Nakagawara J, Minematsu K, Okada Y, Tanahashi N, Nagahiro S, Mori E, Shinohara Y, Yamaguchi T; J-MARS Investigators.
Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice: the Japan post-Marketing Alteplase Registration Study (J-MARS).
Stroke. 2010 Sep;41(9):1984-9. doi: 10.1161/STROKEAHA.110.589606. Epub 2010 Jul 22.
Abstract/Text
BACKGROUND AND PURPOSE: In Japan, alteplase at 0.6 mg/kg was approved in October 2005 for use within 3 hours of stroke onset by the Ministry of Health, Labor and Welfare (MHLW). The aim of the Japan post-Marketing Alteplase Registration Study (J-MARS), which was requested by MHLW at the time of approval, was to assess the safety and efficacy of 0.6 mg/kg alteplase in routine clinical practice for the Japanese.
METHODS: A total of 7492 patients from 942 centers were enrolled in the J-MARS, an open-label, nonrandomized, observational study, from October 2005 to October 2007. Primary outcome measures were symptomatic intracranial hemorrhage (a deterioration in NIHSS score >or=4 from baseline) and favorable outcome (modified Rankin Scale score, 0-1) at 3 months after stroke onset.
RESULTS: The proportion of patients with symptomatic intracranial hemorrhage in 7492 patients (safety analysis) was 3.5% (95% confidence interval [CI], 3.1%-3.9%) within 36 hours and 4.4% (95% CI, 3.9%-4.9%) at 3 months. The overall mortality rate was 13.1% (95% CI, 12.4%-13.9%) and the proportion of patients with fatal symptomatic intracranial hemorrhage was 0.9% (95% CI, 0.7%-1.2%). The outcomes at 3 months were available for 4944 patients and the proportion of favorable outcome (efficacy analysis) was 33.1% (95% CI, 31.8%-34.4%). The subgroup analysis in patients between 18 and 80 years with a baseline NIHSS score <25 demonstrated that favorable outcome at 3 months was 39.0% (95% CI, 37.4%-40.6%).
CONCLUSIONS: These data suggest that 0.6 mg/kg intravenous alteplase within 3 hours of stroke onset could be safe and effective in routine clinical practice for the Japanese.
Kimura K, Inoue T, Iguchi Y, Shibazaki K.
Kurashiki prehospital stroke scale.
Cerebrovasc Dis. 2008;25(1-2):189-91. doi: 10.1159/000113739. Epub 2008 Jan 25.
Abstract/Text
Indridason OS, Quarles LD.
Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. Durham Renal Osteodystrophy Study Group.
Kidney Int. 2000 Jan;57(1):282-92. doi: 10.1046/j.1523-1755.2000.00819.x.
Abstract/Text
UNLABELLED: Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients.
BACKGROUND: In the management of patients with mild secondary hyperparathyroidism, it is not known whether calcium supplementation alone is sufficient to correct abnormalities in bone and mineral metabolism or if calcitriol is needed in either physiologic oral or intravenous pharmacologic doses.
METHODS: This was a 40-week prospective nonmasked trial of 52 patients [parathyroid hormone (PTH) 150 to 600 pg/mL] who were randomized to receive escalating doses of either calcium carbonate (CaCO3) alone (calcium group, N = 11), daily oral calcitriol (oral group, N = 20), or intermittent intravenous calcitriol (IV group, N = 21). The groups were compared with regard to changes in serum intact PTH, serum bone-specific alkaline phosphatase (BAP), incidence of hypercalcemia (>10.5 mg/dL), and hyperphosphatemia (>6.5 mg/dL).
RESULTS: PTH levels decreased in all groups (P < 0.01, paired t-test). In the calcium group, PTH (mean +/- SEM) decreased from 325 +/- 46.2 to 160 +/- 44.5 pg/mL. In the oral group, it decreased from 265 +/- 26.4 to 125 +/- 23.7 pg/mL, and in the IV group, it decreased from 240 +/- 27.7 to 65 +/- 10.0 pg/mL. Upon analysis of covariance, controlling for the initial PTH level, we found no differences in the PTH response between the groups (P > 0.10). In contrast, the BAP concentration increased from 20.7 +/- 7.6 to 27.5 +/- 7.0 microg/L in the calcium group (P = 0.17), decreased from 20. 6 +/- 3.9 to 17.8 +/- 4.5 microg/L in the oral group (P = 0.26), and from 19.1 +/- 2.6 to 10.6 +/- 1.1 microg/L in the IV group (P = 0. 007). Serum calcium increased significantly in all groups from 8.4 +/- 0.25 to 9.0 +/- 0.28, 8.5 +/- 0.16 to 9.2 +/- 0.27, and 8.7 +/- 0.16 to 9.4 +/- 0.18 mg/dL in the calcium, oral, and IV groups, respectively (P = NS difference between groups). Serum phosphorus was significantly lower in the calcium group throughout the study (P = 0.02). Hypercalcemic episodes were 2.0 +/- 0.8, 3.0 +/- 0.6, and 3. 4 +/- 0.6 per patient-year (P > 0.10), and hyperphosphatemic episodes were 0.9 +/- 0.56, 4.2 +/- 0.79 and 4.9 +/- 0.84 in the calcium, oral, and IV groups, respectively (P < 0.01).
CONCLUSION: In mild secondary hyperparathyroidism, all three strategies are effective. High-dose CaCO3 alone may be sufficient to control PTH with a favorable side-effect profile, but calcitriol appears to have additional suppressive effects on bone that are greater following the intravenous route of administration and may increase the risk of adynamic bone disease.
Chalela JA, Kidwell CS, Nentwich LM, Luby M, Butman JA, Demchuk AM, Hill MD, Patronas N, Latour L, Warach S.
Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison.
Lancet. 2007 Jan 27;369(9558):293-8. doi: 10.1016/S0140-6736(07)60151-2.
Abstract/Text
BACKGROUND: Although the use of magnetic resonance imaging (MRI) for the diagnosis of acute stroke is increasing, this method has not proved more effective than computed tomography (CT) in the emergency setting. We aimed to prospectively compare CT and MRI for emergency diagnosis of acute stroke.
METHODS: We did a single-centre, prospective, blind comparison of non-contrast CT and MRI (with diffusion-weighted and susceptibility weighted images) in a consecutive series of patients referred for emergency assessment of suspected acute stroke. Scans were independently interpreted by four experts, who were unaware of clinical information, MRI-CT pairings, and follow-up imaging.
RESULTS: 356 patients, 217 of whom had a final clinical diagnosis of acute stroke, were assessed. MRI detected acute stroke (ischaemic or haemorrhagic), acute ischaemic stroke, and chronic haemorrhage more frequently than did CT (p<0.0001, for all comparisons). MRI was similar to CT for the detection of acute intracranial haemorrhage. MRI detected acute ischaemic stroke in 164 of 356 patients (46%; 95% CI 41-51%), compared with CT in 35 of 356 patients (10%; 7-14%). In the subset of patients scanned within 3 h of symptom onset, MRI detected acute ischaemic stroke in 41 of 90 patients (46%; 35-56%); CT in 6 of 90 (7%; 3-14%). Relative to the final clinical diagnosis, MRI had a sensitivity of 83% (181 of 217; 78-88%) and CT of 26% (56 of 217; 20-32%) for the diagnosis of any acute stroke.
INTERPRETATION: MRI is better than CT for detection of acute ischaemia, and can detect acute and chronic haemorrhage; therefore it should be the preferred test for accurate diagnosis of patients with suspected acute stroke. Because our patient sample encompassed the range of disease that is likely to be encountered in emergency cases of suspected stroke, our results are directly applicable to clinical practice.
荒木信夫，大櫛陽一，小林祥泰，病型別・年代別頻度─欧米・アジアとの比較，小林祥泰（編）．脳卒中データバンク2009．東京：中山書店；2004.
木村和美．急性期虚血性脳血管障害の診断と治療．臨床神経 50；753：2010.
Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA.
International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).
J Thromb Haemost. 2006 Feb;4(2):295-306. doi: 10.1111/j.1538-7836.2006.01753.x.
Abstract/Text
New clinical, laboratory and experimental insights, since the 1999 publication of the Sapporo preliminary classification criteria for antiphospholipid syndrome (APS), had been addressed at a workshop in Sydney, Australia, before the Eleventh International Congress on antiphospholipid antibodies. In this document, we appraise the existing evidence on clinical and laboratory features of APS addressed during the forum. Based on this, we propose amendments to the Sapporo criteria. We also provide definitions on features of APS that were not included in the updated criteria.
Ueno Y, Iguchi Y, Inoue T, Shibazaki K, Urabe T, Kimura K.
Paradoxical brain embolism may not be uncommon-prospective study in acute ischemic stroke.
J Neurol. 2007 Jun;254(6):763-6. doi: 10.1007/s00415-006-0430-6. Epub 2007 Mar 22.
Abstract/Text
BACKGROUND: Proving that right-to-left shunt (RLS) represents the precise causative mechanism in ischemic stroke patients with RLS is difficult. The aim of this study was to examine the frequency and clarify the clinical characteristics of paradoxical brain embolism (PBE).
METHODS: We prospectively enrolled consecutive acute ischemic stroke patients, who underwent transcranial Doppler and/or transesophageal echocardiography. For patients with RLS, diagnostic criteria for PBE were established as follows: 1) brain images suggesting embolic strokes; 2) presence of deep venous thrombus or pulmonary embolism; and 3) absence of any embolic sources. Patients were divided into 4 groups: patients meeting all 3 criteria (Definite); fulfilling 2 criteria (Probable); fulfilling 1 or 0 criteria (Possible); and patients without RLS (Non-RLS).
RESULTS: A total of 240 subjects were analyzed for this study. The Definite group comprised 5% of patients, and displayed significantly more females (p = 0.038), and infarcts involving both anterior and posterior circulations (p < 0.001). Patients having neither hypertension nor diabetes mellitus also predominantly belonged to the Definite group (p < 0.001).
CONCLUSIONS: Clinical characteristics of PBE are a female preponderance, infarcts affecting both anterior and posterior circulations, and an absence of risk factors.
Yasaka M, Otsubo R, Oe H, Minematsu K.
Is stroke a paradoxical embolism in patients with patent foramen ovale?
Intern Med. 2005 May;44(5):434-8. doi: 10.2169/internalmedicine.44.434.
Abstract/Text
OBJECTIVE: Purpose was to assess the stroke mechanism in patients with patent foramen ovale (PFO).
METHODS: We reviewed the medical records of 111 stroke patients with PFO and sinus rhythm (PFO-S group), 25 with PFO and atrial fibrillation (AF) (PFO-AF group) and 67 with AF but not PFO (AF group), who had received contrast transesophageal echocardiography. The clinical and neuroradiological findings were then compared among the three groups. Deep vein thrombosis was investigated in 93 patients with PFO. We determined the number of patients with definite paradoxical embolism who met three criteria: deep vein thrombosis, neuroradiological features indicating embolic stroke, and the absence of other sources of emboli. We also evaluated those with probable paradoxical embolism who met two of the three criteria.
RESULTS: The PFO-S group more frequently exhibited hypercholesterolemia (p<0.0001) and lesions limited to the posterior circulation (p<0.0004), and less frequently exhibited large or cortical lesions in the anterior circulation (p=0.0008, p<0.0001, respectively), than the PFO-AF and AF groups. In the PFO-S and PFO-AF groups, other sources of emboli such as a cardiac source of emboli, cerebral artery stenosis > or =50%, or complicated atheroma in the aortic arch were identified in 72 cases (52.9%). In the 93 patients with examination for deep vein thrombosis, the definite and probable criteria of paradoxical embolism were fulfilled only in three (3.2%) and 33 cases (35.5%), respectively.
CONCLUSION: In stroke patients with PFO, not only paradoxical brain embolism through the PFO but also other causes of stroke may contribute to the development of stroke.
Kent DM, Ruthazer R, Weimar C, Mas JL, Serena J, Homma S, Di Angelantonio E, Di Tullio MR, Lutz JS, Elkind MS, Griffith J, Jaigobin C, Mattle HP, Michel P, Mono ML, Nedeltchev K, Papetti F, Thaler DE.
An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke.
Neurology. 2013 Aug 13;81(7):619-25. doi: 10.1212/WNL.0b013e3182a08d59. Epub 2013 Jul 17.
Abstract/Text
OBJECTIVE: We aimed to create an index to stratify cryptogenic stroke (CS) patients with patent foramen ovale (PFO) by their likelihood that the stroke was related to their PFO.
METHODS: Using data from 12 component studies, we used generalized linear mixed models to predict the presence of PFO among patients with CS, and derive a simple index to stratify patients with CS. We estimated the stratum-specific PFO-attributable fraction and stratum-specific stroke/TIA recurrence rates.
RESULTS: Variables associated with a PFO in CS patients included younger age, the presence of a cortical stroke on neuroimaging, and the absence of these factors: diabetes, hypertension, smoking, and prior stroke or TIA. The 10-point Risk of Paradoxical Embolism score is calculated from these variables so that the youngest patients with superficial strokes and without vascular risk factors have the highest score. PFO prevalence increased from 23% (95% confidence interval [CI]: 19%-26%) in those with 0 to 3 points to 73% (95% CI: 66%-79%) in those with 9 or 10 points, corresponding to attributable fraction estimates of approximately 0% to 90%. Kaplan-Meier estimated stroke/TIA 2-year recurrence rates decreased from 20% (95% CI: 12%-28%) in the lowest Risk of Paradoxical Embolism score stratum to 2% (95% CI: 0%-4%) in the highest.
CONCLUSION: Clinical characteristics identify CS patients who vary markedly in PFO prevalence, reflecting clinically important variation in the probability that a discovered PFO is likely to be stroke-related vs incidental. Patients in strata more likely to have stroke-related PFOs have lower recurrence risk.
Fujimoto S, Yasaka M, Otsubo R, Oe H, Nagatsuka K, Minematsu K.
Aortic arch atherosclerotic lesions and the recurrence of ischemic stroke.
Stroke. 2004 Jun;35(6):1426-9. doi: 10.1161/01.STR.0000127788.32550.d4. Epub 2004 Apr 29.
Abstract/Text
BACKGROUND AND PURPOSE: Aortic arch atherosclerotic lesions are often associated with embolic brain infarction. We investigated the relationship between stroke recurrence and the characteristics of aortic arch atherosclerotic lesions.
METHODS: Among 487 stroke patients who underwent transesophageal echocardiography, 283 patients with brain embolism diagnosed without significant occlusive lesions (> or =50%) in their cerebral arteries were included in this study. We measured the intima-media thickness (IMT) and evaluated the extension and mobility of the aortic arch atherosclerotic lesions. During a mean follow-up period of 3.4 years, we investigated the relationship between stroke recurrence and the various characteristics of the aortic arch atherosclerotic lesions.
RESULTS: An IMT > or =4.0 mm was found in 67 patients (25.3%). In 51 of these patients, the aortic lesions extended to the origin of the branches of the arch. Recurrences of cerebral ischemic events were found in 32 patients (recurrence group) and not in the other 251 (nonrecurrence group). Aortic atheroma > or =4.0 mm (41% versus 22%), aortic atheroma extending to the branches (63% versus 39%), and both (38% versus 16%) were more frequently seen in the recurrence group than in the nonrecurrence group (P<0.05, P<0.1, P<0.01, respectively). After adjustment for age and the presence of hypertension, an aortic atheroma that was > or =4.0 mm as well as extending to the branches was found to be an independent predictor of ischemic stroke recurrence (hazard ratio=2.42, P<0.05).
CONCLUSIONS: Stroke recurrence is associated with the severity of the atheroma (IMT > or =4.0 mm) and plaque extension to the branches.
Sen S, Hinderliter A, Sen PK, Simmons J, Beck J, Offenbacher S, Ohman EM, Oppenheimer SM.
Aortic arch atheroma progression and recurrent vascular events in patients with stroke or transient ischemic attack.
Circulation. 2007 Aug 21;116(8):928-35. doi: 10.1161/CIRCULATIONAHA.106.671727. Epub 2007 Aug 7.
Abstract/Text
BACKGROUND: It is not known whether progression of aortic arch (AA) atheroma is associated with vascular events in patients with stroke or transient ischemic attack (TIA).
METHODS AND RESULTS: AA atheroma was detected on baseline transesophageal echocardiogram in 167 consecutive patients who had prevalent stroke or TIA. Of these, 125 consented to a follow-up transesophageal echocardiogram at 12 months. Adequate paired AA images were obtained in 117 (78 with strokes, 39 with TIAs), which allowed detailed measurements of plaques. On admission for their index stroke or TIA, patients were assessed for stroke risk factors, stroke subtypes, baseline AA plaque characteristics, and laboratory parameters. Progression of AA atheroma was observed in 33 patients (28%) on 12-month follow-up transesophageal echocardiogram. It was determined that the progression group had significantly higher adjusted homocysteine levels (P<0.0001) and neutrophil counts (P<0.0001) than the no-progression group. These patients were followed up for a median of 1.7 years from the index stroke/TIA (range 0.5 to 4.5 years) for vascular events including stroke, TIA, myocardial infarction, and death due to vascular causes. Kaplan-Meier curves showed fewer patients with AA atheroma progression remained free of the composite vascular end point (49% compared with 89% in the no-progression group; P<0.0001). AA atheroma progression was associated with composite vascular events (hazard ratio 5.8, 95% confidence interval 2.3 to 14.5, P=0.0002) after adjustment for a propensity score based on confounders.
CONCLUSIONS: In this preliminary study of stroke/TIA patients with AA atheroma on transesophageal echocardiogram, AA atheroma progression was associated with recurrent vascular events.
Ueno Y, Kimura K, Iguchi Y, Shibazaki K, Inoue T, Hattori N, Urabe T.
Mobile aortic plaques are a cause of multiple brain infarcts seen on diffusion-weighted imaging.
Stroke. 2007 Sep;38(9):2470-6. doi: 10.1161/STROKEAHA.107.482497. Epub 2007 Aug 2.
Abstract/Text
BACKGROUND AND PURPOSE: Multiple brain infarcts are often seen on diffusion-weighted images in cardioembolic stroke patients. Recently, mobile aortic plaques (MAPs) have been proposed as embolic sources. However, the clinical characteristics of patients with MAPs are unclear.
METHODS: We prospectively studied patients with acute ischemic stroke who underwent transesophageal echocardiography. The patients were classified into 3 groups based on transesophageal echocardiography findings: atheromatous aortic plaques <4 mm, atheromatous aortic plaques > or =4 mm without mobility, and MAPs. Based on their diffusion-weighted image findings, the patients were divided into 3 subgroups: (1) single lesion; (2) multiple lesions in a single vascular territory; and (3) multiple lesions in multiple vascular territories. We assessed the clinical characteristics and the diffusion-weighted image findings of stroke patients with MAPs.
RESULTS: One hundred sixty-seven patients (age, 70+/-12 years; 98 males) were enrolled; 128 (77%) had atheromatous aortic plaques <4 mm, 27 (16%) had atheromatous aortic plaques > or =4 mm, and 12 (7%) had MAPs. Older age, male gender, coronary artery disease, and cerebral arterial stenotic lesions were seen most frequently in patients with MAPs. On diffusion-weighted image findings, patients with MAPs were most frequent in the multiple lesions in multiple vascular territories group (P=0.001). On multiple logistic regression analysis, the National Institutes of Health Stroke Scale score (OR: 1.11; 95% CI: 1.01 to 1.22; P=0.039), arterial stenotic lesions (OR: 4.71; 95% CI: 1.35 to 16.41; P=0.015), and mobile aortic plaques (OR: 14.44; 95% CI: 2.87 to 72.66; P=0.001) were significantly associated with the multiple lesions in multiple vascular territories group.
CONCLUSIONS: MAPs were not uncommonly observed in patients with acute ischemic stroke. MAPs could cause multiple brain infarcts on diffusion-weighted images.
French Study of Aortic Plaques in Stroke Group; Amarenco P, Cohen A, Hommel M, Moulin T, Leys D, Bousser M-G.
Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke.
N Engl J Med. 1996 May 9;334(19):1216-21. doi: 10.1056/NEJM199605093341902.
Abstract/Text
BACKGROUND: Atherosclerotic disease of the aortic arch is found in 60 percent of patients 60 years of age or older who have had brain infarction. The aim of this study was to determine whether atherosclerotic plaques in the aortic arch are a risk factor for recurrent brain infarction and for vascular events in general (i.e., brain infarction, myocardial infarction, peripheral embolism, and death from vascular causes).
METHODS: For a period of two to four years, we followed a cohort of 331 patients 60 years of age or older who were consecutively admitted to the hospital with brain infarction (a total of 788 person-years of follow up). All patients underwent transesophageal echocardiography to determine whether atherosclerotic plaques were present in the aortic arch proximal to the ostium of the left subclavian artery. The patients were divided into three groups according to the thickness of the wall of the aortic arch ( < 1 mm, 1 to 3.9 mm, and > or = 4 mm).
RESULTS: The incidence of recurrent brain infarction was 11.9 per 100 person-years in patients with an aortic-wall thickness of > or = 4 mm, as compared with 3.5 per 100 person-years in patients with a wall thickness of 1 to 3.9 mm and 2.8 per 100 person-years in patients with a wall thickness of < 1 mm (P < 0.001). The overall incidence of vascular events was 26.0, 9.1, and 5.9 per 100 person-years of follow-up in the respective groups (P < 0.001). After adjustment for the presence of carotid stenosis, atrial fibrillation, peripheral arterial disease, and other risk factors, aortic plaques > or = 4 mm thick (including the thickness of the aortic wall) were found to be independent predictors of recurrent brain infarction (relative risk, 3.8; 95 percent confidence interval, 1.8 to 7.8; P = 0.0012) and of all vascular events (relative risk, 3.5; 95 percent confidence interval, 2.1 to 5.9; P < 0.001).
CONCLUSIONS: Atherosclerotic plaques > or = 4 mm thick in the aortic arch are significant predictors of recurrent brain infarction and other vascular events.
Krinsky GA, Freedberg R, Lee VS, Rockman C, Tunick PA.
Innominate artery atheroma: a lesion seen with gadolinium-enhanced MR angiography and often missed by transesophageal echocardiography.
Clin Imaging. 2001 Jul-Aug;25(4):251-7. doi: 10.1016/s0899-7071(01)00292-3.
Abstract/Text
Transesophageal echocardiography (TEE) is the procedure of choice for identifying aortic atheromas, which may result in stroke, transient ischemic attack and peripheral embolization. However, because of anatomic constraints, the innominate artery may not be visualized. We investigated gadolinium-enhanced MR angiography (MRA) as an alternative technique for evaluation of suspected atheromas of the innominate artery. From a retrospective review of 520 examinations, we identified five patients who had innominate artery atheromas diagnosed prospectively with gadolinium-enhanced MRA who also underwent TEE within 1 month. A total of 10 innominate artery atheromas were demonstrated on MRA; none of these were visualized on TEE. One patient had three atheromas, two patients had two atheromas and three patients had one atheroma. They ranged in size from 3 mm to 1.5 cm (mean 6.5 mm). One atheroma was flat, two were filiform, and seven were protruding. Gadolinium-enhanced MRA is superior to TEE for the diagnosis of atheromas of the innominate artery. In the setting of right cerebral or right arm embolization, when no source is seen in the arch on TEE, gadolinium-enhanced MRA should be considered.
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J.
Interobserver agreement for the assessment of handicap in stroke patients.
Stroke. 1988 May;19(5):604-7. doi: 10.1161/01.str.19.5.604.
Abstract/Text
Interobserver agreement for the assessment of handicap in stroke patients was investigated in a group of 10 senior neurologists and 24 residents from two centers. One hundred patients were separately interviewed by two physicians in different combinations. The degree of handicap was recorded by each observer on the modified Rankin scale, which has six grades (0-5). The agreement rates were corrected for chance (kappa statistics). Both physicians agreed on the degree of handicap in 65 patients; they differed by one grade in 32 patients and by two grades in 3 patients. Kappa for all pairwise observations was 0.56; the value for weighted kappa (with quadratic disagreement weights) was 0.91. Our results confirm the value of the modified Rankin scale in the assessment of handicap in stroke patients; nevertheless, further improvements are possible.
MAHONEY FI, BARTHEL DW.
FUNCTIONAL EVALUATION: THE BARTHEL INDEX.
Md State Med J. 1965 Feb;14:61-5.
Abstract/Text
山口武典．脳梗塞急性期治療の実態に関する研究. 厚生省健康科学総合研究事業研究報告書; 2001年.
Jørgensen HS, Nakayama H, Raaschou HO, Olsen TS.
Stroke. Neurologic and functional recovery the Copenhagen Stroke Study.
Phys Med Rehabil Clin N Am. 1999 Nov;10(4):887-906.
Abstract/Text
Neurologic and functional recovery is dependent on a large variety of factors such as initial stroke severity, body temperature and blood glucose in the acute phase of stroke, stroke in progression, and treatment and rehabilitation on a dedicated stroke unit. The most important factor for recovery remains the initial severity of the stroke. In unselected patients 19% of the strokes are very severe, 14% are severe, 26% are moderate, and 41% are mild. In survivors, neurologic impairment after completed rehabilitation is still severe or very severe in 11%, moderate in 11%, mild in 47%, and 31% have achieved normal neurologic function. The ability to perform basic activities of daily living initially is reduced in three out of four patients with stroke. Most often affected is the ability to transfer, dress, and walk. After completed rehabilitation the group with moderate and severe disability is reduced from 50% to 25%, and the group with mild or no disability is increased from 50% to 75%. The prognosis of patients with mild or moderate stroke generally is excellent. Patients with severe stroke have a very variable recovery. Although the prognosis of patients with the most severe stroke is generally poor, one third of the survivors in this group are able to be discharged back to their own homes with no or only mild disability, if rehabilitated on a dedicated stroke unit. Functional recovery generally was completed within 3 months of stroke onset. Patients with mild stroke, however, recover within 2 months, patients with moderate stroke within 3 months, patients with severe stroke within 4 months, and patients with the most severe strokes have their functional recovery within 5 months from onset. Functional recovery is preceded by neurologic recovery by a mean of 2 weeks.
Hankey GJ, Spiesser J, Hakimi Z, Bego G, Carita P, Gabriel S.
Rate, degree, and predictors of recovery from disability following ischemic stroke.
Neurology. 2007 May 8;68(19):1583-7. doi: 10.1212/01.wnl.0000260967.77422.97.
Abstract/Text
OBJECTIVE: To determine the rate, degree, and predictors of recovery from disabling ischemic stroke.
METHODS: Patients with ischemic stroke enrolled in the Management of Atherothrombosis With Clopidogrel in High-Risk Patients (MATCH) study underwent long-term prospective assessment of their modified Rankin Scale (mRS) score. Disability (functionally dependent state) was defined as mRS > or = 3, and recovery (functionally independent state) was defined as mRS < 3. The timing and the independent predictors of recovery were determined using a Cox proportional hazards multiple regression analysis.
RESULTS: Of 7,599 patients enrolled with ischemic stroke or TIA, 1,662 (21.8%) were disabled (mRS > or = 3) at baseline (median of 14 [0 to 96] days after stroke onset). Disability was moderate (mRS 3) in 931 (56%) patients, severe (mRS 4) in 691 (42%), and very severe (mRS 5) in 40 (2%). By 18 months, 877 (52.8%, 95% CI 50% to 55%) patients had recovered, 589 (63%, 60% to 66%) with moderate disability, 281 (41%, 37% to 44%) with severe disability, and 7 (17%, 7 to 33%) with very severe disability. Median time to recovery was 3 months for patients with moderate disability and 18 months for severe disability; 82.5% of severely disabled patients remained so at 18 months. Predictors of recovery were moderate disability (mRS 3) at baseline compared with severe (mRS 4: hazard ratio [HR] 2.13, 1.86 to 2.44) or very severe disabling stroke (HR 5.88, 2.86 to 12.5); younger women (aged <65 years, compared with > or =75 years; HR 1.85, 1.47 to 2.33); decreasing time (days) between the qualifying event and the baseline assessment (HR 1.01, 1.01 to 1.02); and the absence of previous ischemic stroke (HR 1.61, 1.35 to 1.92), concurrent peripheral artery disease (HR 1.61, 1.23 to 2.13), or diabetes (HR 1.30, 1.10 to 1.54).
CONCLUSIONS: Half of patients with disabling ischemic stroke recovered within 18 months, and recovery was greatest within 6 months. Significant predictors of recovery included the severity of the index stroke and no history of ischemic stroke, peripheral artery disease, or diabetes.
Cramer SC.
Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery.
Ann Neurol. 2008 Mar;63(3):272-87. doi: 10.1002/ana.21393.
Abstract/Text
Stroke remains a leading cause of adult disability. Some degree of spontaneous behavioral recovery is usually seen in the weeks after stroke onset. Variability in recovery is substantial across human patients. Some principles have emerged; for example, recovery occurs slowest in those destined to have less successful outcomes. Animal studies have extended these observations, providing insight into a broad range of underlying molecular and physiological events. Brain mapping studies in human patients have provided observations at the systems level that often parallel findings in animals. In general, the best outcomes are associated with the greatest return toward the normal state of brain functional organization. Reorganization of surviving central nervous system elements supports behavioral recovery, for example, through changes in interhemispheric lateralization, activity of association cortices linked to injured zones, and organization of cortical representational maps. A number of factors influence events supporting stroke recovery, such as demographics, behavioral experience, and perhaps genetics. Such measures gain importance when viewed as covariates in therapeutic trials of restorative agents that target stroke recovery.
Cassidy TP, Lewis S, Gray CS.
Recovery from visuospatial neglect in stroke patients.
J Neurol Neurosurg Psychiatry. 1998 Apr;64(4):555-7. doi: 10.1136/jnnp.64.4.555.
Abstract/Text
OBJECTIVES: To describe the natural recovery of visuospatial neglect in stroke patients and the distribution of errors made on cancellation tests using a standardised neuropsychological test battery.
METHOD: A prospective study of acute (< seven days) patients with right hemispheric stroke. Patients identified with visuospatial neglect were followed up for three months with monthly clinical and neuropsychological testing
RESULTS: There were 66 patients with acute right hemispheric stroke assessed of whom 27 (40.9%) had evidence of visuospatial neglect. Patients with neglect, on admission, had a mean behavioural inattention test (BIT) score of 56.3, range 10-126 (normal>129). Three of the subtests identified errors being made in both the right and left hemispaces. During follow up, recovery occurred across both hemispaces, maximal in the right hemispace. Recovery from visuospatial neglect was associated with improvement in function as assessed by the Barthel score. At the end of the study period only six (31.5%) patients had persisting evidence of neglect. On admission the best predictor of recovery of visuospatial neglect was the line cancellation test (Spearman's rank correlation r=-0.4217, p=0.028).
CONCLUSION: The demonstration of errors in both hemispaces has implications for the theory that neglect is a lateralised attentional problem and is important to recognise in planning the rehabilitation of stroke patients.
Hier DB, Mondlock J, Caplan LR.
Recovery of behavioral abnormalities after right hemisphere stroke.
Neurology. 1983 Mar;33(3):345-50. doi: 10.1212/wnl.33.3.345.
Abstract/Text
We studied recovery of function in 41 patients with right hemisphere stroke. Recovery was rapid for left neglect, prosopagnosia, anosognosia, and unilateral spatial neglect on drawing (USN). Recovery was slower for h mianopia, hemiparesis, motor impersistence, and extinction. Rates of recovery were intermediate for constructional apraxia and dressing apraxia. Sex had no influence on the rate of recovery. Younger patients recovered from prosopagnosia more rapidly than older patients. Patients with smaller lesions recovered more quickly from anosognosia, USN, and hemiparesis than patients with larger lesions. Patients with hemorrhages recovered more rapidly from constructional apraxia, neglect, and motor impersistence than patients with infarcts. Recovery of function and the factors influencing recovery can by studied systematically by life table methods.
Kimura K, Kazui S, Minematsu K, Yamaguchi T; Japan Multicenter Stroke Investigators' Collaboration (J-MUSIC).
Hospital-based prospective registration of acute ischemic stroke and transient ischemic attack in Japan.
J Stroke Cerebrovasc Dis. 2004 Jan-Feb;13(1):1-11. doi: 10.1016/j.jstrokecerebrovasdis.2003.11.025.
Abstract/Text
The purpose of this study was to obtain fundamental information on patients with acute ischemic stroke and transient ischemic attack (TIA) in Japan. We prospectively registered consecutive stroke and TIA patients who visited 156 participating hospitals within 7 days of onset between May 1, 1999 and April 30, 2000. A total of 16,922 patients with 70.6 +/- 11.5 years old (median 71, range 18-107) were enrolled in the study. TIA was seen in 7% of registered patients, lacunar stroke in 36%, atherothrombotic in 31%, cardioembolic stroke in 20%, and other in 6%. Hypertension was present in 61%, diabetes mellitus in 24%, atrial fibrillation (AF) in 21%, smoking in 18%, and hypercholesterolemia in 17%. Overall, 37% of patients arrived at hospital within 3 hours of symptom onset, and 50% within 6 hours. Among those who visited the hospital within 6 hours, 64% used an ambulance service. Mean NIHSS score was 8.0 +/- 7.9 (median, 5). Only 3% were treated with thrombolytic agents in acute phase of stroke. Only 19% of all patients were treated in stroke care unit or intensive care unit. The modified Rankin Scale score of 0 to 2 at discharge was observed in 61% of the patients, 3 to 5 in 32%, and the mortality rate was 7%. More than half of the acute stroke patients arrived at the hospital after 6 hours of onset, and the stroke care unit was used only in one fifth of all patients. Establishment of ideal emergency system and arrangement of stroke units are also awaited for better management and improvement of patients' outcome.
Ntaios G, Faouzi M, Ferrari J, Lang W, Vemmos K, Michel P.
An integer-based score to predict functional outcome in acute ischemic stroke: the ASTRAL score.
Neurology. 2012 Jun 12;78(24):1916-22. doi: 10.1212/WNL.0b013e318259e221. Epub 2012 May 30.
Abstract/Text
OBJECTIVE: To develop and validate a simple, integer-based score to predict functional outcome in acute ischemic stroke (AIS) using variables readily available after emergency room admission.
METHODS: Logistic regression was performed in the derivation cohort of previously independent patients with AIS (Acute Stroke Registry and Analysis of Lausanne [ASTRAL]) to identify predictors of unfavorable outcome (3-month modified Rankin Scale score >2). An integer-based point-scoring system for each covariate of the fitted multivariate model was generated by their β-coefficients; the overall score was calculated as the sum of the weighted scores. The model was validated internally using a 2-fold cross-validation technique and externally in 2 independent cohorts (Athens and Vienna Stroke Registries).
RESULTS: Age (A), severity of stroke (S) measured by admission NIH Stroke Scale score, stroke onset to admission time (T), range of visual fields (R), acute glucose (A), and level of consciousness (L) were identified as independent predictors of unfavorable outcome in 1,645 patients in ASTRAL. Their β-coefficients were multiplied by 4 and rounded to the closest integer to generate the score. The area under the receiver operating characteristic curve (AUC) of the score in the ASTRAL cohort was 0.850. The score was well calibrated in the derivation (p = 0.43) and validation cohorts (0.22 [Athens, n = 1,659] and 0.49 [Vienna, n = 653]). AUCs were 0.937 (Athens), 0.771 (Vienna), and 0.902 (when pooled). An ASTRAL score of 31 indicates a 50% likelihood of unfavorable outcome.
CONCLUSIONS: The ASTRAL score is a simple integer-based score to predict functional outcome using 6 readily available items at hospital admission. It performed well in double external validation and may be a useful tool for clinical practice and stroke research.
Papavasileiou V, Milionis H, Michel P, Makaritsis K, Vemmou A, Koroboki E, Manios E, Vemmos K, Ntaios G.
ASTRAL score predicts 5-year dependence and mortality in acute ischemic stroke.
Stroke. 2013 Jun;44(6):1616-20. doi: 10.1161/STROKEAHA.113.001047. Epub 2013 Apr 4.
Abstract/Text
BACKGROUND AND PURPOSE: The ASTRAL score was externally validated showing remarkable consistency on 3-month outcome prognosis in patients with acute ischemic stroke. The present study aimed to evaluate ASTRAL score's prognostic accuracy to predict 5-year outcome.
METHODS: All consecutive patients with acute ischemic stroke registered in the Athens Stroke Registry between January 1, 1998, and December 31, 2010, were included. Patients were excluded if admitted >24 hours after symptom onset or if any ASTRAL score component was missing. End points were 5-year unfavorable functional outcome, defined as modified Rankin Scale 3 to 6, and 5-year mortality. For each outcome, the area under the receiver operating characteristics curve was calculated; also, a multivariate Cox proportional hazards analysis was performed to investigate whether the ASTRAL score was an independent predictor of outcome. The Kaplan-Meier product limit method was used to estimate the probability of 5-year survival for each ASTRAL score quartile.
RESULTS: The area under the receiver operating characteristics curve of the score to predict 5-year unfavorable functional outcome was 0.89, 95% confidence interval 0.88 to 0.91. In multivariate Cox proportional hazards analysis, the ASTRAL score was independently associated with 5-year unfavorable functional outcome (hazard ratio, 1.09; 95% confidence interval, 1.08-1.10). The area under the receiver operating characteristics curve for the ASTRAL score's discriminatory power to predict 5-year mortality was 0.81 (95% confidence interval, 0.78-0.83). In multivariate analysis, the ASTRAL score was independently associated with 5-year mortality (hazard ratio, 1.09, 95% confidence interval, 1.08-1.10). During the 5-year follow-up, the probability of survival was significantly lower with increasing ASTRAL score quartiles (log-rank test <0.001).
CONCLUSIONS: The ASTRAL score reliably predicts 5-year functional outcome and mortality in patients with acute ischemic stroke.
Strbian D, Meretoja A, Ahlhelm FJ, Pitkäniemi J, Lyrer P, Kaste M, Engelter S, Tatlisumak T.
Predicting outcome of IV thrombolysis-treated ischemic stroke patients: the DRAGON score.
Neurology. 2012 Feb 7;78(6):427-32. doi: 10.1212/WNL.0b013e318245d2a9.
Abstract/Text
OBJECTIVE: To develop a functional outcome prediction score, based on immediate pretreatment parameters, in ischemic stroke patients receiving IV alteplase.
METHODS: The derivation cohort consists of 1,319 ischemic stroke patients treated with IV alteplase at the Helsinki University Central Hospital, Helsinki, Finland. We evaluated the predictive value of parameters associated with the 3-month outcome and developed the score according to the magnitude of logistic regression coefficients. We assessed accuracy of the model with bootstrapping. External validation was performed in a cohort of 330 patients treated at the University Hospital Basel, Basel, Switzerland. We assessed the score performance with area under the receiver operating characteristic curve (AUC-ROC).
RESULTS: The DRAGON score (0-10 points) consists of (hyper)Dense cerebral artery sign/early infarct signs on admission CT scan (both = 2, either = 1, none = 0), prestroke modified Rankin Scale (mRS) score >1 (yes = 1), Age (≥ 80 years = 2, 65-79 years = 1, <65 years = 0), Glucose level at baseline (>8 mmol/L [>144 mg/dL] = 1), Onset-to-treatment time (>90 minutes = 1), and baseline National Institutes of Health Stroke Scale score (>15 = 3, 10-15 = 2, 5-9 = 1, 0-4 = 0). AUC-ROC was 0.84 (0.80-0.87) in the derivation cohort and 0.80 (0.74-0.86) in the validation cohort. Proportions of patients with good outcome (mRS score 0-2) were 96%, 88%, 74%, and 0% for 0-1, 2, 3, and 8-10 points, respectively. Proportions of patients with miserable outcome (mRS score 5-6) were 0%, 2%, 5%, 70%, and 100% for 0-1, 2, 3, 8, and 9-10 points, respectively. External validation showed similar results.
CONCLUSIONS: The DRAGON score is valid at our site and was reliable externally. It can support clinical decision-making, especially when invasive add-on strategies are considered. The score was not studied in patients with basilar artery occlusion. Further external validation is warranted.
Saposnik G, Raptis S, Kapral MK, Liu Y, Tu JV, Mamdani M, Austin PC; Investigators of the Registry of the Canadian Stroke Network and the Stroke Outcome Research Canada Working Group.
The iScore predicts poor functional outcomes early after hospitalization for an acute ischemic stroke.
Stroke. 2011 Dec;42(12):3421-8. doi: 10.1161/STROKEAHA.111.623116. Epub 2011 Sep 29.
Abstract/Text
BACKGROUND AND PURPOSE: The iScore is a prediction tool originally developed to estimate the risk of death after hospitalization for an acute ischemic stroke. Our objective was to determine whether the iScore could also predict poor functional outcomes.
METHODS: We applied the iScore to patients presenting with an acute ischemic stroke at multiple hospitals in Ontario, Canada, between 2003 and 2008, who had been identified from the Registry of the Canadian Stroke Network regional stroke center database (n=3818) and from an external data set, the Registry of the Canadian Stroke Network Ontario Stroke Audit (n=4635). Patients were excluded if they were included in the sample used to develop and validate the initial iScore. Poor functional outcomes were defined as: (1) death at 30 days or disability at discharge, in which disability was defined as having a modified Rankin Scale 3 to 5; and (2) death at 30 days or institutionalization at discharge.
RESULTS: The prevalence of poor functional outcomes in the Registry of the Canadian Stroke Network and the Ontario Stroke Audit, respectively, were 55.7% and 44.1% for death at 30 days or disability at discharge and 16.9% and 16.2%, respectively, for death at 30 days or institutionalization at discharge. The iScore stratified the risk of poor outcomes in low- and high-risk individuals. Observed versus predicted outcomes showed high correlations: 0.988 and 0.940 for mortality or disability and 0.985 and 0.993 for mortality or institutionalization in the Registry of the Canadian Stroke Network and Ontario Stroke Audit cohorts.
CONCLUSIONS: The iScore can be used to estimate the risk of death or a poor functional outcome after an acute ischemic stroke.
Saposnik G, Reeves MJ, Johnston SC, Bath PM, Ovbiagele B; VISTA Collaboration.
Predicting clinical outcomes after thrombolysis using the iScore: results from the Virtual International Stroke Trials Archive.
Stroke. 2013 Oct;44(10):2755-9. doi: 10.1161/STROKEAHA.113.001343. Epub 2013 Jul 25.
Abstract/Text
BACKGROUND AND PURPOSE: The ischemic stroke risk score (iScore) is a validated tool developed to estimate the risk of death and functional outcomes early after an acute ischemic stroke. Our goal was to determine the ability of the iScore to estimate clinical outcomes after intravenous thrombolysis tissue-type plasminogen activator (tPA) in the Virtual International Stroke Trials Archive (VISTA).
METHODS: We applied the iScore (www.sorcan.ca/iscore) to patients with an acute ischemic stroke within the VISTA collaboration to examine the effect of tPA. We explored the association between the iScore (<200 and ≥200) and the primary outcome of favorable outcome at 3 months defined as a modified Rankin scale score of 0 to 2. Secondary outcomes included death at 3 months, catastrophic outcomes (modified Rankin scale, 4-6), and Barthel index >90 at 3 months.
RESULTS: Among 7140 patients with an acute ischemic stroke, 2732 (38.5%) received tPA and 711 (10%) had an iScore ≥200. Overall, tPA treatment was associated with a significant improvement in the primary outcome among patients with an iScore <200 (38.9% non-tPA versus 47.5% tPA; P<0.001) but was not associated with a favorable outcome among patients with an iScore ≥200 (5.5% non-tPA versus 7.6% tPA; P=0.45). In the multivariable analysis after adjusting for age, baseline National Institutes of Health Stroke Scale, and onset-to-treatment time, there was a significant interaction between tPA administration and iScore; tPA administration was associated with 47% higher odds of a favorable outcome at 3 months among patients with an iScore <200 (odds ratio, 1.47; 95% confidence interval, 1.30-1.67), whereas the association between tPA and favorable outcome among those with an iScore ≥200 remained nonsignificant (odds ratio, 0.80; 95% confidence interval, 0.45-1.42). A similar pattern of benefit with tPA among patients with an iScore <200, but not ≥200, was observed for secondary outcomes including death.
CONCLUSIONS: The iScore is a useful and validated tool that helps clinicians estimate stroke outcomes. In stroke patients participating in VISTA, an iScore <200 was associated with better outcomes at 3 months after tPA.
O'Donnell MJ, Fang J, D'Uva C, Saposnik G, Gould L, McGrath E, Kapral MK; Investigators of the Registry of the Canadian Stroke Network.
The PLAN score: a bedside prediction rule for death and severe disability following acute ischemic stroke.
Arch Intern Med. 2012 Nov 12;172(20):1548-56. doi: 10.1001/2013.jamainternmed.30.
Abstract/Text
BACKGROUND: We sought to develop and validate a simple clinical prediction rule for death and severe disability after acute ischemic stroke that can be used by general clinicians at the time of hospital admission.
METHODS: We analyzed data from a registry of 9847 patients (4943 in the derivation cohort and 4904 in the validation cohort) hospitalized with acute ischemic stroke and included in the Registry of the Canadian Stroke Network (July 1, 2003, to March 31, 2008; 11 regional stroke centers in Ontario, Canada). Outcome measures were 30-day and 1-year mortality and a modified Rankin score of 5 to 6 at discharge.
RESULTS: Overall 30-day mortality was 11.5% (derivation cohort) and 13.5% (validation cohort). In the final multivariate model, we included 9 clinical variables that could be categorized as preadmission comorbidities (5 points for preadmission dependence [1.5], cancer [1.5], congestive heart failure [1.0], and atrial fibrillation [1.0]), level of consciousness (5 points for reduced level of consciousness), age (10 points, 1 point/decade), and neurologic focal deficit (5 points for significant/total weakness of the leg [2], weakness of the arm [2], and aphasia or neglect [1]). Maximum score is 25. In the validation cohort, the PLAN score (derived from preadmission comorbidities, level of consciousness, age, and neurologic deficit) predicted 30-day mortality (C statistic, 0.87), death or severe dependence at discharge (0.88), and 1-year mortality (0.84). The PLAN score also predicted favorable outcome (modified Rankin score, 0-2) at discharge (C statistic, 0.80).
CONCLUSIONS: The PLAN clinical prediction rule identifies patients who will have a poor outcome after hospitalization for acute ischemic stroke. The score comprises clinical data available at the time of admission and may be determined by nonspecialist clinicians. Additional studies to independently validate the PLAN rule in different populations and settings are required.
Aoki J, Kimura K, Koga M, Kario K, Nakagawara J, Furui E, Shiokawa Y, Hasegawa Y, Okuda S, Yamagami H, Okada Y, Shibazaki K, Sakamoto Y, Toyoda K.
NIHSS-time score easily predicts outcomes in rt-PA patients: the SAMURAI rt-PA registry.
J Neurol Sci. 2013 Apr 15;327(1-2):6-11. doi: 10.1016/j.jns.2013.01.029. Epub 2013 Feb 20.
Abstract/Text
BACKGROUND: We aimed to devise a scale comprising a simple multiplication of initial National Institutes of Health Stroke Scale (NIHSS) score and onset-to-treatment time (OTT) as a scale for predicting outcomes after recombinant tissue plasminogen activator (rt-PA) therapy.
METHODS: Data from rt-PA patients in 10 stroke centers in Japan were investigated. NIHSS-time score was calculated as initial NIHSS score×OTT.
RESULTS: Subjects comprised 526 patients. Median NIHSS score was 12 (7-18), and median OTT was 2.42 h (2.00-2.75 h). Median NIHSS-time score was 27.7 (16.9-41.7). Good (modified Rankin Scale [mRS] 0-1) and poor (mRS 4-6) outcome rates at 3months for patients with NIHSS-time scores ≤ 10 were 71.1% and 7.8%, compared to 54.7% and 16.5% for scores >10 and ≤ 20, 38.9% and 31.9% for scores >20 and ≤ 30, 25.0% and 44.6% for scores >30 and ≤ 40, and 17.4% and 61.8% for scores >40, respectively. Cut-off NIHSS-time scores to predict good and poor outcomes with 50% probability were defined as 20 and 40, respectively. Multivariate logistic regression analysis revealed NIHSS-time score as an independent predictor of good (odds ratio [OR], 0.587; 95% confidence interval [CI], 0.422-0.818, p=0.002) and poor (OR, 1.756; 95%CI, 1.227-2.514, p=0.002) outcomes after adjusting for age, sex, NIHSS score, OTT, Alberta Stroke Program Early CT Score, internal carotid artery occlusion, and glucose level.
CONCLUSIONS: NIHSS-time score predicts clinical outcomes in rt-PA patients.
Copyright © 2013 Elsevier B.V. All rights reserved.
Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, Albers GW, Kaste M, Marler JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke W; ECASS, ATLANTIS, NINDS and EPITHET rt-PA Study Group; Allen K, Mau J, Meier D, del Zoppo G, De Silva DA, Butcher KS, Parsons MW, Barber PA, Levi C, Bladin C, Byrnes G.
Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials.
Lancet. 2010 May 15;375(9727):1695-703. doi: 10.1016/S0140-6736(10)60491-6.
Abstract/Text
BACKGROUND: Early administration of intravenous recombinant tissue plasminogen activator (rt-PA) after ischaemic stroke improves outcome. Previous analysis of combined data from individual patients suggested potential benefit beyond 3 h from stroke onset. We re-examined the effect of time to treatment with intravenous rt-PA (alteplase) on therapeutic benefit and clinical risk by adding recent trial data to the analysis.
METHODS: We added data from ECASS III (821 patients) and EPITHET (100 patients) to a pool of common data elements from six other trials of alteplase for acute stroke (2775 patients). We used multivariate logistic regression to assess the relation of stroke onset to start of treatment (OTT) with treatment on favourable 3-month outcome (defined as modified Rankin score 0-1), mortality, and occurrence and outcome of clinically relevant parenchymal haemorrhage. The presence of an arterial occlusion was inferred from the patient's symptoms and absence of haemorrhage or other causes of ischaemic stroke. Vascular imaging was not a requirement in the trials. All patients with confirmed OTT within 360 min were included in the analysis.
FINDINGS: Treatment was started within 360 min of stroke onset in 3670 patients randomly allocated to alteplase (n=1850) or to placebo (n=1820). Odds of a favourable 3-month outcome increased as OTT decreased (p=0.0269) and no benefit of alteplase treatment was seen after around 270 min. Adjusted odds of a favourable 3-month outcome were 2.55 (95% CI 1.44-4.52) for 0-90 min, 1.64 (1.12-2.40) for 91-180 min, 1.34 (1.06-1.68) for 181-270 min, and 1.22 (0.92-1.61) for 271-360 min in favour of the alteplase group. Large parenchymal haemorrhage was seen in 96 (5.2%) of 1850 patients assigned to alteplase and 18 (1.0%) of 1820 controls, with no clear relation to OTT (p=0.4140). Adjusted odds of mortality increased with OTT (p=0.0444) and were 0.78 (0.41-1.48) for 0-90 min, 1.13 (0.70-1.82) for 91-180 min, 1.22 (0.87-1.71) for 181-270 min, and 1.49 (1.00-2.21) for 271-360 min.
INTERPRETATION: Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous alteplase when treated up to 4.5 h. To increase benefit to a maximum, every effort should be taken to shorten delay in initiation of treatment. Beyond 4.5 h, risk might outweigh benefit.
FUNDING: None.
Copyright 2010 Elsevier Ltd. All rights reserved.
篠原幸人，峰松一夫．アルテプラーゼ適正使用のための注意事項：胸部大動脈解離について．脳卒中 2008;30:443-4.
Tsivgoulis G, Alexandrov AV, Chang J, Sharma VK, Hoover SL, Lao AY, Liu W, Stamboulis E, Alexandrov AW, Malkoff MD, Frey JL.
Safety and outcomes of intravenous thrombolysis in stroke mimics: a 6-year, single-care center study and a pooled analysis of reported series.
Stroke. 2011 Jun;42(6):1771-4. doi: 10.1161/STROKEAHA.110.609339. Epub 2011 Apr 14.
Abstract/Text
BACKGROUND AND PURPOSE: Efforts to increase the availability and shorten the time delivery of intravenous thrombolysis in patients with acute ischemic stroke carry the potential for tissue plasminogen activator administration in patients with diseases other than stroke, that is, stroke mimics (SMs). We aimed to determine safety and to describe outcomes of intravenous thrombolysis in SM.
METHODS: We retrospectively analyzed stroke registry data of consecutive acute ischemic stroke admissions treated with intravenous thrombolysis over a 6-year-period. The admission National Institutes of Health Stroke Scale score, vascular risk factors, ischemic lesions on brain MRI (routinely performed as part of diagnostic work-up), and discharge modified Rankin Scale scores were documented. Initial stroke diagnosis in the emergency department was compared with final discharge diagnosis. SM diagnosis was based on the absence of ischemic lesions on diffusion-weighted imaging sequences in addition to an alternate discharge diagnosis. Symptomatic intracranial hemorrhage was defined as brain imaging evidence of intracranial hemorrhage with clinical worsening by National Institutes of Health Stroke Scale score increase of ≥4 points.
RESULTS: Intravenous thrombolysis was administered in 539 patients with acute ischemic stroke (55% men; mean age, 66 ± 15 years). Misdiagnosis of acute ischemic stroke was documented in 56 cases (10.4%; 95% CI, 7.9% to 13.3%). Conversion disorder (26.8%), complicated migraine (19.6%), and seizures (19.6%) were the 3 most common final diagnoses in SM. SMs were younger (mean age, 56 ± 13 years) and had milder baseline stroke severity (median National Institutes of Health Stroke Scale, 6; interquartile range, 4) compared with patients with confirmed acute ischemic stroke (mean age, 67 ± 14 years; median National Institutes of Health Stroke Scale, 8; interquartile range, 10; P<0.001). There was no case of symptomatic intracranial hemorrhage in SMs (0%; 95% CI, 0% to 5.5%); 96% of SMs were functionally independent at hospital discharge (modified Rankin Scale, 0 to 1).
CONCLUSIONS: Our single-center data indicate favorable safety and outcomes of intravenous thrombolysis administered to SM.
National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.
Tissue plasminogen activator for acute ischemic stroke.
N Engl J Med. 1995 Dec 14;333(24):1581-7. doi: 10.1056/NEJM199512143332401.
Abstract/Text
BACKGROUND: Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials. We performed a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke.
METHODS: The trial had two parts. Part 1 (in which 291 patients were enrolled) tested whether t-PA had clinical activity, as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. Part 2 (in which 333 patients were enrolled) used a global test statistic to assess clinical outcome at three months, according to scores on the Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS:
RESULTS: In part 1, there was no significant difference between the group given t-PA and that given placebo in the percentages of patients with neurologic improvement at 24 hours, although a benefit was observed for the t-PA group at three months for all four outcome measures. In part 2, the long-term clinical benefit of t-PA predicted by the results of part 1 was confirmed (global odds ratio for a favorable outcome, 1.7; 95 percent confidence interval, 1.2 to 2.6). As compared with patients given placebo, patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales. Symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke occurred in 6.4 percent of patients given t-PA but only 0.6 percent of patients given placebo (P < 0.001). Mortality at three months was 17 percent in the t-PA group and 21 percent in the placebo group (P = 0.30).
CONCLUSIONS: Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.
Wardlaw JM, Zoppo G, Yamaguchi T, Berge E.
Thrombolysis for acute ischaemic stroke.
Cochrane Database Syst Rev. 2003;(3):CD000213. doi: 10.1002/14651858.CD000213.
Abstract/Text
BACKGROUND: The majority of strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred. Successful treatment could mean that the patient is more likely to make a good recovery from their stroke. Thrombolytic drugs however, can also cause serious bleeding in the brain which can be fatal. Thrombolytic therapy has now been evaluated in several randomised trials in acute ischaemic stroke.
OBJECTIVES: The objective of this review was to assess the safety and efficacy of thrombolytic agents in patients with acute ischaemic stroke.
SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched January 2003), MEDLINE (1966- January 2003) and EMBASE (1980-January 2003). In addition we contacted researchers and pharmaceutical companies, attended relevant conferences and handsearched four Japanese journals.
SELECTION CRITERIA: Randomised trials of any thrombolytic agent compared with control in patients with definite ischaemic stroke.
DATA COLLECTION AND ANALYSIS: One reviewer applied the inclusion criteria and extracted the data. Trial quality was assessed. The extracted data were verified by the principal investigators of all major trials. Thus published and unpublished data were obtained where available.
MAIN RESULTS: Eighteen trials including 5727 patients were included, but not all trials contributed data to each outcome examined in this review. Sixteen trials were double-blind. The trials tested urokinase, streptokinase, recombinant tissue plasminogen activator or recombinant pro-urokinase. Two trials used intra-arterial administration but the rest used the intravenous route. About 50% of the data (patients and trials) come from trials testing intravenous tissue plasminogen activator. There are few data from patients aged over 80 years. Much of the data comes from trials conducted in the first half of the 1990s when, in an effort to reduce delays to trial drug administration, on site randomisation methods were used that, in consequence, limited the ability to stratify randomisation on key prognostic variables. Several trials, because of the biological effects of thrombolysis combined with the follow-up methods used, did not have complete blinding of outcome assessment. Thrombolytic therapy, administered up to six hours after ischaemic stroke, significantly reduced the proportion of patients who were dead or dependent (modified Rankin 3 to 6) at the end of follow-up at three to six months (OR 0.84, 95% CI 0.75 to 0.95). This was in spite of a significant increase in : the odds of death within the first ten days (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.46 to 2.24), the main cause of which was fatal intracranial haemorrhage (OR 4.34, 95% CI 3.14 to 5.99). Symptomatic intracranial haemorrhage was increased following thrombolysis (OR 3.37, 95% CI 2.68 to 4.22). Thrombolytic therapy also increased the odds of death at the end of follow-up at three to six months (OR 1.33, 95% CI 1.15 to 1.53). For patients treated within three hours of stroke, thrombolytic therapy appeared more effective in reducing death or dependency (OR 0.66, 95% CI 0.53 to 0.83) with no statistically significant adverse effect on death (OR 1.13, 95% CI 0.86 to 1.48). There was heterogeneity between the trials that could have been due to many trial features including : thrombolytic drug used, variation in the use of aspirin and heparin, severity of the stroke (both between trials and between treatment groups within trials), and time to treatment. Trials testing intravenous recombinant tissue plasminogen activator suggested that it may be associated with slightly less hazard and more benefit than other drugs when given up to six hours after stroke but these are non-random comparisons - death within the first ten days OR 1.24, 95% CI 0.85 to 1.81, death at the end of follow-up OR 1.17, 95% CI 0.95 to 1.45, dead or dependent at the end of follow-up OR 0.80, 95% CI 0.69 to 0.93. However, no trial has directly comparedup OR 0.80, 95% CI 0.69 to 0.93. However, no trial has directly compared rt-PA with any other thrombolytic agent. There is some evidence that antithrombotic drugs given soon after thrombolysis may increase the risk of death.
REVIEWER'S CONCLUSIONS: Overall, thrombolytic therapy appears to result in a significant net reduction in the proportion of patients dead or dependent in activities of daily living. However, this appears to be net of an increase in deaths within the first seven to ten days, symptomatic intracranial haemorrhage, and deaths at follow-up at three to six months. The data from trials using intravenous recombinant tissue plasminogen activator, from which there are the most evidence on thrombolytic therapy so far, suggest that it may be associated with less hazard and more benefit. There was heterogeneity between the trials for some outcomes and the optimum criteria to identify the patients most likely to benefit and least likely to be harmed, the latest time window, the agent, dose, and route of administration, are not clear. The data are promising and may justify the use of thrombolytic therapy with intravenous recombinant tissue plasminogen activator in experienced centres in highly selected patients where a licence exists. However, the data do not support the widespread use of thrombolytic therapy in routine clinical practice at this time, but suggest that further trials are needed to identify which patients are most likely to benefit from treatment and the environment in which it may best be given. To avoid the problem of data missing from some trials for some key outcomes encountered in this review to date, and to assist future metaanalyses, future trialists should try to collect data in such a way as to be compatible with the basic outcome assessments reviewed here (eg early death, fatal intracranial haemorrhage, poor functional outcome).
Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D; ECASS Investigators.
Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.
N Engl J Med. 2008 Sep 25;359(13):1317-29. doi: 10.1056/NEJMoa0804656.
Abstract/Text
BACKGROUND: Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.
METHODS: After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.
RESULTS: We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.
CONCLUSIONS: As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)
2008 Massachusetts Medical Society
Yamaguchi T, Mori E, Minematsu K, Nakagawara J, Hashi K, Saito I, Shinohara Y; Japan Alteplase Clinical Trial (J-ACT) Group.
Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT).
Stroke. 2006 Jul;37(7):1810-5. doi: 10.1161/01.STR.0000227191.01792.e3. Epub 2006 Jun 8.
Abstract/Text
BACKGROUND AND PURPOSE: Based on previous studies comparing different recombinant tissue plasminogen activator (rt-PA) doses, we performed a clinical trial with 0.6 mg/kg, which is lower than the internationally approved dosage of 0.9 mg/kg, aiming to assess the efficacy and safety of alteplase in acute ischemic stroke for the Japanese.
METHODS: Our prospective, multicenter, single-arm, open-label trial was designed with a target sample size of 100 patients. The primary end points were the proportion of patients with a modified Rankin Scale (mRS) score of 0 to 1 at 3 months and the incidence of symptomatic intracranial hemorrhage (sICH) within 36 hours. Thresholds for these end points were determined by calculating 90% CIs of weighted averages derived from published reports. The protocol was defined according to the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA stroke study with slight modifications.
RESULTS: Among the 103 patients enrolled, 38 had an mRS of 0 to 1 at 3 months; this proportion (36.9%) exceeded the predetermined threshold of 33.9%. sICH within 36 hours occurred in 6 patients; this incidence (5.8%) was lower than the threshold of 9.6%.
CONCLUSIONS: In patients receiving 0.6 mg/kg alteplase, the outcome and the incidence of sICH were comparable to published data for 0.9 mg/kg. These findings indicate that alteplase, when administered at 0.6 mg/kg to Japanese patients, might offer a clinical efficacy and safety that are compatible with data reported in North America and the European Union for a 0.9 mg/kg dose.
Mori E, Minematsu K, Nakagawara J, Yamaguchi T, Sasaki M, Hirano T; Japan Alteplase Clinical Trial II Group.
Effects of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in middle cerebral artery occlusion: Japan Alteplase Clinical Trial II (J-ACT II).
Stroke. 2010 Mar;41(3):461-5. doi: 10.1161/STROKEAHA.109.573477. Epub 2010 Jan 14.
Abstract/Text
BACKGROUND AND PURPOSE: The purpose of this study was to evaluate further the efficacy of 0.6 mg/kg intravenous alteplase on vascular and clinical outcomes in patients with middle cerebral artery occlusion in a postmarketing Phase IV trial of prospective cohort study design.
METHODS: Alteplase was given intravenously at 0.6 mg/kg to patients with ischemic stroke within 3 hours of onset with MR angiography-documented middle cerebral artery occlusion. Vascular outcome was evaluated by MR angiography at 6 and 24 hours after symptom onset based on the modified Mori grade. The primary end points also included a favorable outcome (modified Rankin Scale 0 to 1 at 3 months after onset) and incidence of symptomatic intracranial hemorrhage within 36 hours after treatment. The impact of recanalization on clinical outcome was assessed by stepwise logistic regression analysis.
RESULTS: Fifty-eight patients were enrolled. Recanalization was noted in 51.7% on 6-hour MR angiography and 69.0% on 24-hour MR angiography. A favorable clinical outcome was achieved in 46.6%. None had symptomatic intracranial hemorrhage. In logistic regression models, recanalization on either 6-hour or 24-hour MR angiography was an independent predictor for clinical outcome as well as the baseline National Institutes of Health Stroke Scale score.
CONCLUSIONS: Early recanalization of an occluded middle cerebral artery can be provoked by 0.6 mg/kg intravenous alteplase and may induce a favorable clinical outcome. The rates of recanalization and favorable outcome are comparable to that previously reported with the 0.9-mg/kg dose.
日本脳卒中学会医療向上・社会保険委員会 rt-PA（アルテプラーゼ）静注療法指針部会：rt-PA（アルテプラーゼ）静注療法適正治療指針第二版 2012年10月．脳卒中 2012;34:443-480.
Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators.
Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials.
Lancet. 2004 Mar 6;363(9411):768-74. doi: 10.1016/S0140-6736(04)15692-4.
Abstract/Text
BACKGROUND: Quick administration of intravenous recombinant tissue plasminogen activator (rt-PA) after stroke improved outcomes in previous trials. We aimed to analyse combined data for individual patients to confirm the importance of rapid treatment.
METHODS: We pooled common data elements from six randomised placebo-controlled trials of intravenous rt-PA. Using multivariable logistic regression we assessed the relation of the interval from stroke onset to start of treatment (OTT) on favourable 3-month outcome and on the occurrence of clinically relevant parenchymal haemorrhage.
FINDINGS: Treatment was started within 360 min of onset of stroke in 2775 patients randomly allocated to rt-PA or placebo. Median age was 68 years, median baseline National Institute of Health Stroke Scale (NIHSS) 11, and median OTT 243 min. Odds of a favourable 3-month outcome increased as OTT decreased (p=0.005). Odds were 2.8 (95% CI 1.8-4.5) for 0-90 min, 1.6 (1.1-2.2) for 91-180 min, 1.4 (1.1-1.9) for 181-270 min, and 1.2 (0.9-1.5) for 271-360 min in favour of the rt-PA group. The hazard ratio for death adjusted for baseline NIHSS was not different from 1.0 for the 0-90, 91-180, and 181-270 min intervals; for 271-360 min it was 1.45 (1.02-2.07). Haemorrhage was seen in 82 (5.9%) rt-PA patients and 15 (1.1%) controls (p<0.0001). Haemorrhage was not associated with OTT but was with rt-PA treatment (p=0.0001) and age (p=0.0002).
INTERPRETATION: The sooner that rt-PA is given to stroke patients, the greater the benefit, especially if started within 90 min. Our results suggest a potential benefit beyond 3 h, but this potential might come with some risks.
日本脳卒中学会 脳卒中医療向上・社会保険委員会、rt -PA （アルテプラーゼ）静注療法指針改訂部会：発症3時間超4.5時間以内の虚血性脳管障害患者に対するrt-PA（アルテプラーゼ）静注療法の適正な施行に関する緊急声明. Available from: http://www.jsts.gr.jp/img/info02.pdf
Karolinska Stroke Update Consensus Statements 2010: Reperfusion Therapy -Intravenous Thrombolysis. Available from: http://www.strokeupdate.org/Cons_Reperf_IVT_2010.aspx
Koga M, Shiokawa Y, Nakagawara J, Furui E, Kimura K, Yamagami H, Okada Y, Hasegawa Y, Kario K, Okuda S, Endo K, Miyagi T, Osaki M, Minematsu K, Toyoda K.
Low-dose intravenous recombinant tissue-type plasminogen activator therapy for patients with stroke outside European indications: Stroke Acute Management with Urgent Risk-factor Assessment and Improvement (SAMURAI) rtPA Registry.
Stroke. 2012 Jan;43(1):253-5. doi: 10.1161/STROKEAHA.111.631176. Epub 2011 Sep 29.
Abstract/Text
BACKGROUND AND PURPOSE: The purpose of this study was to determine the safety and efficacy of intravenous recombinant tissue-type plasminogen activator (0.6 mg/kg alteplase) within 3 hours of stroke onset in Japanese patients outside the indications in the European license.
METHODS: Of the 600 patients who were treated with recombinant tissue-type plasminogen activator, 422 met the inclusion criteria of the European license (IN group) and 178 did not (OUT group).
RESULTS: The OUT group was inversely associated with any intracerebral hemorrhage (adjusted OR, 0.50; 95% CI, 0.29-0.84), positively associated with an unfavorable outcome (2.48; 1.55-3.94) and mortality (2.04; 1.02-4.04), and not associated with symptomatic intracerebral hemorrhage (0.53; 0.11-1.79) or complete independency (0.65; 0.40-1.03) after multivariate adjustment.
CONCLUSIONS: Functional and vital outcomes 3 months after low-dose recombinant tissue-type plasminogen activator in patients outside the European indications were less favorable compared with those included in the indications; however, the risk of intracerebral hemorrhage was not.
日本脳卒中学会 脳卒中医療向上・社会保険委員会、静注血栓溶解療法指針改訂部会：静注血栓溶解（rt-PA）療法 適正治療指針 第三版 [Internet]. Available from: https://www.jsts.gr.jp/img/rt-PA03.pdf
日本脳卒中学会 脳卒中医療 向上・社会保険委員会、静注血栓溶解療法指針改訂PT：静注血栓溶解（rt-PA）療法 適正治療指針 第三版（2023年9月追補） [Internet]. Available from: https://www.jsts.gr.jp/img/rt-pa03_supple.pdf
Ciccone A, Valvassori L; SYNTHESIS Expansion Investigators.
Endovascular treatment for acute ischemic stroke.
N Engl J Med. 2013 Jun 20;368(25):2433-4. doi: 10.1056/NEJMc1304759.
Abstract/Text
Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, Jauch EC, Jovin TG, Yan B, Silver FL, von Kummer R, Molina CA, Demaerschalk BM, Budzik R, Clark WM, Zaidat OO, Malisch TW, Goyal M, Schonewille WJ, Mazighi M, Engelter ST, Anderson C, Spilker J, Carrozzella J, Ryckborst KJ, Janis LS, Martin RH, Foster LD, Tomsick TA; Interventional Management of Stroke (IMS) III Investigators.
Endovascular therapy after intravenous t-PA versus t-PA alone for stroke.
N Engl J Med. 2013 Mar 7;368(10):893-903. doi: 10.1056/NEJMoa1214300. Epub 2013 Feb 7.
Abstract/Text
BACKGROUND: Endovascular therapy is increasingly used after the administration of intravenous tissue plasminogen activator (t-PA) for patients with moderate-to-severe acute ischemic stroke, but whether a combined approach is more effective than intravenous t-PA alone is uncertain.
METHODS: We randomly assigned eligible patients who had received intravenous t-PA within 3 hours after symptom onset to receive additional endovascular therapy or intravenous t-PA alone, in a 2:1 ratio. The primary outcome measure was a modified Rankin scale score of 2 or less (indicating functional independence) at 90 days (scores range from 0 to 6, with higher scores indicating greater disability).
RESULTS: The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], -6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8-19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, -4.4 to 18.1) and those with a score of 19 or lower (-1.0 percentage point; 95% CI, -10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P=0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P=0.83).
CONCLUSIONS: The trial showed similar safety outcomes and no significant difference in functional independence with endovascular therapy after intravenous t-PA, as compared with intravenous t-PA alone. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00359424.).
Kidwell CS, Jahan R, Gornbein J, Alger JR, Nenov V, Ajani Z, Feng L, Meyer BC, Olson S, Schwamm LH, Yoo AJ, Marshall RS, Meyers PM, Yavagal DR, Wintermark M, Guzy J, Starkman S, Saver JL; MR RESCUE Investigators.
A trial of imaging selection and endovascular treatment for ischemic stroke.
N Engl J Med. 2013 Mar 7;368(10):914-23. doi: 10.1056/NEJMoa1212793. Epub 2013 Feb 8.
Abstract/Text
BACKGROUND: Whether brain imaging can identify patients who are most likely to benefit from therapies for acute ischemic stroke and whether endovascular thrombectomy improves clinical outcomes in such patients remains unclear.
METHODS: In this study, we randomly assigned patients within 8 hours after the onset of large-vessel, anterior-circulation strokes to undergo mechanical embolectomy (Merci Retriever or Penumbra System) or receive standard care. All patients underwent pretreatment computed tomography or magnetic resonance imaging of the brain. Randomization was stratified according to whether the patient had a favorable penumbral pattern (substantial salvageable tissue and small infarct core) or a nonpenumbral pattern (large core or small or absent penumbra). We assessed outcomes using the 90-day modified Rankin scale, ranging from 0 (no symptoms) to 6 (dead).
RESULTS: Among 118 eligible patients, the mean age was 65.5 years, the mean time to enrollment was 5.5 hours, and 58% had a favorable penumbral pattern. Revascularization in the embolectomy group was achieved in 67% of the patients. Ninety-day mortality was 21%, and the rate of symptomatic intracranial hemorrhage was 4%; neither rate differed across groups. Among all patients, mean scores on the modified Rankin scale did not differ between embolectomy and standard care (3.9 vs. 3.9, P=0.99). Embolectomy was not superior to standard care in patients with either a favorable penumbral pattern (mean score, 3.9 vs. 3.4; P=0.23) or a nonpenumbral pattern (mean score, 4.0 vs. 4.4; P=0.32). In the primary analysis of scores on the 90-day modified Rankin scale, there was no interaction between the pretreatment imaging pattern and treatment assignment (P=0.14).
CONCLUSIONS: A favorable penumbral pattern on neuroimaging did not identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke, nor was embolectomy shown to be superior to standard care. (Funded by the National Institute of Neurological Disorders and Stroke; MR RESCUE ClinicalTrials.gov number, NCT00389467.).
Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, Schonewille WJ, Vos JA, Nederkoorn PJ, Wermer MJ, van Walderveen MA, Staals J, Hofmeijer J, van Oostayen JA, Lycklama à Nijeholt GJ, Boiten J, Brouwer PA, Emmer BJ, de Bruijn SF, van Dijk LC, Kappelle LJ, Lo RH, van Dijk EJ, de Vries J, de Kort PL, van Rooij WJ, van den Berg JS, van Hasselt BA, Aerden LA, Dallinga RJ, Visser MC, Bot JC, Vroomen PC, Eshghi O, Schreuder TH, Heijboer RJ, Keizer K, Tielbeek AV, den Hertog HM, Gerrits DG, van den Berg-Vos RM, Karas GB, Steyerberg EW, Flach HZ, Marquering HA, Sprengers ME, Jenniskens SF, Beenen LF, van den Berg R, Koudstaal PJ, van Zwam WH, Roos YB, van der Lugt A, van Oostenbrugge RJ, Majoie CB, Dippel DW; MR CLEAN Investigators.
A randomized trial of intraarterial treatment for acute ischemic stroke.
N Engl J Med. 2015 Jan 1;372(1):11-20. doi: 10.1056/NEJMoa1411587. Epub 2014 Dec 17.
Abstract/Text
BACKGROUND: In patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion, intraarterial treatment is highly effective for emergency revascularization. However, proof of a beneficial effect on functional outcome is lacking.
METHODS: We randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary outcome was the modified Rankin scale score at 90 days; this categorical scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower modified Rankin scores, as compared with usual care alone (shift analysis).
RESULTS: We enrolled 500 patients at 16 medical centers in The Netherlands (233 assigned to intraarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before randomization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of symptomatic intracerebral hemorrhage.
CONCLUSIONS: In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.).
Goyal M, Demchuk AM, Menon BK, Eesa M, Rempel JL, Thornton J, Roy D, Jovin TG, Willinsky RA, Sapkota BL, Dowlatshahi D, Frei DF, Kamal NR, Montanera WJ, Poppe AY, Ryckborst KJ, Silver FL, Shuaib A, Tampieri D, Williams D, Bang OY, Baxter BW, Burns PA, Choe H, Heo JH, Holmstedt CA, Jankowitz B, Kelly M, Linares G, Mandzia JL, Shankar J, Sohn SI, Swartz RH, Barber PA, Coutts SB, Smith EE, Morrish WF, Weill A, Subramaniam S, Mitha AP, Wong JH, Lowerison MW, Sajobi TT, Hill MD; ESCAPE Trial Investigators.
Randomized assessment of rapid endovascular treatment of ischemic stroke.
N Engl J Med. 2015 Mar 12;372(11):1019-30. doi: 10.1056/NEJMoa1414905. Epub 2015 Feb 11.
Abstract/Text
BACKGROUND: Among patients with a proximal vessel occlusion in the anterior circulation, 60 to 80% of patients die within 90 days after stroke onset or do not regain functional independence despite alteplase treatment. We evaluated rapid endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core, a proximal intracranial arterial occlusion, and moderate-to-good collateral circulation.
METHODS: We randomly assigned participants to receive standard care (control group) or standard care plus endovascular treatment with the use of available thrombectomy devices (intervention group). Patients with a proximal intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients with a large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography were excluded. Workflow times were measured against predetermined targets. The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. A proportional odds model was used to calculate the common odds ratio as a measure of the likelihood that the intervention would lead to lower scores on the modified Rankin scale than would control care (shift analysis).
RESULTS: The trial was stopped early because of efficacy. At 22 centers worldwide, 316 participants were enrolled, of whom 238 received intravenous alteplase (120 in the intervention group and 118 in the control group). In the intervention group, the median time from study CT of the head to first reperfusion was 84 minutes. The rate of functional independence (90-day modified Rankin score of 0 to 2) was increased with the intervention (53.0%, vs. 29.3% in the control group; P<0.001). The primary outcome favored the intervention (common odds ratio, 2.6; 95% confidence interval, 1.7 to 3.8; P<0.001), and the intervention was associated with reduced mortality (10.4%, vs. 19.0% in the control group; P=0.04). Symptomatic intracerebral hemorrhage occurred in 3.6% of participants in intervention group and 2.7% of participants in control group (P=0.75).
CONCLUSIONS: Among patients with acute ischemic stroke with a proximal vessel occlusion, a small infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality. (Funded by Covidien and others; ESCAPE ClinicalTrials.gov number, NCT01778335.).
Campbell BC, Mitchell PJ, Kleinig TJ, Dewey HM, Churilov L, Yassi N, Yan B, Dowling RJ, Parsons MW, Oxley TJ, Wu TY, Brooks M, Simpson MA, Miteff F, Levi CR, Krause M, Harrington TJ, Faulder KC, Steinfort BS, Priglinger M, Ang T, Scroop R, Barber PA, McGuinness B, Wijeratne T, Phan TG, Chong W, Chandra RV, Bladin CF, Badve M, Rice H, de Villiers L, Ma H, Desmond PM, Donnan GA, Davis SM; EXTEND-IA Investigators.
Endovascular therapy for ischemic stroke with perfusion-imaging selection.
N Engl J Med. 2015 Mar 12;372(11):1009-18. doi: 10.1056/NEJMoa1414792. Epub 2015 Feb 11.
Abstract/Text
BACKGROUND: Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes.
METHODS: We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (≥8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days.
RESULTS: The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P=0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P=0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage.
CONCLUSIONS: In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome. (Funded by the Australian National Health and Medical Research Council and others; EXTEND-IA ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical Trials Registry number, ACTRN12611000969965.).
Jovin TG, Chamorro A, Cobo E, de Miquel MA, Molina CA, Rovira A, San Román L, Serena J, Abilleira S, Ribó M, Millán M, Urra X, Cardona P, López-Cancio E, Tomasello A, Castaño C, Blasco J, Aja L, Dorado L, Quesada H, Rubiera M, Hernandez-Pérez M, Goyal M, Demchuk AM, von Kummer R, Gallofré M, Dávalos A; REVASCAT Trial Investigators.
Thrombectomy within 8 hours after symptom onset in ischemic stroke.
N Engl J Med. 2015 Jun 11;372(24):2296-306. doi: 10.1056/NEJMoa1503780. Epub 2015 Apr 17.
Abstract/Text
BACKGROUND: We aimed to assess the safety and efficacy of thrombectomy for the treatment of stroke in a trial embedded within a population-based stroke reperfusion registry.
METHODS: During a 2-year period at four centers in Catalonia, Spain, we randomly assigned 206 patients who could be treated within 8 hours after the onset of symptoms of acute ischemic stroke to receive either medical therapy (including intravenous alteplase when eligible) and endovascular therapy with the Solitaire stent retriever (thrombectomy group) or medical therapy alone (control group). All patients had confirmed proximal anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all study patients, the use of alteplase either did not achieve revascularization or was contraindicated. The primary outcome was the severity of global disability at 90 days, as measured on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]). Although the maximum planned sample size was 690, enrollment was halted early because of loss of equipoise after positive results for thrombectomy were reported from other similar trials.
RESULTS: Thrombectomy reduced the severity of disability over the range of the modified Rankin scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval [CI], 1.05 to 2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90 days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% CI, 1.1 to 4.0). At 90 days, the rates of symptomatic intracranial hemorrhage were 1.9% in both the thrombectomy group and the control group (P=1.00), and rates of death were 18.4% and 15.5%, respectively (P=0.60). Registry data indicated that only eight patients who met the eligibility criteria were treated outside the trial at participating hospitals.
CONCLUSIONS: Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post-stroke disability and increased the rate of functional independence. (Funded by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien and others; REVASCAT ClinicalTrials.gov number, NCT01692379.).
2015 AHA/ASA Focused Update of the 2013 Guidelines for the Early Management of Patients With Acute Ischemic Stroke Regarding Endovascular Treatment: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. .
Saver JL, Jahan R, Levy EI, Jovin TG, Baxter B, Nogueira RG, Clark W, Budzik R, Zaidat OO; SWIFT Trialists.
Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial.
Lancet. 2012 Oct 6;380(9849):1241-9. doi: 10.1016/S0140-6736(12)61384-1. Epub 2012 Aug 26.
Abstract/Text
BACKGROUND: The Solitaire Flow Restoration Device is a novel, self-expanding stent retriever designed to yield rapid flow restoration in acute cerebral ischaemia. We compared the efficacy and safety of Solitaire with the standard, predicate mechanical thrombectomy device, the Merci Retrieval System.
METHODS: In this randomised, parallel-group, non-inferiority trial, we enrolled patients from 18 sites (17 in the USA and one in France). Patients were eligible for inclusion if they had acute ischaemic stroke with moderate to severe neurological deficits and were treatable by thrombectomy within 8 h of stroke symptom onset. We used a computer-generated randomisation sequence to randomly allocate patients to receive thrombectomy treatment with either Solitaire or Merci (1:1; block sizes of four and stratified by centre and stroke severity). The primary endpoint was Thrombolysis In Myocardial Ischemia (TIMI) scale 2 or 3 flow in all treatable vessels without symptomatic intracranial haemorrhage, after up to three passes of the assigned device, as assessed by an independent core laboratory, which was masked to study assignment. Primary analysis was done by intention to treat. A prespecified efficacy stopping rule triggered an early halt to the trial. The study is registered with ClinicalTrials.gov, number NCT 01054560.
RESULTS: Between February, 2010, and February, 2011, we randomly allocated 58 patients to the Solitaire group and 55 patients to the Merci group. The primary efficacy outcome was achieved more often in the Solitaire group than it was in the Merci group (61%vs 24%; difference 37% [95% CI 19-53], odds ratio [OR] 4·87 [95% CI 2·14-11·10]; p(non-inferiority)<0·0001, p(superiority)=0·0001). More patients had good 3-month neurological outcome with Solitaire than with Merci (58%vs 33%; difference 25% [6-43], OR 2·78 [1·25-6·22]; p(non-inferiority)=0·0001, p(superiority)=0·02). 90-day mortality was lower in the Solitaire group than it was in the Merci group (17 vs 38; difference -21% [-39 to -3], OR 0·34 [0·14-0·81]; p(non-inferiority)=0·0001, p(superiority)=0·02).
INTERPRETATION: The Solitaire Flow Restoration Device achieved substantially better angiographic, safety, and clinical outcomes than did the Merci Retrieval System. The Solitaire device might be a future treatment of choice for endovascular recanalisation in acute ischaemic stroke.
FUNDING: Covidien/ev3.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Nogueira RG, Lutsep HL, Gupta R, Jovin TG, Albers GW, Walker GA, Liebeskind DS, Smith WS; TREVO 2 Trialists.
Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial.
Lancet. 2012 Oct 6;380(9849):1231-40. doi: 10.1016/S0140-6736(12)61299-9. Epub 2012 Aug 26.
Abstract/Text
BACKGROUND: Present mechanical devices are unable to achieve recanalisation in up to 20-40% of large vessel occlusion strokes. We compared efficacy and safety of the Trevo Retriever, a new stent-like device, with its US Food and Drug Administration-cleared predecessor, the Merci Retriever.
METHODS: In this open-label randomised controlled trial, we recruited patients at 26 sites in the USA and one in Spain. We included adults aged 18-85 years with angiographically confirmed large vessel occlusion strokes and US National Institutes of Health Stroke Scale (NIHSS) scores of 8-29 within 8 h of symptom onset. We randomly assigned patients (1:1) with sequentially numbered sealed envelopes to thrombectomy with Trevo or Merci devices. Randomisation was stratified by age (≤68 years vs 69-85 years) and NIHSS scores (≤18 vs 19-29) with alternating blocks of various sizes. The primary efficacy endpoint, assessed by an unmasked core laboratory, was thrombolysis in cerebral infarction (TICI) scores of 2 or greater reperfusion with the assigned device alone. The primary safety endpoint was a composite of procedure-related adverse events. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01270867.
FINDINGS: Between Feb 3, 2011, and Dec 1, 2011, we randomly assigned 88 patients to the Trevo Retriever group and 90 patients to Merci Retriever group. 76 (86%) patients in the Trevo group and 54 (60%) in the Merci group met the primary endpoint after the assigned device was used (odds ratio 4·22, 95% CI 1·92-9·69; p(superiority)<0·0001). Incidence of the primary safety endpoint did not differ between groups (13 [15%] patients in the Trevo group vs 21 [23%] in the Merci group; p=0·1826).
INTERPRETATION: Patients who have had large vessel occlusion strokes but are ineligible for (or refractory to) intravenous tissue plasminogen activator should be treated with the Trevo Retriever in preference to the Merci Retriever.
FUNDING: Stryker Neurovascular.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Shinohara Y, Saito I, Kobayashi S, Uchiyama S.
Edaravone (radical scavenger) versus sodium ozagrel (antiplatelet agent) in acute noncardioembolic ischemic stroke (EDO trial).
Cerebrovasc Dis. 2009;27(5):485-92. doi: 10.1159/000210190. Epub 2009 Mar 26.
Abstract/Text
BACKGROUND: Edaravone, a free radical scavenger approved by the Japanese Ministry of Health, Labor and Welfare in 2001 for treating acute ischemic stroke, was recommended by the Japanese Guidelines for the Management of Stroke 2004. While edaravone also has a neuroprotective profile, there is no other recognized drug that can verify its effect in clinical trials despite the need for neuroprotection. We performed a postmarketing clinical trial to provide further reliable evidence concerning edaravone in patients with acute ischemic stroke.
METHODS: We conducted a multicenter randomized parallel-group open-label trial of edaravone intravenously and a control drug, sodium ozagrel (ozagrel), a thromboxane A(2) synthase inhibitor, intravenously in acute noncardioembolic ischemic stroke. The primary endpoint was the modified Rankin Scale at 3 months after treatment initiation.
RESULTS: In total, 401 patients were initially enrolled. The rate of 'grade 0-1' on the modified Rankin Scale, as assessed at 3 months, was 57.1 and 50.3% in the edaravone and ozagrel groups, respectively. The intergroup difference was 6.8% (95% confidence interval = -3.1 to 16.7), indicating noninferiority of edaravone to ozagrel, since the lower limit of the confidence interval did not exceed -11.4%. There were no particular concerns over the safety of edaravone.
CONCLUSION: This trial verified that edaravone was not inferior to ozagrel. Edaravone was at least as effective as ozagrel for the treatment of acute noncardioembolic ischemic stroke.
Copyright 2009 S. Karger AG, Basel.
Edaravone Acute Infarction Study Group.
Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters.
Cerebrovasc Dis. 2003;15(3):222-9. doi: 10.1159/000069318.
Abstract/Text
Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.
Jüttler E, Schwab S, Schmiedek P, Unterberg A, Hennerici M, Woitzik J, Witte S, Jenetzky E, Hacke W; DESTINY Study Group.
Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY): a randomized, controlled trial.
Stroke. 2007 Sep;38(9):2518-25. doi: 10.1161/STROKEAHA.107.485649. Epub 2007 Aug 9.
Abstract/Text
BACKGROUND AND PURPOSE: Decompressive surgery (hemicraniectomy) for life-threatening massive cerebral infarction represents a controversial issue in neurocritical care medicine. We report here the 30-day mortality and 6- and 12-month functional outcomes from the DESTINY trial.
METHODS: DESTINY (ISRCTN01258591) is a prospective, multicenter, randomized, controlled, clinical trial based on a sequential design that used mortality after 30 days as the first end point. When this end point was reached, patient enrollment was interrupted as per protocol until recalculation of the projected sample size was performed on the basis of the 6-month outcome (primary end point=modified Rankin Scale score, dichotomized to 0 to 3 versus 4 to 6). All analyses were based on intention to treat.
RESULTS: A statistically significant reduction in mortality was reached after 32 patients had been included: 15 of 17 (88%) patients randomized to hemicraniectomy versus 7 of 15 (47%) patients randomized to conservative therapy survived after 30 days (P=0.02). After 6 and 12 months, 47% of patients in the surgical arm versus 27% of patients in the conservative treatment arm had a modified Rankin Scale score of 0 to 3 (P=0.23).
CONCLUSIONS: DESTINY showed that hemicraniectomy reduces mortality in large hemispheric stroke. With 32 patients included, the primary end point failed to demonstrate statistical superiority of hemicraniectomy, and the projected sample size was calculated to 188 patients. Despite this failure to meet the primary end point, the steering committee decided to terminate the trial in light of the results of the joint analysis of the 3 European hemicraniectomy trials.
Hofmeijer J, Kappelle LJ, Algra A, Amelink GJ, van Gijn J, van der Worp HB; HAMLET investigators.
Surgical decompression for space-occupying cerebral infarction (the Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial [HAMLET]): a multicentre, open, randomised trial.
Lancet Neurol. 2009 Apr;8(4):326-33. doi: 10.1016/S1474-4422(09)70047-X. Epub 2009 Mar 5.
Abstract/Text
BACKGROUND: Patients with space-occupying hemispheric infarctions have a poor prognosis, with case fatality rates of up to 80%. In a pooled analysis of randomised trials, surgical decompression within 48 h of stroke onset reduced case fatality and improved functional outcome; however, the effect of surgery after longer intervals is unknown. The aim of HAMLET was to assess the effect of decompressive surgery within 4 days of the onset of symptoms in patients with space-occupying hemispheric infarction.
METHODS: Patients with space-occupying hemispheric infarction were randomly assigned within 4 days of stroke onset to surgical decompression or best medical treatment. The primary outcome measure was the modified Rankin scale (mRS) score at 1 year, which was dichotomised between good (0-3) and poor (4-6) outcome. Other outcome measures were the dichotomy of mRS score between 4 and 5, case fatality, quality of life, and symptoms of depression. Analysis was by intention to treat. This trial is registered, ISRCTN94237756.
FINDINGS: Between November, 2002, and October, 2007, 64 patients were included; 32 were randomly assigned to surgical decompression and 32 to best medical treatment. Surgical decompression had no effect on the primary outcome measure (absolute risk reduction [ARR] 0%, 95% CI -21 to 21) but did reduce case fatality (ARR 38%, 15 to 60). In a meta-analysis of patients in DECIMAL (DEcompressive Craniectomy In MALignant middle cerebral artery infarction), DESTINY (DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY), and HAMLET who were randomised within 48 h of stroke onset, surgical decompression reduced poor outcome (ARR 16%, -0.1 to 33) and case fatality (ARR 50%, 34 to 66).
INTERPRETATION: Surgical decompression reduces case fatality and poor outcome in patients with space-occupying infarctions who are treated within 48 h of stroke onset. There is no evidence that this operation improves functional outcome when it is delayed for up to 96 h after stroke onset. The decision to perform the operation should depend on the emphasis patients and relatives attribute to survival and dependency.
Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, Amelink GJ, Schmiedeck P, Schwab S, Rothwell PM, Bousser MG, van der Worp HB, Hacke W; DECIMAL, DESTINY, and HAMLET investigators.
Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials.
Lancet Neurol. 2007 Mar;6(3):215-22. doi: 10.1016/S1474-4422(07)70036-4.
Abstract/Text
BACKGROUND: Malignant infarction of the middle cerebral artery (MCA) is associated with an 80% mortality rate. Non-randomised studies have suggested that decompressive surgery reduces this mortality without increasing the number of severely disabled survivors. To obtain sufficient data as soon as possible to reliably estimate the effects of decompressive surgery, results from three European randomised controlled trials (DECIMAL, DESTINY, HAMLET) were pooled. The trials were ongoing when the pooled analysis was planned.
METHODS: Individual data for patients aged between 18 years and 60 years, with space-occupying MCA infarction, included in one of the three trials, and treated within 48 h after stroke onset were pooled for analysis. The protocol was designed prospectively when the trials were still recruiting patients and outcomes were defined without knowledge of the results of the individual trials. The primary outcome measure was the score on the modified Rankin scale (mRS) at 1 year dichotomised between favourable (0-4) and unfavourable (5 and death) outcome. Secondary outcome measures included case fatality rate at 1 year and a dichotomisation of the mRS between 0-3 and 4 to death. Data analysis was done by an independent data monitoring committee.
FINDINGS: 93 patients were included in the pooled analysis. More patients in the decompressive-surgery group than in the control group had an mRSINTERPRETATION: In patients with malignant MCA infarction, decompressive surgery undertaken within 48 h of stroke onset reduces mortality and increases the number of patients with a favourable functional outcome. The decision to perform decompressive surgery should, however, be made on an individual basis in every patient.
日本脳卒中学会 脳卒中ガイドライン委員会 編：脳卒中治療ガイドライン2021[改訂2023]．協和企画、2023.
Righetti E, Celani MG, Cantisani T, Sterzi R, Boysen G, Ricci S.
Glycerol for acute stroke.
Cochrane Database Syst Rev. 2004;2004(2):CD000096. doi: 10.1002/14651858.CD000096.pub2.
Abstract/Text
BACKGROUND: Brain oedema is a major cause of early death after stroke. A 10% solution of glycerol is a hyperosmolar agent that is claimed to reduce brain oedema.
OBJECTIVES: To determine whether intravenous (I.V.) glycerol treatment in acute stroke, either ischaemic or haemorrhagic, influences death rates and functional outcome in the short or long term, and whether the treatment is safe.
SEARCH STRATEGY: The Cochrane Stroke Group trials register was searched (January 2003), and some trialists were personally contacted.
SELECTION CRITERIA: All completed, randomised and quasi-randomised, controlled, published and unpublished comparisons, evaluating clinical outcome in which I.V. glycerol treatment was initiated within the first days after stroke onset.
DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria, assessed the trial quality and extracted data and this was checked with all co-reviewers. Death from all causes, functional outcome, and adverse effects were analysed.
MAIN RESULTS: Eleven completed, randomised trials comparing I.V. glycerol and control were considered. Analysis of death during the scheduled treatment period for acute ischaemic and/or haemorrhagic stroke was possible in 10 trials where 482 glycerol treated patients were compared with 463 control patients. Glycerol was associated with a non-significant reduction in the odds of death within the scheduled treatment period (Odds Ratio (OR) 0.78, 95% Confidence Intervals (CI) 0.58 to 1.06). Among patients with definite or probable ischaemic stroke, glycerol was associated with a significant reduction in the odds of death during the scheduled treatment period (OR 0.65, 95% CI 0.44 to 0.97). However, at the end of the scheduled follow up period, there was no significant difference in the odds of death (OR 0.98, 95% CI 0.73 to 1.31). Functional outcome was reported in only two studies but there were non-significantly more patients who had a good outcome at the end of scheduled follow up (OR 0.73, 95% CI 0.37 to 1.42). Haemolysis seems to be the only relevant adverse effect of glycerol treatment.
REVIEWERS' CONCLUSIONS: This systematic review suggests a favourable effect of glycerol treatment on short term survival in patients with probable or definite ischaemic stroke but the confidence intervals were wide and the magnitude of the treatment effect may be only minimal. Due to the relatively small number of patients, and that the trials were performed in the pre-CT era, the results must be interpreted cautiously. The lack of evidence of benefit in long term survival does not support the routine or selective use of glycerol treatment in patients with acute stroke.
Vahedi K, Vicaut E, Mateo J, Kurtz A, Orabi M, Guichard JP, Boutron C, Couvreur G, Rouanet F, Touzé E, Guillon B, Carpentier A, Yelnik A, George B, Payen D, Bousser MG; DECIMAL Investigators.
Sequential-design, multicenter, randomized, controlled trial of early decompressive craniectomy in malignant middle cerebral artery infarction (DECIMAL Trial).
Stroke. 2007 Sep;38(9):2506-17. doi: 10.1161/STROKEAHA.107.485235. Epub 2007 Aug 9.
Abstract/Text
BACKGROUND AND PURPOSE: There is no effective medical treatment of malignant middle cerebral artery (MCA) infarction. The purpose of this clinical trial was to assess the efficacy of early decompressive craniectomy in patients with malignant MCA infarction.
METHODS: We conducted in France a multicenter, randomized trial involving patients between 18 and 55 years of age with malignant MCA infarction to compare functional outcomes with or without decompressive craniectomy. A sequential, single-blind, triangular design was used to compare the rate of development of moderate disability (modified Rankin scale score < or =3) at 6 months' follow-up (primary outcome) between the 2 treatment groups.
RESULTS: After randomization of 38 patients, the data safety monitoring committee recommended stopping the trial because of slow recruitment and organizing a pooled analysis of individual data from this trial and the 2 other ongoing European trials of decompressive craniectomy in malignant MCA infarction. Among the 38 patients randomized, the proportion of patients with a modified Rankin scale score < or =3 at the 6-month and 1-year follow-up was 25% and 50%, respectively, in the surgery group compared with 5.6% and 22.2%, respectively, in the no-surgery group (P=0.18 and P=0.10, respectively). There was a 52.8% absolute reduction of death after craniectomy compared with medical therapy only (P<0.0001).
CONCLUSIONS: In this trial, early decompressive craniectomy increased by more than half the number of patients with moderate disability and very significantly reduced (by more than half) the mortality rate compared with that after medical therapy.
Hofmeijer J, Amelink GJ, Algra A, van Gijn J, Macleod MR, Kappelle LJ, van der Worp HB; HAMLET investigators.
Hemicraniectomy after middle cerebral artery infarction with life-threatening Edema trial (HAMLET). Protocol for a randomised controlled trial of decompressive surgery in space-occupying hemispheric infarction.
Trials. 2006 Sep 11;7:29. doi: 10.1186/1745-6215-7-29. Epub 2006 Sep 11.
Abstract/Text
BACKGROUND: Patients with a hemispheric infarct and massive space-occupying brain oedema have a poor prognosis. Despite maximal conservative treatment, the case fatality rate may be as high as 80%, and most survivors are left severely disabled. Non-randomised studies suggest that decompressive surgery reduces mortality substantially and improves functional outcome of survivors. This study is designed to compare the efficacy of decompressive surgery to improve functional outcome with that of conservative treatment in patients with space-occupying supratentorial infarction
METHODS: The study design is that of a multi-centre, randomised clinical trial, which will include 112 patients aged between 18 and 60 years with a large hemispheric infarct with space-occupying oedema that leads to a decrease in consciousness. Patients will be randomised to receive either decompressive surgery in combination with medical treatment or best medical treatment alone. Randomisation will be stratified for the intended mode of conservative treatment (intensive care or stroke unit care). The primary outcome measure will be functional outcome, as determined by the score on the modified Rankin Scale, at one year.
小笠原邦昭、甲州啓二、長嶺義秀、他：重症小脳梗塞に対する外科的減圧術．Neurological Surgery 1995；23：43-48.
大川弥生、上田敏：脳卒中片麻痺患者の廃用性筋萎縮に関する研究「健側」の筋力低下について．リハビリテーション医学 1988；25：143-147.
近藤克則、太田正：脳卒中早期リハビリテーション患者の下肢筋断面積の経時的変化 廃用性筋萎縮と回復経過．リハビリテーション医学 1997；34：129-133.
前田真治、長沢弘、平賀よしみ、他：発症当日からの脳内出血・脳梗塞リハビリテーション．リハビリテーション医学 1993；30：191-200.
Hayes SH, Carroll SR.
Early intervention care in the acute stroke patient.
Arch Phys Med Rehabil. 1986 May;67(5):319-21.
Abstract/Text
Early intervention care has been identified as an important factor in the functional outcome of patients with completed stroke. Little has been published, however, on the efficacy of early intervention in the acute hospital setting. In a retrospective study of 30 patients in an acute care hospital, there was a statistically significant difference in length of stay and ambulatory status (p less than 0.05) for the group receiving rehabilitation treatment within the first 72 hours after admission. There was no significant difference between the two groups with regard to age, sex, site of lesion, or previous cardiovascular disease. The present study indicates that early intervention shortens hospital stay and improves outcome, considerations especially important with the adoption of Diagnosis-Related Groups (DRGs), as hospitals seek measures of cost-containment in the provision of quality cost-effective health care.
Bernhardt J, Dewey H, Thrift A, Collier J, Donnan G.
A very early rehabilitation trial for stroke (AVERT): phase II safety and feasibility.
Stroke. 2008 Feb;39(2):390-6. doi: 10.1161/STROKEAHA.107.492363. Epub 2008 Jan 3.
Abstract/Text
BACKGROUND AND PURPOSE: Very early rehabilitation, with an emphasis on mobilization, may contribute to improved outcomes after stroke. We hypothesized that a very early rehabilitation protocol would be safe and feasible.
METHODS: We performed a randomized, controlled trial with blinded outcome assessment. Patients at <24 hours after stroke were recruited from 2 Melbourne metropolitan stroke units. Patients were randomly assigned to receive standard care (SC) or SC plus very early mobilization (VEM) until discharge or 14 days (whichever was sooner). The primary safety outcome was the number of deaths at 3 months. The primary feasibility outcome was a higher "dose" of mobilization achieved in VEM. Secondary safety outcomes included adverse events (including falls and early neurologic deterioration), compliance with physiologic monitoring criteria, and patient fatigue after interventions. Secondary feasibility outcomes included "contamination" of standard care.
RESULTS: Overall, 18% of patients screened were suitable for recruitment. Seventy-one patients were recruited and randomized, with 2 dropouts by 12 months. The majority experienced ischemic strokes (87%). The group mean+/-SD age was 74.7+/-12.5 years, and 58% (n=41) had a National Institutes of Health Stroke Scale score >7. There was no significant difference in the number of deaths between groups (SC, 3 of 33; VEM, 8 of 38; P=0.20). Almost all deaths occurred in patients with severe stroke. Secondary safety outcomes were similar between groups. The intervention protocol was successfully delivered, achieving VEM dose targets (double SC, P=0.003) and faster time to first mobilization (P<0.001).
CONCLUSIONS: VEM of patients within 24 hours of acute stroke appears safe and feasible. Intervention efficacy and cost-effectiveness are currently being tested in a large randomized, controlled trial.
Sandercock P, Gubitz G, Foley P, Counsell C.
Antiplatelet therapy for acute ischaemic stroke.
Cochrane Database Syst Rev. 2003;(2):CD000029. doi: 10.1002/14651858.CD000029.
Abstract/Text
BACKGROUND: In patients with acute ischaemic stroke, platelets become activated. Antiplatelet therapy might reduce the volume of brain damaged by ischaemia and reduce the risk of early recurrent ischaemic stroke. This might reduce the risk of early death and improve long-term outcome in survivors. However, antiplatelet therapy might also increase the risk of fatal or disabling intracranial haemorrhage.
OBJECTIVES: The aim of this review is to assess the efficacy and safety of antiplatelet therapy in acute ischaemic stroke.
SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched August 2002), the Cochrane Controlled Trials Register (CCTR) (Cochrane Library Issue 1 2002), MEDLINE (June 1998-October 2001), and EMBASE (June 1998-February 2002). In 1998, for previous versions of this review, we searched the register of the Antiplatelet Trialists Collaboration, MedStrategy and contacted relevant drug companies.
SELECTION CRITERIA: Randomised trials comparing antiplatelet therapy (started within 14 days of the stroke) with control in patients with definite or presumed ischaemic stroke.
DATA COLLECTION AND ANALYSIS: Two reviewers independently applied the inclusion criteria and assessed trial quality, and for the included trials, extracted and cross-checked the data.
MAIN RESULTS: Nine trials involving 41,399 patients were included. Two trials testing aspirin 160 to 300 mg once daily started within 48 hours of onset contributed 98% of the data. The maximum follow-up was six months. With treatment, there was a significant decrease in death or dependency at the end of follow-up (OR = 0.94; 95% CI 0.91 to 0.98). In absolute terms, 13 more patients were alive and independent at the end of follow-up for every 1000 patients treated. Furthermore, treatment increased the odds of making a complete recovery from the stroke (OR = 1.06; 95% CI 1.01 to 1.11). In absolute terms, 10 more patients made a complete recovery for every 1000 patients treated. Antiplatelet therapy was associated with a small but definite excess of 2 symptomatic intracranial haemorrhages for every 1000 patients treated, but this was more than offset by a reduction of 7 recurrent ischaemic strokes and about one pulmonary embolus for every 1000 patients treated.
REVIEWER'S CONCLUSIONS: Antiplatelet therapy with aspirin 160 to 300 mg daily, given orally (or per rectum in patients who cannot swallow), and started within 48 hours of onset of presumed ischaemic stroke reduces the risk of early recurrent ischaemic stroke without a major risk of early haemorrhagic complications and improves long-term outcome.
Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC; CHANCE Investigators.
Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.
N Engl J Med. 2013 Jul 4;369(1):11-9. doi: 10.1056/NEJMoa1215340. Epub 2013 Jun 26.
Abstract/Text
BACKGROUND: Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke. Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone.
METHODS: In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to-treat analysis. Treatment differences were assessed with the use of a Cox proportional-hazards model, with study center as a random effect.
RESULTS: Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of hemorrhagic stroke was 0.3% in each group.
CONCLUSIONS: Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage. (Funded by the Ministry of Science and Technology of the People's Republic of China; CHANCE ClinicalTrials.gov number, NCT00979589.).
Lee YS, Bae HJ, Kang DW, Lee SH, Yu K, Park JM, Cho YJ, Hong KS, Kim DE, Kwon SU, Lee KB, Rha JH, Koo J, Han MG, Lee SJ, Lee JH, Jung SW, Lee BC, Kim JS.
Cilostazol in Acute Ischemic Stroke Treatment (CAIST Trial): a randomized double-blind non-inferiority trial.
Cerebrovasc Dis. 2011;32(1):65-71. doi: 10.1159/000327036. Epub 2011 May 25.
Abstract/Text
BACKGROUND: Aspirin is a proven antiplatelet agent in acute ischemic stroke, and there are no current guidelines for other antiplatelet treatments. We aimed to compare the efficacy and safety of cilostazol with aspirin in acute stroke.
METHODS: Patients with measurable neurological deficits (NIHSS score ≤15) within 48 h of onset were randomly assigned to cilostazol (200 mg/day) or aspirin (300 mg/day) for 90 days. The primary endpoint was a modified Rankin Scale (mRS) score of 0-2 at 90 days. Cardiovascular events, bleeding complications, and other functional outcomes were also assessed. Statistical analysis was carried out by intention-to-treat and per-protocol bases. This trial is registered with ClinicalTrials.gov (NCT00272454).
RESULTS: In total, 458 patients were enrolled (mean age of 63 years, median NIHSS of 3), and mRS at 90 days was obtained in 447 patients. The primary endpoint was achieved in 76% (173/228) of those randomized to cilostazol and in 75% (165/219) assigned to aspirin, which supported the pre-specified non-inferiority of cilostazol to aspirin (95% CI of proportion difference: -6.15 to 7.22%, p = 0.0004). These results were also supported by per-protocol analysis (p = 0.045). Cardiovascular events occurred in 6 patients (3%) treated with cilostazol, and in 9 patients (4%) treated with aspirin (p = 0.41). Adverse events were more common in cilostazol-treated patients during the trial (91 vs. 85%, p = 0.055), while the frequencies of bleeding complications (cilostazol 11%, aspirin 13%, p = 0.43) or drug discontinuation (cilostazol 10%, aspirin 7%, p = 0.32) were not different.
CONCLUSION: Cilostazol is feasible in acute ischemic stroke, and comparable to aspirin in its efficacy and safety.
Copyright © 2011 S. Karger AG, Basel.
Nakamura T, Tsuruta S, Uchiyama S.
Cilostazol combined with aspirin prevents early neurological deterioration in patients with acute ischemic stroke: a pilot study.
J Neurol Sci. 2012 Feb 15;313(1-2):22-6. doi: 10.1016/j.jns.2011.09.038. Epub 2011 Oct 19.
Abstract/Text
Recent randomized trials have shown that cilostazol is superior to aspirin for secondary stroke prevention. We hypothesized that combining cilostazol with aspirin is more effective than aspirin alone in patients with acute ischemic stroke. This randomized study compared the effects of oral aspirin alone to aspirin plus cilostazol in patients with non-cardioembolic ischemic stroke within 48 h of stroke onset. NIH Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores were checked before and after 14 days and 6 months of drug administration. The primary and secondary endpoints were neurological deterioration or stroke recurrence (NIHSS score ≥ 1) within 14 days and 6 months, respectively. For statistical analysis, on-treatment analysis was conducted. Seventy-six patients were enrolled in the study. The primary endpoint was significantly higher in the aspirin group than in the aspirin plus cilostazol group (28% vs. 6%, relative risk (RR): 0.21, 95% confidence intervals (CI): 0.05-0.87, p=0.013). Among the patients who did not reach these endpoints, the mean improvement in the NIHSS score at day 14 tended to be better (-1.8 ± 1.2 vs. -1.2 ± 1.0, p=0.078) and the frequency of the favorable functional status of mRS 0-1 at month 6 was significantly higher (RR: 1.48, 95% CI: 1.07-2.06, p=0.0048) in the aspirin plus cilostazol group than in the aspirin group. Patients treated with aspirin plus cilostazol during the acute phase of stroke had less neurological deterioration and more favorable functional status than those treated with aspirin alone.
Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.
Aoki J, Iguchi Y, Urabe T, Yamagami H, Todo K, Fujimoto S, Idomari K, Kaneko N, Iwanaga T, Terasaki T, Tanaka R, Yamamoto N, Tsujino A, Nomura K, Abe K, Uno M, Okada Y, Matsuoka H, Yamagata S, Yamamoto Y, Yonehara T, Inoue T, Yagita Y, Kimura K; ADS Investigators.
Acute Aspirin Plus Cilostazol Dual Therapy for Noncardioembolic Stroke Patients Within 48 Hours of Symptom Onset.
J Am Heart Assoc. 2019 Aug 6;8(15):e012652. doi: 10.1161/JAHA.119.012652. Epub 2019 Jul 26.
Abstract/Text
Background The aim of the present study was to investigate the efficacy and safety of antiplatelet (aspirin plus cilostazol) dual therapy for patients with noncardioembolic stroke within 48 hours of symptom onset. Methods and Results The ADS (Acute Aspirin Plus Cilostazol Dual Therapy for Non-Cardiogenic Stroke Patients Within 48 Hours of Symptom Onset ) study is an investigator-initiated, prospective, multicenter (34 hospitals in Japan), randomized, open-label, and aspirin-controlled trial. Acute stroke patients with noncardioembolic stroke within 48 hours of onset were studied. The subjects were randomly allocated to combination therapy with aspirin 81 to 200 mg plus cilostazol 200 mg (dual group) and single therapy with aspirin 81 to 200 mg (aspirin group) for 14 days. After the 14 days, all patients took the cilostazol 200 mg for 3 months. A primary efficacy outcome was defined as any one of the following occurring (neurological deterioration, symptomatic stroke recurrence, or transient ischemic attack) within 14 days. A primary safety outcome included intracerebral hemorrhage and subarachnoid hemorrhage. Between May 2011 and June 2017, 1201 patients (796 [66%] men; median age, 69 [61-77] years) randomized 1:1 to either the dual group or the aspirin group were analyzed. Initial National Institutes of Health Stroke Scale score was 2 (1-4) in both groups (P=0.830). A primary efficacy outcome was observed in 11% in the dual group and 11% in the aspirin group (P=0.853). A primary safety outcome occurred in 2 (0.3%) in the dual group and in 1 (0.2%) in the aspirin group (P=0.624). Conclusions Dual antiplatelet therapy using cilostazol and aspirin was safe but did not reduce the rate of short-term neurological worsening. Clinical Trial Registration URL: umin.ac.jp/ctr/index/htm. Unique identifier: UMIN000004950.
Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, Held P, Jonasson J, Minematsu K, Molina CA, Wang Y, Wong KS; SOCRATES Steering Committee and Investigators.
Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack.
N Engl J Med. 2016 Jul 7;375(1):35-43. doi: 10.1056/NEJMoa1603060. Epub 2016 May 10.
Abstract/Text
BACKGROUND: Ticagrelor may be a more effective antiplatelet therapy than aspirin for the prevention of recurrent stroke and cardiovascular events in patients with acute cerebral ischemia.
METHODS: We conducted an international double-blind, controlled trial in 674 centers in 33 countries, in which 13,199 patients with a nonsevere ischemic stroke or high-risk transient ischemic attack who had not received intravenous or intraarterial thrombolysis and were not considered to have had a cardioembolic stroke were randomly assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive either ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2 through 90) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2 through 90). The primary end point was the time to the occurrence of stroke, myocardial infarction, or death within 90 days.
RESULTS: During the 90 days of treatment, a primary end-point event occurred in 442 of the 6589 patients (6.7%) treated with ticagrelor, versus 497 of the 6610 patients (7.5%) treated with aspirin (hazard ratio, 0.89; 95% confidence interval [CI], 0.78 to 1.01; P=0.07). Ischemic stroke occurred in 385 patients (5.8%) treated with ticagrelor and in 441 patients (6.7%) treated with aspirin (hazard ratio, 0.87; 95% CI, 0.76 to 1.00). Major bleeding occurred in 0.5% of patients treated with ticagrelor and in 0.6% of patients treated with aspirin, intracranial hemorrhage in 0.2% and 0.3%, respectively, and fatal bleeding in 0.1% and 0.1%.
CONCLUSIONS: In our trial involving patients with acute ischemic stroke or transient ischemic attack, ticagrelor was not found to be superior to aspirin in reducing the rate of stroke, myocardial infarction, or death at 90 days. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT01994720.).
Johnston SC, Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson M, Ladenvall P, Molina CA, Wang Y; THALES Investigators.
Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA.
N Engl J Med. 2020 Jul 16;383(3):207-217. doi: 10.1056/NEJMoa1916870.
Abstract/Text
BACKGROUND: Trials have evaluated the use of clopidogrel and aspirin to prevent stroke after an ischemic stroke or transient ischemic attack (TIA). In a previous trial, ticagrelor was not better than aspirin in preventing vascular events or death after stroke or TIA. The effect of the combination of ticagrelor and aspirin on prevention of stroke has not been well studied.
METHODS: We conducted a randomized, placebo-controlled, double-blind trial involving patients who had had a mild-to-moderate acute noncardioembolic ischemic stroke, with a National Institutes of Health Stroke Scale (NIHSS) score of 5 or less (range, 0 to 42, with higher scores indicating more severe stroke), or TIA and who were not undergoing thrombolysis or thrombectomy. The patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive a 30-day regimen of either ticagrelor (180-mg loading dose followed by 90 mg twice daily) plus aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily) or matching placebo plus aspirin. The primary outcome was a composite of stroke or death within 30 days. Secondary outcomes were first subsequent ischemic stroke and the incidence of disability within 30 days. The primary safety outcome was severe bleeding.
RESULTS: A total of 11,016 patients underwent randomization (5523 in the ticagrelor-aspirin group and 5493 in the aspirin group). A primary-outcome event occurred in 303 patients (5.5%) in the ticagrelor-aspirin group and in 362 patients (6.6%) in the aspirin group (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P = 0.02). Ischemic stroke occurred in 276 patients (5.0%) in the ticagrelor-aspirin group and in 345 patients (6.3%) in the aspirin group (hazard ratio, 0.79; 95% CI, 0.68 to 0.93; P = 0.004). The incidence of disability did not differ significantly between the two groups. Severe bleeding occurred in 28 patients (0.5%) in the ticagrelor-aspirin group and in 7 patients (0.1%) in the aspirin group (P = 0.001).
CONCLUSIONS: Among patients with a mild-to-moderate acute noncardioembolic ischemic stroke (NIHSS score ≤5) or TIA who were not undergoing intravenous or endovascular thrombolysis, the risk of the composite of stroke or death within 30 days was lower with ticagrelor-aspirin than with aspirin alone, but the incidence of disability did not differ significantly between the two groups. Severe bleeding was more frequent with ticagrelor. (Funded by AstraZeneca; THALES ClinicalTrial.gov number, NCT03354429.).
Copyright © 2020 Massachusetts Medical Society.
Medranda GA, Zhang C, Doros G, Yerasi C, Case BC, Weintraub WS, Waksman R.
Meta-Analysis of Usefulness of Antiplatelet Therapy in Ischemic Stroke or Transient Ischemic Attack.
Am J Cardiol. 2021 Aug 15;153:129-134. doi: 10.1016/j.amjcard.2021.05.028. Epub 2021 Jul 2.
Abstract/Text
The efficacy of early administration of dual antiplatelet therapy (DAPT) for secondary prevention after acute ischemic stroke or transient ischemic attack (TIA) is uncertain. This systematic review and meta-analysis compares the safety and efficacy of early administration (<24 hours) of DAPT (using either clopidogrel or ticagrelor with aspirin) versus single antiplatelet therapy (SAPT; aspirin alone) in acute non-cardioembolic ischemic stroke or TIA, incorporating data from large randomized controlled trials. Published trials fulfilling our criteria were identified from an electronic search of MEDLINE, with key words including: "clopidogrel or ticagrelor", "aspirin", "ischemic stroke", "transient ischemic attack", and "randomized controlled trial". Included were 3 randomized controlled trials of 21,067 patients assessing early administration (<24 hours from symptom onset) of DAPT versus SAPT in non-cardioembolic acute ischemic stroke or TIA. Our efficacy outcomes were ischemic stroke and all-cause mortality. Our safety outcome was severe bleeding. We performed a meta-analysis to pool results with a hierarchical Bayesian random-effects model. Dual antiplatelet therapy significantly reduced the risk of ischemic stroke (hazard ratio [HR], 0.73; 95% credible interval [CrI]: 0.54, 0.97), while increasing the risk of severe bleeding (HR, 2.48; 95% CrI: 1.07, 5.26). There was a non-significant numerical trend toward increased mortality with DAPT (HR, 1.29; 95% CrI: 0.73, 2.23). These observations were robust under the sensitivity analysis. In the present systematic review and meta-analysis of randomized controlled trials, DAPT reduced the risk of ischemic stroke at the cost of an increase in severe bleeding. Additional trials examining the ideal timing of DAPT administration are needed to thoroughly investigate the role, if any, of routine DAPT in patients with non-cardioembolic ischemic stroke or high-risk TIA.
Copyright © 2021 Elsevier Inc. All rights reserved.
Trifan G, Gorelick PB, Testai FD.
Efficacy and Safety of Using Dual Versus Monotherapy Antiplatelet Agents in Secondary Stroke Prevention: Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.
Circulation. 2021 Jun 22;143(25):2441-2453. doi: 10.1161/CIRCULATIONAHA.121.053782. Epub 2021 Apr 30.
Abstract/Text
BACKGROUND: Dual antiplatelet treatment (DAPT) with aspirin plus clopidogrel for a limited time is recommended after minor noncardioembolic stroke.
METHODS: We performed a meta-analysis of all major studies that compared the efficacy and safety of DAPT versus monotherapy for the secondary prevention of recurrent stroke or transient ischemic attack. The primary outcomes were stroke and the composite of stroke, transient ischemic attack, acute coronary syndrome, and death from any cause. The safety outcome was major hemorrhage. Relative risk (RR) and 95% CIs were calculated. Heterogeneity was assessed by I2 and Cochrane Q statistics.
RESULTS: The analysis included 27 358 patients, the quality of evidence was moderate to low, and the heterogeneity for all the comparisons was low (I2≤25%). Compared with monotherapy, DAPT reduced the risk of recurrent stroke (RR, 0.71 [95% CI, 0.63-0.81]) and composite outcome (RR, 0.76 [95% CI, 0.69-0.83]) but increased the risk of major bleeding (RR, 2.17 [95% CI, 1.45-3.25]). In the subgroup analysis, ≤30 days of DAPT increased the risk of hemorrhage relative to monotherapy (RR, 1.94 [95% CI, 1.08-3.52]). In the sensitivity analysis, the risk for hemorrhage with ≤30 days of DAPT after excluding the combination of aspirin plus ticagrelor was comparable to monotherapy (RR, 1.42 [95% CI, 0.77-2.60]). However, the risk for stroke recurrence and composite outcomes in the subgroup and sensitivity analyses remain decreased compared with monotherapy.
CONCLUSIONS: DAPT decreases the risk of recurrent stroke and composite events compared with monotherapy. DAPT increases the risk of major hemorrhage, except if the treatment is limited to 30 days and does not include the combination of aspirin plus ticagrelor.
Bhatia K, Jain V, Aggarwal D, Vaduganathan M, Arora S, Hussain Z, Uberoi G, Tafur A, Zhang C, Ricciardi M, Qamar A.
Dual Antiplatelet Therapy Versus Aspirin in Patients With Stroke or Transient Ischemic Attack: Meta-Analysis of Randomized Controlled Trials.
Stroke. 2021 Jun;52(6):e217-e223. doi: 10.1161/STROKEAHA.120.033033. Epub 2021 Apr 27.
Abstract/Text
BACKGROUND AND PURPOSE: Antiplatelet therapy is key for preventing thrombotic events after transient ischemic attack or ischemic stroke. Although the role of aspirin is well established, there is emerging evidence for the role of short-term dual antiplatelet therapy (DAPT) in preventing recurrent stroke.
METHODS: We conducted a systematic review and study-level meta-analyses of randomized controlled trials comparing outcomes of early initiation of short-term DAPT (aspirin+P2Y12 inhibitor for up to 3 months) versus aspirin alone in patients with acute stroke or transient ischemic attack. Primary efficacy outcome was risk of recurrent stroke and primary safety outcome was incidence of major bleeding. Secondary outcomes studied were risk of any ischemic stroke, hemorrhagic stroke, major adverse cardiovascular events, and all-cause death. Pooled risk ratios (RRs) and CIs were calculated using a random-effects model.
RESULTS: Four trials with a total of 21 459 patients were included. As compared to aspirin alone, DAPT had a lower risk of recurrent stroke (RR, 0.76 [95% CI, 0.68–0.83]; P<0.001; I2=0%) but a higher risk of major bleeding events (RR, 2.22 [95% CI, 1.14–4.34], P=0.02, I2=46.5%). Patients receiving DAPT had a lower risk of major adverse cardiovascular events (RR, 0.76 [95% CI, 0.69–0.84], P<0.001, I2=0%) and recurrent ischemic events (RR, 0.74 [95% CI, 0.67–0.82], P<0.001, I2=0%).
CONCLUSIONS: As compared to aspirin alone, short-term DAPT within 24 hours of high-risk transient ischemic attack or mild-moderate ischemic stroke reduces the risk of recurrent stroke at the expense of higher risk of major bleeding.
Li ZX, Xiong Y, Gu HQ, Fisher M, Xian Y, Johnston SC, Wang YJ.
P2Y12 Inhibitors Plus Aspirin Versus Aspirin Alone in Patients With Minor Stroke or High-Risk Transient Ischemic Attack.
Stroke. 2021 Jul;52(7):2250-2257. doi: 10.1161/STROKEAHA.120.033040. Epub 2021 May 27.
Abstract/Text
BACKGROUND AND PURPOSE: We performed a systemic review and meta-analysis to elucidate the effectiveness and safety of dual antiplatelet (DAPT) therapy with P2Y12 inhibitors (clopidogrel/ticagrelor) and aspirin versus aspirin monotherapy in patients with mild ischemic stroke or high-risk transient ischemic attack.
METHODS: Following Preferred Reported Items for Systematic Review and Meta-Analysis standards for meta-analyses, Medline, Embase, Cochrane Central Register of Controlled Trials, and the Cochrane Library were searched for randomized controlled trials that included patients with a diagnosis of an acute mild ischemic stroke or high-risk transient ischemic attack, intervention of DAPT therapy with clopidogrel/ticagrelor and aspirin versus aspirin alone from January 2012 to July 2020. The outcomes included subsequent stroke, all-cause mortality, cardiovascular death, hemorrhage (mild, moderate, or severe), and myocardial infarction. A DerSimonian-Laird random-effects model was used to estimate pooled risk ratio (RR) and corresponding 95% CI in R package meta. We assessed the heterogeneity of data across studies with use of the Cochran Q statistic and I2 test.
RESULTS: Four eligible trials involving 21 493 participants were included in the meta-analysis. DAPT therapy started within 24 hours of symptom onset reduced the risk of stroke recurrence by 24% (RR, 0.76 [95% CI, 0.68-0.83], I2=0%) but was not associated with a change in all-cause mortality (RR, 1.30 [95% CI, 0.90-1.89], I2=0%), cardiovascular death (RR, 1.34 [95% CI, 0.56-3.17], I2=0%), mild bleeding (RR, 1.25 [95% CI, 0.37-4.29], I2=94%), or myocardial infarction (RR, 1.45 [95% CI, 0.62-3.39], I2=0%). However, DAPT was associated with an increased risk of severe or moderate bleeding (RR, 2.17 [95% CI, 1.16-4.08], I2=41%); further sensitivity tests found that the association was limited to trials with DAPT treatment duration over 21 days (RR, 2.86 [95% CI, 1.75-4.67], I2=0%) or ticagrelor (RR, 2.17 [95% CI, 1.16-4.08], I2=37%) but not within 21 days or clopidogrel.
CONCLUSIONS: In patients with noncardioembolic mild stroke or high-risk transient ischemic attack, DAPT with aspirin and clopidogrel/ticagrelor is more effective than aspirin alone for recurrent stroke prevention with a small absolute increase in the risk of severe or moderate bleeding.
Ciccone A, Motto C, Abraha I, Cozzolino F, Santilli I.
Glycoprotein IIb-IIIa inhibitors for acute ischaemic stroke.
Cochrane Database Syst Rev. 2014 Mar 8;(3):CD005208. doi: 10.1002/14651858.CD005208.pub3. Epub 2014 Mar 8.
Abstract/Text
BACKGROUND: Glycoprotein (GP) IIb-IIIa inhibitors are antiplatelet agents that act by antagonising GP IIb-IIIa receptors on the platelet surface and block the final common pathway to platelet aggregation by preventing the binding of fibrinogen molecules that form bridges between adjacent platelets. Thus, GP IIb-IIIa inhibitors could favour endogenous thrombolysis by reducing thrombus growth and preventing thrombus re-formation through competitive inhibition with fibrinogen and, due to their mechanism of action, are likely to have a more profound antiplatelet effect with more rapid onset than conventional antiplatelet agents, such as aspirin or clopidogrel. Currently used in clinical practice for the treatment of individuals with acute coronary syndromes and during coronary angioplasty, GP IIb-IIIa inhibitors could also be useful for the treatment of people with acute ischaemic stroke.
OBJECTIVES: To assess the use of GP IIb-IIIa inhibitors in people with acute ischaemic stroke to evaluate whether such treatments (1) reduce the proportion of patients who die or remain dependent, and (2) are sufficiently safe for general use. We wished to examine the effects GP IIb-IIIa inhibitors alone or in combination with thrombolytic agents.
SEARCH METHODS: We searched the Cochrane Stroke Group trials register (last searched 10 June 2013), MEDLINE (1966 to June 2013), EMBASE (1980 to June 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 5, 2013), and major ongoing clinical trials registers (June 2013). We also searched reference lists and contacted trial authors and pharmaceutical companies.
SELECTION CRITERIA: We aimed to analyse unconfounded randomised controlled trials (RCTs) of GP IIb-IIIa inhibitors in the treatment of people with acute ischaemic stroke. Only individuals who started treatment within six hours of stroke onset were included.
DATA COLLECTION AND ANALYSIS: We independently selected trials for inclusion, assessed trial quality and extracted the data.
MAIN RESULTS: We included four trials involving 1365 participants. Three trials compared the intravenous GP IIb-IIIa inhibitor Abciximab with intravenous placebo (1215 participants) and one trial compared the intravenous GP IIb-IIIa inhibitor Tirofiban with intravenous aspirin (150 participants). Treatment with either of these GP IIb-IIIa inhibitors did not significantly reduce long-term death or dependency (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.77 to 1.22, for the comparison between Abciximab and placebo; OR 1.00, 95% CI 0.52 to 1.92, for the comparison between Tirofiban and aspirin) and had no effect on deaths from all causes (OR 1.08, 95% CI 0.77 to 1.53, for the comparison between Abciximab and placebo; OR 1.00, 95% CI 0.35 to 2.82, for the comparison between Tirofiban and aspirin). Abciximab was associated with a significant increase in symptomatic intracranial haemorrhage (OR 4.6, 95% CI 2.01 to 10.54) and with a non-significant increase in major extracranial haemorrhage (OR 1.81, 95% CI 0.96 to 3.41), whereas the only small trial comparing Tirofiban with aspirin showed no increased risk of bleeding complications with Tirofiban (OR 0.32, 95% CI 0.03 to 3.19, for symptomatic intracranial haemorrhage; OR 3.04, 95% CI 0.12 to 75.83, for major extracranial haemorrhages). There was no significant inconsistency across the studies.
AUTHORS' CONCLUSIONS: The available trial evidence showed that, for individuals with acute ischaemic stroke, GP IIb-IIIa inhibitors are associated with a significant risk of intracranial haemorrhage with no evidence of any reduction in death or disability in survivors. These data do not support their routine use in clinical practice. The conclusion is driven by trials of Abciximab, which contributed 89% of the total number of study participants considered.
Gong J, Shang J, Yu H, Wan Q, Su D, Sun Z, Liu G.
Tirofiban for acute ischemic stroke: systematic review and meta-analysis.
Eur J Clin Pharmacol. 2020 Apr;76(4):475-481. doi: 10.1007/s00228-019-02817-8. Epub 2020 Jan 3.
Abstract/Text
BACKGROUND: The safety and efficacy of tirofiban for patients with acute ischemic stroke (AIS) remains controversial. We therefore conducted a systematic review and meta-analysis.
METHODS: We searched PubMed, EMBASE, Cochrane Library, Web of Science, and related international clinical trials registries through March 31, 2019, using the terms "tirofiban" and "stroke". All apparently unconfounded randomized controlled trials (RCTs) and cohort studies with two arms comparing treatment with and without tirofiban for AIS were included in this review. Primary outcomes included symptomatic intracranial hemorrhage (sICH), fatal ICH, mortality, and modified Rankin Scale (mRS 0-2) at 3 months.
RESULTS: Seventeen studies including 2914 AIS patients were identified. Pooled results showed that tirofiban treatment in AIS did not increase the risk of sICH (OR, 0.95; 95% CI, 0.71-1.28; p = 0.75) or mortality (OR, 0.80; 95% CI; 0.64-1.02; p = 0.07). However, fatal ICH increased significantly in the tirofiban treatment group (OR, 2.84; 95% CI, 1.38-5.85; p = 0.005), and subgroup analysis showed that tirofiban via intra-arterial (IA) administration was associated with increased risk of fatal ICH (OR, 2.90; 95% CI, 1.12-7.55; p = 0.03), while intravenous (IV) administration was not (OR, 2.75; 95% CI, 0.92-8.20; p = 0.07). In addition, tirofiban showed no obvious improvement in functional outcome (mRS 0-2) (OR, 1.29; 95% CI, 0.97-1.71; p = 0.08).
CONCLUSION: Tirofiban seems to be safe in systemic treatment and may represent a potential choice for management of AIS. However, intra-arterial administration requires further adequately controlled studies in order to develop an appropriate protocol, similar to that in cardiology.
田崎義昭、小林祥泰、東儀英夫、他：脳血栓症急性期に対する抗トロンビン薬MD-805の臨床的有用性 プラセボを対照とした多施設二重盲検群間比較試験．医学のあゆみ 1992；161：887-907.
大友英一、沓沢尚之、小暮久也．脳血栓症急性期におけるOKY-046の臨床的有用性 プラセボを対照とした多施設二重盲検試験．臨床医薬 1991；7：353-388.
Toyoda K, Yasaka M, Iwade K, Nagata K, Koretsune Y, Sakamoto T, Uchiyama S, Gotoh J, Nagao T, Yamamoto M, Takahashi JC, Minematsu K; Bleeding with Antithrombotic Therapy (BAT) Study Group.
Dual antithrombotic therapy increases severe bleeding events in patients with stroke and cardiovascular disease: a prospective, multicenter, observational study.
Stroke. 2008 Jun;39(6):1740-5. doi: 10.1161/STROKEAHA.107.504993. Epub 2008 Apr 3.
Abstract/Text
BACKGROUND AND PURPOSE: We sought to determine the incidence and severity of bleeding events in patients with stroke and cardiovascular diseases who were taking oral antithrombotic agents in Japan, where the incidence of hemorrhagic stroke is higher than in Western countries.
METHODS: A prospective, multicenter, observational study was conducted; 4009 patients who were taking oral antithrombotic agents for stroke and cardiovascular diseases were enrolled. The patients were classified into 4 groups according to their antithrombotic treatment: the single antiplatelet agent group (47.2%); the dual antiplatelet agent group (8.7%); the warfarin group (32.4%); and the warfarin plus antiplatelet agent group (11.7%). The primary end point was life-threatening or major bleeding according to the MATCH trial definition.
RESULTS: During a median follow-up of 19 months, there were 57 life-threatening and 51 major bleeding events, including 31 intracranial hemorrhages. The annual incidence of the primary end point was 1.21% in the single antiplatelet agent group, 2.00% in the dual antiplatelet agent group, 2.06% in the warfarin group, and 3.56% in the warfarin plus antiplatelet agent group (P<0.001). After adjustment for baseline characteristics, adding an antiplatelet agent to warfarin increased the risk of the primary end point (relative risk=1.76; 95% CI, 1.05 to 2.95), and adding another antiplatelet agent to single antiplatelet agent therapy increased the secondary end point of any bleeding, including minor events (relative risk=1.37; 95% CI, 1.07 to 1.76).
CONCLUSIONS: The incidence of bleeding events during antithrombotic therapy in Japan was similar to that reported for Western countries, although the trials used different study designs. Dual antithrombotic therapy was independently related to an increased risk of bleeding events.
Toyoda K, Yasaka M, Uchiyama S, Nagao T, Gotoh J, Nagata K, Koretsune Y, Sakamoto T, Iwade K, Yamamoto M, Takahashi JC, Minematsu K; Bleeding with Antithrombotic Therapy (BAT) Study Group.
Blood pressure levels and bleeding events during antithrombotic therapy: the Bleeding with Antithrombotic Therapy (BAT) Study.
Stroke. 2010 Jul;41(7):1440-4. doi: 10.1161/STROKEAHA.110.580506. Epub 2010 May 20.
Abstract/Text
BACKGROUND AND PURPOSE: A prospective, multicenter, observational cohort study was conducted to clarify the association between major bleeding events and blood pressure (BP) levels during follow-up before development of bleeding events in antithrombotic users.
METHODS: A total of 4009 patients taking oral antithrombotic agents for cardiovascular or cerebrovascular diseases (2728 men, 69+/-10 years old) were followed. Changes in systolic and diastolic BPs between entry and the last clinic visit before intracranial hemorrhage (ICH) or extracranial hemorrhage were assessed.
RESULTS: Over a median follow-up of 19 months, ICH developed in 31 patients and extracranial hemorrhage developed in 77. Entry BP levels were similar among patients with ICH, those with extracranial hemorrhage, and those without hemorrhagic events. Both systolic BP and diastolic BP were relatively high during follow-up as compared with the levels at entry in patients with ICH, whereas they showed plateaus in patients with extracranial hemorrhage and patients without hemorrhagic events. Average systolic BP levels between 1 and 6 months (hazard ratio, 1.45; 95% CI, 1.08 to 1.92 per 10-mm Hg increase) and between 7 and 12 months (hazard ratio, 1.47; 95% CI, 1.05 to 2.01) as well as average diastolic BP levels between 7 and 12 months (hazard ratio, 2.05; 95% CI, 1.15 to 3.62) were independently associated with development of ICH after adjustment for established ICH predictors. The optimal cutoff BP level to predict impending risk of ICH was >or=130/81 mm Hg using receiver operating characteristic curve analysis.
CONCLUSIONS: An increase in BP levels during antithrombotic medication was positively associated with development of ICH, suggesting the importance of adequate BP control for avoiding ICH. BP levels did not appear to be associated with extracranial hemorrhage.
Toyoda K, Uchiyama S, Yamaguchi T, Easton JD, Kimura K, Hoshino H, Sakai N, Okada Y, Tanaka K, Origasa H, Naritomi H, Houkin K, Yamaguchi K, Isobe M, Minematsu K; CSPS.com Trial Investigators.
Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open-label, randomised controlled trial.
Lancet Neurol. 2019 Jun;18(6):539-548. doi: 10.1016/S1474-4422(19)30148-6.
Abstract/Text
BACKGROUND: Although dual antiplatelet therapy with aspirin and clopidogrel reduces early recurrence of ischaemic stroke, with long-term use this type of therapy is no longer effective and the risk of bleeding increases. Given that cilostazol prevents stroke recurrence without increasing the incidence of serious bleeding compared with aspirin, we aimed to establish whether dual antiplatelet therapy involving cilostazol is safe and appropriate for long-term use.
METHODS: In a multicentre, open-label, randomised controlled trial across 292 hospitals in Japan, patients with high-risk non-cardioembolic ischaemic stroke identified on MRI were randomly assigned to two groups in a 1:1 ratio to receive monotherapy with either oral aspirin (81 or 100 mg, once per day) or clopidogrel (50 or 75 mg, once per day) alone, or a combination of cilostazol (100 mg, twice per day) with aspirin or clopidogrel. Randomisation was done centrally (using block randomisation with a block size of six per each participating hospital) through a web-based registration system and was done by EPS Corporation. The patients were required to have at least 50% stenosis of a major intracranial or extracranial artery or two or more of the vascular risk factors. Trial medication was continued for half a year or longer, for a maximum of 3·5 years. The primary efficacy outcome was the rate of first recurrence of symptomatic ischaemic stroke. Safety outcomes were severe or life-threatening bleeding; any adverse events; serious adverse events; and any bleeding events. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in the as-treated population. This trial was registered with ClinicalTrials.gov (number NCT01995370) and UMIN Clinical Trials Registry (number 000012180).
FINDINGS: Participants were recruited from Dec 13, 2013, to March 31, 2017. 932 patients assigned to the dual therapy group and 947 patients assigned to the monotherapy group were included in the intention-to-treat analysis. The trial was stopped after the enrolment of 1884 patients of an anticipated 4000 patients because of the delay in recruitment. Ischaemic stroke recurred in 29 (3%) of 932 patients (annualised rate 2·2%) on dual therapy including cilostazol and 64 (7%) of 947 patients (annualised rate 4·5%) on monotherapy during a median 1·4 years follow-up (hazard ratio [HR] 0·49, 95% CI 0·31-0·76, p=0·0010). Severe or life-threatening bleeding occurred in eight patients (annualised rate 0·6%) on dual therapy and 13 patients (annualised rate 0·9%) on monotherapy (HR 0·66, 95% CI 0·27-1·60, p=0·35). Occurrence of any type of adverse event was similar between the groups (255 [28%] of 910 patients in the dual therapy group vs 219 [24%] of 921 patients in the monotherapy group); as was occurrence of serious adverse events (87 [10%] vs 142 [15%]) and bleeding events (38 [4%] vs 33 [4%]). Gastrointestinal bleeding, which affected nine (<1%) of 910 patients in the monotherapy group and nine (<1%) of 921 patients in the dual therapy group, was the most common type of bleeding.
INTERPRETATION: The combination of cilostazol with aspirin or clopidogrel had a reduced incidence of ischaemic stroke recurrence and a similar risk of severe or life-threatening bleeding compared with treatment with aspirin or clopidogrel alone in patients at high risk for recurrent ischaemic stroke.
FUNDING: Otsuka Pharmaceutical.
Copyright © 2019 Elsevier Ltd. All rights reserved.
堀正二、池田康夫、石丸新、ほか：循環器病の診断と治療に関するガイドライン（2008年度合同研究班報告）．循環器疾患における抗凝固・抗血小板療法に関するガイドライン（2009年改訂版）.
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The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group.
Lancet. 1997 May 31;349(9065):1569-81.
Abstract/Text
BACKGROUND: Only a few small trials have compared antithrombotic therapy (antiplatelet or anticoagulant agents) versus control in acute ischaemic stroke, and none has been large enough to provide reliable evidence on safety or efficacy.
METHODS: The International Stroke Trial (IST) was a large, randomised, open trial of up to 14 days of antithrombotic therapy started as soon as possible after stroke onset. The aim was to provide reliable evidence on the safety and efficacy of aspirin and of subcutaneous heparin. Half the patients were allocated unfractionated heparin (5000 or 12,500 IU bd [twice daily]), and half were allocated "avoid heparin"; and, in a factorial design, half were allocated aspirin 300 mg daily and half "avoid aspirin". The primary outcomes were death within 14 days and death or dependency at 6 months. 19,435 patients with suspected acute ischaemic stroke entering 467 hospitals in 36 countries were randomised within 48 hours of symptom onset.
RESULTS: Among heparin-allocated patients, there were non-significantly fewer deaths within 14 days (876 [9.0%] heparin vs 905 [9.3%] no heparin), corresponding to 3 (SD 4) fewer deaths per 1000 patients. At 6 months the percentage dead or dependent was identical in both groups (62.9%). Patients allocated to heparin had significantly fewer recurrent ischaemic strokes within 14 days (2.9% vs 3.8%) but this was offset by a similar-sized increase in haemorrhagic strokes (1.2% vs 0.4%), so the difference in death or non-fatal recurrent stroke (11.7% vs 12.0%) was not significant. Heparin was associated with a significant excess of 9 (SD 1) transfused or fatal extracranial bleeds per 1000. Compared with 5000 IU bd heparin, 12,500 IU bd heparin was associated with significantly more transfused or fatal extracranial bleeds, more haemorrhagic strokes, and more deaths or non-fatal strokes within 14 days (12.6% vs 10.8%). Among aspirin-allocated patients there were non-significantly fewer deaths within 14 days (872 [9.0%] vs 909 [9.4%]), corresponding to 4 (SD 4) fewer deaths per 1000 patients. At 6 months there was a non-significant trend towards a smaller percentage of the aspirin group being dead or dependent (62.2% vs 63.5%, 2p = 0.07), a difference of 13 (SD 7) per 1000; after adjustment for baseline prognosis the benefit from aspirin was significant (14 [SD 6] per 1000, 2p = 0.03). Aspirin-allocated patients had significantly fewer recurrent ischaemic strokes within 14 days (2.8% vs 3.9%) with no significant excess of haemorrhagic strokes (0.9% vs 0.8%), so the reduction in death or non-fatal recurrent stroke with aspirin (11.3% vs 12.4%) was significant. Aspirin was associated with a significant excess of 5 (SD 1) transfused or fatal extracranial bleeds per 1000; in the absence of heparin the excess was 2 (SD 1) and was not significant. There was no interaction between aspirin and heparin in the main outcomes.
INTERPRETATION: Neither heparin regimen offered any clinical advantage at 6 months. The results suggest that if heparin is given in routine clinical practice, the dose should not exceed 5000 IU subcutaneously twice daily. For aspirin, the IST suggests a small but worthwhile improvement at 6 months. Taking the IST together with the comparably large Chinese Acute Stroke Trial, aspirin produces a small but real reduction of about 10 deaths or recurrent strokes per 1000 during the first few weeks. Both trials suggest that aspirin should be started as soon as possible after the onset of ischaemic stroke; previous trials have already shown that continuation of low-dose aspirin gives protection in the longer term.
Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd.
Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.
Stroke. 1993 Jan;24(1):35-41. doi: 10.1161/01.str.24.1.35.
Abstract/Text
BACKGROUND AND PURPOSE: The etiology of ischemic stroke affects prognosis, outcome, and management. Trials of therapies for patients with acute stroke should include measurements of responses as influenced by subtype of ischemic stroke. A system for categorization of subtypes of ischemic stroke mainly based on etiology has been developed for the Trial of Org 10172 in Acute Stroke Treatment (TOAST).
METHODS: A classification of subtypes was prepared using clinical features and the results of ancillary diagnostic studies. "Possible" and "probable" diagnoses can be made based on the physician's certainty of diagnosis. The usefulness and interrater agreement of the classification were tested by two neurologists who had not participated in the writing of the criteria. The neurologists independently used the TOAST classification system in their bedside evaluation of 20 patients, first based only on clinical features and then after reviewing the results of diagnostic tests.
RESULTS: The TOAST classification denotes five subtypes of ischemic stroke: 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) stroke of other determined etiology, and 5) stroke of undetermined etiology. Using this rating system, interphysician agreement was very high. The two physicians disagreed in only one patient. They were both able to reach a specific etiologic diagnosis in 11 patients, whereas the cause of stroke was not determined in nine.
CONCLUSIONS: The TOAST stroke subtype classification system is easy to use and has good interobserver agreement. This system should allow investigators to report responses to treatment among important subgroups of patients with ischemic stroke. Clinical trials testing treatments for acute ischemic stroke should include similar methods to diagnose subtypes of stroke.
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Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators.
JAMA. 1998 Apr 22-29;279(16):1265-72.
Abstract/Text
CONTEXT: Anticoagulation with unfractionated heparin is used commonly for treatment of acute ischemic stroke, but its use remains controversial because it has not been shown to be effective or safe. Low molecular weight heparins and heparinoids have been shown to be effective in preventing deep vein thrombosis in persons with stroke, and they might be effective in reducing unfavorable outcomes following ischemic stroke.
OBJECTIVE: To test whether an intravenously administered low molecular weight heparinoid, ORG 10172 (danaparoid sodium), increases the likelihood of a favorable outcome at 3 months after acute ischemic stroke.
DESIGN: Randomized, double-blind, placebo-controlled, multicenter trial.
SETTING AND PARTICIPANTS: Between December 22, 1990, and December 6, 1997, 1281 persons with acute stroke were enrolled at 36 centers across the United States.
INTERVENTION: A 7-day course of ORG 10172 or placebo was given initially as a bolus within 24 hours of stroke, followed by continuous infusion in addition to the best medical care. Doses were adjusted in response to anti-factor Xa activity.
MAIN OUTCOME MEASURES: Favorable outcome rated as the combination of a Glasgow Outcome Scale score of I or II and a modified Barthel Index of 12 or greater on a scale of 0 to 20 at 3 months or 7 days; very favorable outcome was recorded for the combination of a Glasgow Outcome Scale of I and a Barthel Index of 19 or 20 at 3 months or 7 days.
RESULTS: At 3 months, 482 (75.2%) of 641 persons assigned to treatment with ORG 10172 and 467 (73.7%) of 634 patients treated with placebo had favorable outcomes (P=.49); 49.5% and 47%, respectively, of patients in each group had very favorable outcomes at 3 months. At 7 days, 376 (59.2%) of 635 persons given ORG 10172 and 344 (54.3%) of 633 receiving placebo had favorable outcomes (P=.07). For the same interval, 215 (33.9%) of 635 persons given ORG 10172 and 176 (27.8%) of 633 persons administered placebo had very favorable outcomes (P=.01; odds ratio, 1.36; 95% confidence interval, 1.06-1.73). Within 10 days of onset of treatment, serious intracranial bleeding events occurred in 14 patients given ORG 10172 (15 events) and in 4 placebo-treated patients (5 events) (P=.05).
CONCLUSION: Despite an apparent positive response to treatment at 7 days, emergent administration of the antithrombotic agent, ORG 10172, is not associated with an improvement in favorable outcome at 3 months.
Paciaroni M, Agnelli G, Micheli S, Caso V.
Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials.
Stroke. 2007 Feb;38(2):423-30. doi: 10.1161/01.STR.0000254600.92975.1f. Epub 2007 Jan 4.
Abstract/Text
BACKGROUND AND PURPOSE: The role of anticoagulant treatment for acute cardioembolic stroke is uncertain. We performed an updated meta-analysis of all randomized trials to obtain the best estimates of the efficacy and safety of anticoagulants for the initial treatment of acute cardioembolic stroke.
METHODS: Using electronic and manual searches of the literature, we identified randomized trials comparing anticoagulants (unfractionated heparin or low-molecular-weight heparin or heparinoids), started within 48 hours, with other treatments (aspirin or placebo) in patients with acute ischemic cardioembolic stroke. Two reviewers independently selected studies and extracted data on study design, quality, and clinical outcomes, including death or disability, all strokes, recurrent ischemic stroke, and cerebral symptomatic bleeding. Odds ratios for individual outcomes were calculated for each trial and data from all the trials were pooled using the Mantel-Haenszel method.
RESULTS: Seven trials, involving 4624 patients with acute cardioembolic stroke, met the criteria for inclusion. Compared with other treatments, anticoagulants were associated with a nonsignificant reduction in recurrent ischemic stroke within 7 to 14 days (3.0% versus 4.9%, odds ratio 0.68, 95% CI: 0.44 to 1.06, P=0.09, number needed to treat=53), a significant increase in symptomatic intracranial bleeding (2.5% versus 0.7%, odds ratio 2.89; 95% CI: 1.19 to 7.01, P=0.02, number needed to harm=55), and a similar rate of death or disability at final follow up (73.5% versus 73.8%, odds ratio 1.01; 95% CI: 0.82 to 1.24, P=0.9).
CONCLUSIONS: Our findings indicate that in patients with acute cardioembolic stroke, early anticoagulation is associated with a nonsignificant reduction in recurrence of ischemic stroke, no substantial reduction in death and disability, and an increased intracranial bleeding.
Adams HP Jr.
Emergent use of anticoagulation for treatment of patients with ischemic stroke.
Stroke. 2002 Mar;33(3):856-61. doi: 10.1161/hs0302.104628.
Abstract/Text
BACKGROUND: Several clinical trials have tested the potential utility of emergent anticoagulation for acute ischemic stroke.
SUMMARY OF REVIEW: Rather than performing a meta-analysis that combines the data from several trials, this review focuses on individual studies. Although these trials do have inherent limitations, they demonstrate that emergent use of an anticoagulant is associated with a modest but significantly increased risk of hemorrhagic transformation of the ischemic stroke or serious nonneurological bleeding. The trials do not demonstrate a benefit from emergent anticoagulation in improving outcome, reducing mortality, and preventing early recurrent stroke.
CONCLUSIONS: These results suggest that most patients with acute stroke should not be treated with unfractionated heparin or other rapidly acting anticoagulants after stroke. Prevention of deep vein thrombosis and pulmonary embolism among bedridden patients is the only established indication for early anticoagulation after acute ischemic stroke.
Cardiovascular Disease Educational and Research Trust; Cyprus Cardiovascular Disease Educational and Research Trust; European Venous Forum; International Surgical Thrombosis Forum; International Union of Angiology; Union Internationale de Phlébologie.
Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence).
Int Angiol. 2006 Jun;25(2):101-61.
Abstract/Text
Yamaguchi T.
Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation : a multicenter, prospective, randomized trial. Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary Prevention Cooperative Study Group.
Stroke. 2000 Apr;31(4):817-21. doi: 10.1161/01.str.31.4.817.
Abstract/Text
BACKGROUND AND PURPOSE: The optimal intensity of warfarin therapy for secondary prevention of stroke in nonvalvular atrial fibrillation (NVAF) remains unclear. We studied the efficacy and safety of conventional- and low-intensity warfarin therapy in a prospective, randomized, multicenter trial.
METHODS: The study population consisted of patients with NVAF (<80 years old) who had a stroke or transient ischemic attack. The patients were randomly allocated into a conventional-intensity group (international normalized ratio [INR] 2.2 to 3.5) and a low-intensity group (INR 1.5 to 2.1). They were carefully monitored, and the annual rate of recurrent ischemic stroke and major hemorrhagic complications were compared between the groups.
RESULTS: We enrolled 115 patients (mean age 66.7+/-6.5 years) into the study. Fifty-five and 60 patients were allocated into the conventional- and low-intensity groups, respectively. The trial was stopped after a follow-up of 658+/-423 days, when major hemorrhagic complications occurred in 6 patients of the conventional-intensity group and the frequency (6.6% per year) was significantly higher than that in the low-intensity group (0% per year, P=0.01, Fisher's exact test). All of the 6 patients with major bleeding were elderly (mean age 74 years), and their mean INR before the major hemorrhage was 2.8. The annual rate of ischemic stroke was low in both groups (1.1% per year in the conventional-intensity group and 1.7% per year in the low-intensity groups) and did not differ significantly.
CONCLUSIONS: For secondary prevention of stroke in persons with NVAF, especially in old patients, the low-intensity warfarin (INR 1.5 to 2. 1) treatment seems to be safer than the conventional-intensity (INR 2.2 to 3.5) treatment.
Yasaka M, Minematsu K, Yamaguchi T.
Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation.
Intern Med. 2001 Dec;40(12):1183-8. doi: 10.2169/internalmedicine.40.1183.
Abstract/Text
OBJECTIVE: To determine optimal intensity of international normalized ratio (INR) of warfarin therapy for the prevention of ischemic events in patients with non-valvular atrial fibrillation (NVAF), we evaluated the risk of severe recurrent stroke, systemic embolism and major hemorrhagic complications according to INR and age.
METHODS: We carried out the National Cardiovascular Center (NCVC) NVAF Secondary Prevention Study and analyzed data with those of Japanese Nonvaluvular Atrial Fibrillation-embolism Secondary Prevention Cooperative Study to elucidate relationships of major stroke and hemorrhage with INR and age. In both studies, all patients with cardioembolic stroke were given warfarin, monitored with INR every month, and followed up for primary endpoints of stroke and embolism to other parts of the body, and for secondary endpoints of major hemorrhagic complications requiring blood transfusion or hospitalization. We regarded ischemic stroke with NIH stroke scale (NIHSS) score > or = 10 or systemic embolism as a major ischemic event and ischemic stroke with NIHSS score <10 as a minor ischemic event. There were 203 patients enrolled in total (152 men and 51 women). We investigated the relationship of occurrence of the events with INR and age, and calculated the incidence rates of major and minor ischemic events and major hemorrhagic events.
RESULTS: During the mean follow-up of 653 days, major ischemic stroke and systemic embolism occurred in only 4 patients with INR <1.6, minor ischemic stroke in 10 patients with INR 1.50-2.66, and major hemorrhage in 9 patients with INR 2.30-3.56. Patients with major ischemic or hemorrhagic events were significantly older than those without any events (75+/-4 years vs. 67+/-7 years, p<0.001 unpaired t test). Incidence rates of any events at INR < or = 1.59, 1.60-1.99, 2.00-2.59 and > or = 2.60 were 8.6%, 3.8%, 4.9%, and 25.7%/year, respectively.
CONCLUSIONS: Major ischemic or hemorrhagic events occur often in the elderly NVAF patients, in whom an INR value of between 1.6 and 2.6 seems optimal to prevent such events.
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators.
Dabigatran versus warfarin in patients with atrial fibrillation.
N Engl J Med. 2009 Sep 17;361(12):1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30.
Abstract/Text
BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor.
METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism.
RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051).
CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)
2009 Massachusetts Medical Society
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators.
Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 10.1056/NEJMoa1009638. Epub 2011 Aug 10.
Abstract/Text
BACKGROUND: The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin.
METHODS: In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism.
RESULTS: In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group.
CONCLUSIONS: In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators.
Apixaban versus warfarin in patients with atrial fibrillation.
N Engl J Med. 2011 Sep 15;365(11):981-92. doi: 10.1056/NEJMoa1107039. Epub 2011 Aug 27.
Abstract/Text
BACKGROUND: Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin.
METHODS: In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause.
RESULTS: The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42).
CONCLUSIONS: In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.).
Giugliano RP, Ruff CT, Rost NS, Silverman S, Wiviott SD, Lowe C, Deenadayalu N, Murphy SA, Grip LT, Betcher JM, Duggal A, Dave J, Shi M, Mercuri M, Antman EM, Braunwald E; ENGAGE AF-TIMI 48 Investigators.
Cerebrovascular events in 21 105 patients with atrial fibrillation randomized to edoxaban versus warfarin: Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48.
Stroke. 2014 Aug;45(8):2372-8. doi: 10.1161/STROKEAHA.114.006025. Epub 2014 Jun 19.
Abstract/Text
BACKGROUND AND PURPOSE: The once-daily oral factor Xa inhibitor, edoxaban, is as effective as warfarin in preventing stroke and systemic embolism while decreasing bleeding in a phase III trial of patients with atrial fibrillation at moderate-high stroke risk. Limited data regarding cerebrovascular events with edoxaban were reported previously.
METHODS: We analyzed the subtypes of cerebrovascular events in 21 105 patients participating in Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) comparing outcomes among patients randomized to warfarin versus 2 edoxaban regimens (high dose, low dose). The primary end point for this prespecified analysis of cerebrovascular events was all stroke (ischemic plus hemorrhagic), defined as an abrupt onset of focal neurological deficit because of infarction or bleeding with symptoms lasting ≥24 hours or fatal in <24 hours. Independent stroke neurologists unaware of treatment adjudicated all cerebrovascular events.
RESULTS: Patients randomized to high-dose edoxaban had fewer strokes on-treatment (hazard ratio, 0.80; 95% confidence interval, 0.65-0.98) than warfarin (median time-in-therapeutic range, 68.4%); patients in the low-dose edoxaban group had similar rates (hazard ratio, 1.10 versus warfarin; 95% confidence interval, 0.91-1.32). Rates of ischemic stroke or transient ischemic attack were similar with high-dose edoxaban (1.76% per year) and warfarin (1.73% per year; P=0.81), but more frequent with low-dose edoxaban (2.48% per year; P<0.001). Both edoxaban regimens significantly reduced hemorrhagic stroke and other subtypes of intracranial bleeds.
CONCLUSIONS: In patients with atrial fibrillation, once-daily edoxaban was as effective as warfarin in preventing all strokes, with significant reductions in various subtypes of intracranial bleeding. Ischemic cerebrovascular event rates were similar with high-dose edoxaban and warfarin, whereas low-dose edoxaban was less effective than warfarin.
CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.
© 2014 American Heart Association, Inc.
Lovelock CE, Cordonnier C, Naka H, Al-Shahi Salman R, Sudlow CL; Edinburgh Stroke Study Group; Sorimachi T, Werring DJ, Gregoire SM, Imaizumi T, Lee SH, Briley D, Rothwell PM.
Antithrombotic drug use, cerebral microbleeds, and intracerebral hemorrhage: a systematic review of published and unpublished studies.
Stroke. 2010 Jun;41(6):1222-8. doi: 10.1161/STROKEAHA.109.572594. Epub 2010 Apr 29.
Abstract/Text
BACKGROUND AND PURPOSE: Cerebral microbleeds (MB) are potential risk factors for intracerebral hemorrhage (ICH), but it is unclear if they are a contraindication to using antithrombotic drugs. Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with ICH and ischemic stroke (IS)/transient ischemic attack (TIA).
METHODS: We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with ICH; (2) antithrombotic users vs nonusers with IS/TIA; and (3) ICH vs ischemic events stratified by antithrombotic use. We also analyzed published and unpublished follow-up data to determine the risk of ICH in antithrombotic users with MB.
RESULTS: In a pooled analysis of 1460 ICH and 3817 IS/TIA, MB were more frequent in ICH vs IS/TIA in all treatment groups, but the excess increased from 2.8 (odds ratio; range, 2.3-3.5) in nonantithrombotic users to 5.7 (range, 3.4-9.7) in antiplatelet users and 8.0 (range, 3.5-17.8) in warfarin users (P difference=0.01). There was also an excess of MB in warfarin users vs nonusers with ICH (OR, 2.7; 95% CI, 1.6-4.4; P<0.001) but none in warfarin users with IS/TIA (OR, 1.3; 95% CI, 0.9-1.7; P=0.33; P difference=0.01). There was a smaller excess of MB in antiplatelet users vs nonusers with ICH (OR, 1.7; 95% CI, 1.3-2.3; P<0.001), but findings were similar for antiplatelet users with IS/TIA (OR, 1.4; 95% CI, 1.2-1.7; P<0.001; P difference=0.25). In pooled follow-up data for 768 antithrombotic users, presence of MB at baseline was associated with a substantially increased risk of subsequent ICH (OR, 12.1; 95% CI, 3.4-42.5; P<0.001).
CONCLUSIONS: The excess of MB in warfarin users with ICH compared to other groups suggests that MB increase the risk of warfarin-associated ICH. Limited prospective data corroborate these findings, but larger prospective studies are urgently required.
Camerlingo M, Salvi P, Belloni G, Gamba T, Cesana BM, Mamoli A.
Intravenous heparin started within the first 3 hours after onset of symptoms as a treatment for acute nonlacunar hemispheric cerebral infarctions.
Stroke. 2005 Nov;36(11):2415-20. doi: 10.1161/01.STR.0000185730.50480.e7. Epub 2005 Oct 13.
Abstract/Text
BACKGROUND AND PURPOSE: Heparin is widely used for acute stroke to prevent thrombus propagation and/or multiple emboli generation, although there is, as yet, no demonstrated efficacy. However, all of the available clinical studies allowed long intervals from stroke to treatment. The purpose of this study was to try an intravenous regimen of unfractionated heparin the acute cerebral infarction starting treatment within the first 3 hours of the onset of symptoms.
METHODS: The study was an outcome evaluator-blind design trial. Patients had to display signs of a nonlacunar hemispheric infarction. Selected patients were randomly allocated to receive intravenous heparin sodium or saline. Heparin was infused at a rate to maintain activated partial thromboplastin time ratio 2.0 to 2.5 x control for 5 days. The primary end point was recovery of a modified Rankin score zero to 2 at 90 days of stroke at phone interview by a single physician blind to treatment. Safety end points were death, symptomatic intracranial hemorrhages, and major extracranial bleedings by 90 days of stroke.
RESULTS: A total of 418 stroke patients were included. In the heparin group, there were more self-independent patients (38.9% versus 28.6%; P=0.025). In addition, in the same group, there were fewer deaths (16.8% versus 21.9%; P=0.189), more symptomatic brain hemorrhages (6.2% versus 1.4%; P=0.008), and more major extracerebral bleedings (2.9% versus 1.4%; P=0.491).
CONCLUSIONS: Intravenous heparin sodium could be of help in the earliest treatment of acute nonlacunar hemispheric cerebral infarction, even keeping into account an increased frequency of intracranial symptomatic brain hemorrhages.
De Schryver EL, Algra A, van Gijn J.
Dipyridamole for preventing stroke and other vascular events in patients with vascular disease.
Cochrane Database Syst Rev. 2007 Jul 18;(3):CD001820. doi: 10.1002/14651858.CD001820.pub3. Epub 2007 Jul 18.
Abstract/Text
BACKGROUND: Patients with limited cerebral ischaemia of arterial origin are at risk of serious vascular events (4% to 11% annually). Aspirin reduces that risk by 13%. In one trial, adding dipyridamole to aspirin was associated with a 22% risk reduction compared with aspirin alone. However, a systematic review of all trials of antiplatelet agents by the Antithrombotic Trialists' Collaboration showed that, in high-risk patients, there was virtually no difference between the aspirin-dipyridamole combination and aspirin alone.
OBJECTIVES: To assess the efficacy and safety of dipyridamole versus control in the secondary prevention of vascular events in patients with vascular disease.
SEARCH STRATEGY: We searched the Cochrane Stroke Group trials register (searched June 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2006), MEDLINE (1966 to May 2006) and EMBASE (1980 to May 2006). We contacted authors and pharmaceutical companies in the search for further data on published and unpublished studies.
SELECTION CRITERIA: We selected randomised long-term secondary prevention trials with concealed treatment allocation, treatment for more than one month, starting within six months after presentation of an arterial vascular disease. Treatment consisted of dipyridamole with or without other antiplatelet drugs compared with no drug or an antiplatelet drug other than dipyridamole.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trial quality and extracted data. Data were analysed according to the intention-to-treat principle.
MAIN RESULTS: Twenty-nine trials were included, with 23019 participants, among whom 1503 vascular deaths and 3438 fatal and non-fatal vascular events occurred during follow up. Compared with control, dipyridamole had no clear effect on vascular death (relative risk (RR) 0.99, 95% confidence interval (CI) 0.87 to 1.12). This result was not influenced by the dose of dipyridamole or type of presenting vascular disease. Compared with control, dipyridamole appeared to reduce the risk of vascular events (RR 0.88, 95% CI 0.81 to 0.95). This effect was only statistically significant in patients presenting with cerebral ischaemia.
AUTHORS' CONCLUSIONS: For patients who presented with arterial vascular disease, there was no evidence that dipyridamole, in the presence or absence of another antiplatelet drug reduced the risk of vascular death, though it reduces the risk of further vascular events. This benefit was found only in patients presenting after cerebral ischaemia. There was no evidence that dipyridamole alone was more efficacious than aspirin.
Uchiyama S, Ikeda Y, Urano Y, Horie Y, Yamaguchi T.
The Japanese aggrenox (extended-release dipyridamole plus aspirin) stroke prevention versus aspirin programme (JASAP) study: a randomized, double-blind, controlled trial.
Cerebrovasc Dis. 2011;31(6):601-13. doi: 10.1159/000327035. Epub 2011 Apr 19.
Abstract/Text
BACKGROUND: Despite improvements in treatment, stroke still carries a high death toll and disability in Asia. Extended-release dipyridamole (ER-DP) plus acetylsalicylic acid (ASA) has consistently been shown to be superior over conventional platelet inhibition by ASA. ER-DP plus ASA is well established in the secondary prevention of stroke in a lot of countries including the USA and Europe. DP has an established benefit in the treatment of heart disease in Japan; however, for the prevention of stroke, the fixed-dose combination of ER-DP plus ASA has only been investigated in a small number of patients in Japan.
METHODS: The aim of this double-blind, randomized clinical trial was to investigate the efficacy and safety of ER-DP plus ASA versus 81 mg ASA over 1 year. The primary end point of this study was the event rate of recurrent ischemic stroke (fatal or nonfatal) using the Kaplan-Meier method and Cox regression analysis.
RESULTS: Of the 1,294 enrolled patients, the primary end point was analyzed in 652 patients in the ER-DP plus ASA group and 639 in the ASA group. The incidence of ischemic stroke was 6.9% for ER-DP plus ASA and 5.0% for ASA with a hazard ratio of 1.47 (95% confidence interval 0.93-2.31) for the primary end point. The ASA treatment group was found to have a lower than expected yearly event rate, compared to other studies in Japanese stroke patients. Noninferiority of ER-DP plus ASA versus ASA could not be shown. The risks of major bleeding events and intracranial hemorrhage were found to be similar between the treatment arms. There were 4 deaths (0.6%) in the ER-DP plus ASA group and 10 (1.6%) in the ASA group.
CONCLUSIONS: The results of the study are inconclusive. Noninferiority of ER-DP plus ASA versus ASA could not be established, a difference between treatments could not be shown for the primary end point. Possible reasons for this result include a small sample size, low event rates and too short a treatment duration (ClinicalTrials. gov number, NCT00311402).
Copyright © 2011 S. Karger AG, Basel.
Rashid P, Leonardi-Bee J, Bath P.
Blood pressure reduction and secondary prevention of stroke and other vascular events: a systematic review.
Stroke. 2003 Nov;34(11):2741-8. doi: 10.1161/01.STR.0000092488.40085.15. Epub 2003 Oct 23.
Abstract/Text
BACKGROUND: High blood pressure is a risk factor for stroke recurrence. We assessed the effectiveness of lowering blood pressure in preventing recurrent vascular events in patients with previous stroke or transient ischemic attack.
SUMMARY OF REVIEW: We performed a systematic review and meta-regression of completed randomized controlled trials that investigated the effect of lowering blood pressure on recurrent vascular events in patients with prior ischemic or hemorrhagic stroke or transient ischemic attack. Trials were identified from searches of 3 electronic databases (Cochrane Library, EMBASE, MEDLINE). Seven randomized controlled trials, with 8 comparison groups, were included. Lowering blood pressure or treating hypertension with a variety of antihypertensive agents reduced stroke (odds ratio [OR], 0.76; 95% CI, 0.63 to 0.92), nonfatal stroke (OR, 0.79; 95% CI, 0.65 to 0.95), myocardial infarction (OR, 0.79; 95% CI, 0.63 to 0.98), and total vascular events (OR, 0.79; 95% CI, 0.66 to 0.95). No effect was seen on vascular or all-cause mortality. Heterogeneity was present for several outcomes and was partly related to the class of antihypertensive drugs used; angiotensin-converting enzyme inhibitors and diuretics separately, and especially together, reduced vascular events, while beta-receptor antagonists had no discernable effect. The reduction in stroke was related to the difference in systolic blood pressure between treatment and control groups (P=0.002).
CONCLUSIONS: Evidence from randomized controlled trials supports the use of antihypertensive agents in lowering blood pressure for the prevention of vascular events in patients with previous stroke or transient ischemic attack. Vascular prevention is associated positively with the magnitude by which blood pressure is reduced.
North American Symptomatic Carotid Endarterectomy Trial Collaborators; Barnett HJM, Taylor DW, Haynes RB, Sackett DL, Peerless SJ, Ferguson GG, Fox AJ, Rankin RN, Hachinski VC, Wiebers DO, Eliasziw M.
Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
N Engl J Med. 1991 Aug 15;325(7):445-53. doi: 10.1056/NEJM199108153250701.
Abstract/Text
BACKGROUND: Without strong evidence of benefit, the use of carotid endarterectomy for prophylaxis against stroke rose dramatically until the mid-1980s, then declined. Our investigation sought to determine whether carotid endarterectomy reduces the risk of stroke among patients with a recent adverse cerebrovascular event and ipsilateral carotid stenosis.
METHODS: We conducted a randomized trial at 50 clinical centers throughout the United States and Canada, in patients in two predetermined strata based on the severity of carotid stenosis--30 to 69 percent and 70 to 99 percent. We report here the results in the 659 patients in the latter stratum, who had had a hemispheric or retinal transient ischemic attack or a nondisabling stroke within the 120 days before entry and had stenosis of 70 to 99 percent in the symptomatic carotid artery. All patients received optimal medical care, including antiplatelet therapy. Those assigned to surgical treatment underwent carotid endarterectomy performed by neurosurgeons or vascular surgeons. All patients were examined by neurologists 1, 3, 6, 9, and 12 months after entry and then every 4 months. End points were assessed by blinded, independent case review. No patient was lost to follow-up.
RESULTS: Life-table estimates of the cumulative risk of any ipsilateral stroke at two years were 26 percent in the 331 medical patients and 9 percent in the 328 surgical patients--an absolute risk reduction (+/- SE) 17 +/- 3.5 percent (P less than 0.001). For a major or fatal ipsilateral stroke, the corresponding estimates were 13.1 percent and 2.5 percent--an absolute risk reduction of 10.6 +/- 2.6 percent (P less than 0.001). Carotid endarterectomy was still found to be beneficial when all strokes and deaths were included in the analysis (P less than 0.001).
CONCLUSIONS: Carotid endarterectomy is highly beneficial to patients with recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and ipsilateral high-grade stenosis (70 to 99 percent) of the internal carotid artery.
.
Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).
Lancet. 1998 May 9;351(9113):1379-87.
Abstract/Text
BACKGROUND: Our objective was to assess the risks and benefits of carotid endarterectomy, primarily in terms of stroke prevention, in patients with recently symptomatic carotid stenosis.
METHODS: This multicentre, randomised controlled trial enrolled 3024 patients. We enrolled men and women of any age, with some degree of carotid stenosis, who within the previous 6 months had had at least one transient or mild symptomatic ischaemic vascular event in the distribution of one or both carotid arteries. Between 1981 and 1994, we allocated 1811 (60%) patients to surgery and 1213 (40%) to control (surgery to be avoided for as long as possible). Follow-up was until the end of 1995 (mean 6.1 years), and the main analyses were by intention to treat.
FINDINGS: The overall outcome (major stroke or death) occurred in 669 (37.0%) surgery-group patients and 442 (36.5%) control-group patients. The risk of major stroke or death complicating surgery (7.0%) did not vary substantially with severity of stenosis. On the other hand, the risk of major ischaemic stroke ipsilateral to the unoperated symptomatic carotid artery increased with severity of stenosis, particularly above about 70-80% of the original luminal diameter, but only for 2-3 years after randomisation. On average, the immediate risk of surgery was worth trading off against the long-term risk of stroke without surgery when the stenosis was greater than about 80% diameter; the Kaplan-Meier estimate of the frequency of a major stroke or death at 3 years was 26.5% for the control group and 14.9% for the surgery group, an absolute benefit from surgery of 11.6%. However, consideration of variations in risk with age and sex modified this simple rule based on stenosis severity. We present a graphical procedure that should improve the selection of patients for surgery.
INTERPRETATION: Carotid endarterectomy is indicated for most patients with a recent non-disabling carotid-territory ischaemic event when the symptomatic stenosis is greater than about 80%. Age and sex should also be taken into account in decisions on whether to operate.
Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJ; Carotid Endarterectomy Trialists Collaboration.
Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery.
Lancet. 2004 Mar 20;363(9413):915-24. doi: 10.1016/S0140-6736(04)15785-1.
Abstract/Text
BACKGROUND: Carotid endarterectomy reduces the risk of stroke in patients with recently symptomatic stenosis. Benefit depends on the degree of stenosis, and we aimed to see whether it might also depend on other clinical and angiographic characteristics, and on the timing of surgery.
METHODS: We analysed pooled data from the European Carotid Surgery Trial and North American Symptomatic Carotid Endarterectomy Trial. The risk of ipsilateral ischaemic stroke for patients on medical treatment, the perioperative risk of stroke and death, and the overall benefit from surgery were determined in relation to seven predefined and seven post hoc subgroups.
RESULTS: 5893 patients with 33000 patient-years of follow-up were analysed. Sex (p=0.003), age (p=0.03), and time from the last symptomatic event to randomisation (p=0.009) modified the effectiveness of surgery. Benefit from surgery was greatest in men, patients aged 75 years or older, and those randomised within 2 weeks after their last ischaemic event, and fell rapidly with increasing delay. For patients with 50% or higher stenosis, the number of patients needed to undergo surgery (ie, number needed to treat) to prevent one ipsilateral stroke in 5 years was nine for men versus 36 for women, five for age 75 years or older versus 18 for younger than 65 years, and five for those randomised within 2 weeks after their last ischaemic event, versus 125 for patients randomised after more than 12 weeks. These results were consistent across the individual trials.
INTERPRETATION: Benefit from endarterectomy depends not only on the degree of carotid stenosis, but also on several other clinical characteristics such as delay to surgery after the presenting event. Ideally, the procedure should be done within 2 weeks of the patient's last symptoms.
日本脳卒中学会、日本循環器学会、日本心血管インターベンション治療学会：潜因性脳梗塞に対する経皮的卵円孔開存閉鎖術の手引き 第2版．脳卒中 2023;45(6):511-537 [Internet]. 2019. Available from: https://www.jsts.gr.jp/img/tebiki_seninsei_noukousoku_ver4_202306.pdf
