Calcium antagonists for aneurysmal subarachnoid haemorrhage
Editorial Group: Cochrane Stroke Group
Published Online: 8 OCT 2008
Assessed as up-to-date: 26 OCT 2006
Copyright © 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
How to Cite
Dorhout Mees S, Rinkel GJE, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD000277. DOI: 10.1002/14651858.CD000277.pub3.
- Publication Status: Edited (no change to conclusions)
- Published Online: 8 OCT 2008
Secondary ischaemia is a frequent cause of poor outcome in patients with subarachnoid haemorrhage (SAH). Its pathogenesis has been incompletely elucidated, but vasospasm probably is a contributing factor. Experimental studies have suggested that calcium antagonists can prevent or reverse vasospasm and have neuroprotective properties.
To determine whether calcium antagonists improve outcome in patients with aneurysmal SAH.
We searched the Cochrane Stroke Group Trials Register (last searched April 2006), MEDLINE (1966 to March 2006) and EMBASE (1980 to March 2006). We handsearched two Russian journals (1990 to 2003), and contacted trialists and pharmaceutical companies in 1995 and 1996.
Randomised controlled trials comparing calcium antagonists with control, or a second calcium antagonist (magnesium sulphate) versus control in addition to another calcium antagonist (nimodipine) in both the intervention and control groups.
Data collection and analysis
Two review authors independently extracted the data and assessed trial quality. Trialists were contacted to obtain missing information.
Sixteen trials, involving 3361 patients, were included in the review; three of the studies were of magnesium sulphate in addition to nimodipine. Overall, calcium antagonists reduced the risk of poor outcome: the relative risk (RR) was 0.81 (95% confidence interval (CI) 0.72 to 0.92); the corresponding number of patients needed to treat was 19 (95% CI 1 to 51). For oral nimodipine alone the RR was 0.67 (95% CI 0.55 to 0.81), for other calcium antagonists or intravenous administration of nimodipine the results were not statistically significant. Calcium antagonists reduced the occurrence of secondary ischaemia and showed a favourable trend for case fatality. For magnesium in addition to standard treatment with nimodipine, the RR was 0.75 (95% CI 0.57 to 1.00) for a poor outcome and 0.66 (95% CI 0.45 to 0.96) for clinical signs of secondary ischaemia.
Calcium antagonists reduce the risk of poor outcome and secondary ischaemia after aneurysmal SAH. The results for 'poor outcome' depend largely on a single large trial of oral nimodipine; the evidence for other calcium antagonists is inconclusive. The evidence for nimodipine is not beyond all doubt, but given the potential benefits and modest risks of this treatment, oral nimodipine is currently indicated in patients with aneurysmal SAH. Intravenous administration of calcium antagonists cannot be recommended for routine practice on the basis of the present evidence. Magnesium sulphate is a promising agent but more evidence is needed before definite conclusions can be drawn.
Plain language summary
Calcium antagonists for aneurysmal subarachnoid haemorrhage
A subarachnoid haemorrhage is a bleed in the so-called subarachnoid space, which is the very small space between the brain and the skull, and which contains blood vessels that supply the brain. The cause of the bleeding usually is a rupture of a bulge in one of these vessels. This bulging or blister on a vessel is called an aneurysm. A subarachnoid haemorrhage is a relatively uncommon type of stroke; it accounts for about one in 20 (5%) of all strokes. Subarachnoid haemorrhage often occurs at a relatively young age: half the patients are younger than 55 years old. The outcome of patients after subarachnoid haemorrhage is generally poor: half the patients die within one month after the haemorrhage, and of those who survive the initial month, half remain dependent on someone else for help with activities of daily living (e.g. walking, dressing, bathing). One of the causes of poor outcome is a complication of subarachnoid haemorrhage called secondary ischaemia (ischaemia means lack of blood). This complication occurs four to 10 days (hence secondary) after the haemorrhage. The cause is not exactly known, but one of the factors involved is narrowing of blood vessels in the brain. Calcium antagonists are a type of drug that block calcium channels in cells and are often used for the treatment of high blood pressure. They have also been shown to counteract the narrowing of blood vessels after subarachnoid haemorrhage and to protect the brain against periods of ischaemia. This review of 16 trials, involving 3361 patients, has found that the outcome after subarachnoid haemorrhage, in terms of survival and being independent in activities of daily living, is improved by treatment with calcium channel blockers (antagonists). If the largest trial is excluded from the analysis, the results are no longer statistically significant, and therefore the evidence is not beyond all doubt. However, given the high likelihood of benefits and the modest risks associated with this treatment, the review authors conclude that calcium antagonists, in the form of oral nimodipine 60 mg every four hours, are useful in patients with subarachnoid haemorrhage from a ruptured aneurysm. Magnesium is another calcium antagonist with promising results, but larger trials with this drug are needed before we can be certain about a beneficial effect.
次發性缺血是造成蜘蛛膜下腔出血(subarachnoid haemorrhage, SAH)不良預後的常見原因之一。其病理機轉尚未闡明，但血管痙攣(vasospasm)可能是促發因素。在實驗室的研究顯示，鈣離子阻斷劑可以防止或逆轉血管痙攣，並有神經保護的特性。
搜尋Cochrane Stroke Group Trials Register (last searched April 2006)、MEDLINE (1966年到2006年3月)和EMBASE (1980年到2006年3月)。並手動搜尋2份俄國期刊 (1990年到2003年)，與1995及1996年的研究作者和製藥公司聯絡。
以隨機對照試驗(Randomised controlled trials)比較鈣離子阻斷劑和對照組，或第二種鈣離子阻斷劑(magnesium sulphate)與對照組加上另一個鈣離子阻斷劑(nimodipine)，分為實驗組和對照組。
此研究共納入16個試驗，共3361位病例； 其中三個試驗以magnesium sulphate加上nimodipine。總體而言，鈣離子阻斷劑減低了不良預後的風險：RR(relative risk)為0.81(95%CI 0.72到0.92); NNT(number needed to treat)為19(95%CI 1到51)。只單獨口服nimodipine其RR為0.67(95%CI 0.55至0.81)，使用其他種類的鈣離子阻斷劑或nimodipine靜脈給藥並沒有統計學上的差異。鈣離子阻斷劑可降低發生次發性缺血的風險，並在病例死亡率當中表現出良好的趨勢。標準治療的nimodipine之外再加上magnesium，在不良預後方面其RR為0.75(95%CI 0.57至1.00)，臨床出現次發性缺血症狀的RR則為0.66(95%CI 0.45至0.96)。
此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。
鈣拮抗劑對動脈瘤性蛛網膜下腔出血. 蛛網膜下腔出血是在所謂的蛛網膜下腔，這是在大腦和頭骨間非常小的空間，它包含供應大腦的血管。出血的原因通常是其中一條血管隆起處破裂. 這在血管上的突起或是小泡稱為動脈瘤。蛛網膜下腔出血是一種較為少見的中風類型，它約佔所有中風的5％。蛛網膜下腔出血往往發生在年齡較輕的病人：有一半的患者年齡小於55歲。蛛網膜下腔出血患者的預後普遍不好：有一半的患者在出血的一個月內死亡，而那些在最初一個月存活的，有一半的日常生活活動(例如走路，穿衣，洗澡)仍然依賴別人的幫助。其中一個不良預後的原因是蛛網膜下腔出血後的併發症稱為繼發缺血(缺血表示缺乏血液供應)。這種併發症發生在出血後4至10天。其原因並不完全清楚，但其中的一個因素是大腦血管狹窄。鈣拮抗劑是一類的藥物，抑制細胞中的鈣離子通道，通常用來治療高血壓。他們也已證明，能抗衡蛛網膜下腔出血後的血管狹窄以保護大腦避免缺血期。本篇回顧包含16個試驗，涉及3361個病例，發現在蛛網膜下腔出血後，就存活率和日常生活活動的獨立，在使用鈣離子通道阻斷劑(拮抗劑)者有進步。如果最大的試驗被排除在分析外，結果將不再具顯著性，因此，證據並非毫無疑問。但是，由於治療可能非常地有效及只有適度的風險，本回顧作者的結論是鈣離子拮抗劑，每四小時口服nimodipine 60毫克，用於因動脈瘤破裂蛛網膜下腔出血患者是有效的。鎂是另一種鈣拮抗劑且有好的結果，但更大規模的試驗是需要的，才可以確定治療的效果。