia and Alzheimer’s disease in Shanghai, China:impact of age, gender, and education.Ann Neurol 1990;27:428–37.
[23] Tsoi KK, Chan JY, Hirai HW, et al. Cognitive tests to detect dementia:a systematic review and meta-analysis. JAMA Intern Med 2015;175:1450–8.
[24] Hachinski VC, Iliff LD, Zilhka E, et al. Cerebral blood flow in dementia. Arch Neurol 1975;32:632–7.
[25] Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack:a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:2160–236.
[26] Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–64.
[27] Rockwood K, Fay S, Gorman M, et al. The clinical meaningfulness of ADAS-Cog changes in Alzheimer’s disease patients treated with donepezil in an openlabel trial. BMC Neurol 2007;7:26.
[28] Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia:a meta-analysis of randomised controlled trials. Lancet Neurol 2007;6:782–92.
[29] Orgogozo JM, Rigaud AS, Stoffler A, et al. Efficacy and safety of memantine in patients with mild to moderate vascular dementia:a randomized, placebocontrolled trial(MMM 300). Stroke 2002;33:1834–9.
[30] Ukawa S, Yuasa M, Ikeno T, et al. Randomised controlled pilot study in Japan comparing a home visit program using a Functioning Improvement Tool with a home visit with conversation alone. Australas J Ageing 2012;31:187–9.
[31] Dubois B, Slachevsky A, Litvan I, et al. The FAB:a Frontal Assessment Battery at bedside. Neurology 2000;55:1621–6.
[2] Blackburn DJ, Bafadhel L, Randall M, et al. Cognitive screening in the acute stroke setting. Age Ageing 2013;42:113–6.
[3] Wentzel C, Rockwood K, MacKnight C, et al. Progression of impairment in patients with vascular cognitive impairment without dementia. Neurology2001;57:714–6.
[4] Park JH, Kim BJ, Bae HJ, et al. Impact of post-stroke cognitive impairment with no dementia on health-related quality of life. J Stroke 2013;15:49–56.
[5] Moroney JT, Bagiella E, Tatemichi TK, et al. Dementia after stroke increases the risk of long-term stroke recurrence. Neurology 1997;48:1317–25.
[6] Desmond DW, Moroney JT, Sano M, et al. Mortality in patients with dementia after ischemic stroke. Neurology 2002;59:537–43.
[7] Oksala NK, Jokinen H, Melkas S, et al. Cognitive impairment predicts poststroke death in long-term follow-up. J Neurol Neurosurg Psychiatry 2009;80:1230–5.
[8] Shah H, Albanese E, Duggan C, et al. Research priorities to reduce the global burden of dementia by 2025. Lancet Neurol 2016;15:1285–94.
[9] Langa KM, Levine DA. The diagnosis and management of mild cognitive impairment:a clinical review. JAMA 2014;312:2551–61.
[10] O’Brien JT, Thomas A. Vascular dementia. Lancet 2015;386:1698–706.
[11] Sachdev PS, Lo JW, Crawford JD, et al. STROKOG(stroke and cognition consortium):an international consortium to examine the epidemiology,diagnosis, and treatment of neurocognitive disorders in relation to cerebrovascular disease. Alzheimers Dement 2017;7:11–23.
[12] Bergantin LB, Caricati-Neto A. Challenges for the pharmacological treatment of neurological and psychiatric disorders:implications of the Ca2+/cAMP intracellular signalling interaction. Eur J Pharmacol 2016;788:255–60.
[13] Lopez-Arrieta JM, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev 2002:Cd000147.
[14] Pantoni L, Bianchi C, Beneke M, et al. The Scandinavian Multi-Infarct Dementia Trial:a double-blind, placebo-controlled trial on nimodipine in multi-infarct dementia. J Neurol Sci 2000;175:116–23.
[15] Pantoni L, Rossi R, Inzitari D, et al. Efficacy and safety of nimodipine in subcortical vascular dementia:a subgroup analysis of the Scandinavian MultiInfarct Dementia Trial. J Neurol Sci 2000;175:124–34.
[16] Pantoni L, del Ser T, Soglian AG, et al. Efficacy and safety of nimodipine in subcortical vascular dementia:a randomized placebo-controlled trial. Stroke2005;36:619–24.
[17] Wang P, Wang Y, Feng T, et al. Rationale and design of a double-blind, placebocontrolled, randomized trial to evaluate the safety and efficacy of nimodipine in preventing cognitive impairment in ischemic cerebrovascular events(NICE).BMC Neurol 2012;12:88.
[18] Sacco RL, Kasner SE, Broderick JP, et al. An updated definition of stroke for the21st century:a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:2064–89.
[19] Kokotailo RA, Hill MD. Coding of stroke and stroke risk factors using international classification of diseases, revisions 9 and 10. Stroke2005;36:1776–81.
[20] Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA:a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695–9.
[21] Folstein MF, Folstein SE, McHugh PR.‘‘Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res1975;12:189–98.
[22] Zhang MY, Katzman R, Salmon D, et al. The prevalence of dementia and Alzheimer’s disease in Shanghai, China:impact of age, gender, and education.Ann Neurol 1990;27:428–37.
[23] Tsoi KK, Chan JY, Hirai HW, et al. Cognitive tests to detect dementia:a systematic review and meta-analysis. JAMA Intern Med 2015;175:1450–8.
[24] Hachinski VC, Iliff LD, Zilhka E, et al. Cerebral blood flow in dementia. Arch Neurol 1975;32:632–7.
[25] Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack:a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:2160–236.
[26] Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:1356–64.
[27] Rockwood K, Fay S, Gorman M, et al. The clinical meaningfulness of ADAS-Cog changes in Alzheimer’s disease patients treated with donepezil in an openlabel trial. BMC Neurol 2007;7:26.
[28] Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia:a meta-analysis of randomised controlled trials. Lancet Neurol 2007;6:782–92.
[29] Orgogozo JM, Rigaud AS, Stoffler A, et al. Efficacy and safety of memantine in patients with mild to moderate vascular dementia:a randomized, placebocontrolled trial(MMM 300). Stroke 2002;33:1834–9.
[30] Ukawa S, Yuasa M, Ikeno T, et al. Randomised controlled pilot study in Japan comparing a home visit program using a Functioning Improvement Tool with a home visit with conversation alone. Australas J Ageing 2012;31:187–9.
[31] Dubois B, Slachevsky A, Litvan I, et al. The FAB:a Frontal Assessment Battery at bedside. Neurology 2000;55:1621–6.