Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2007 Jul 18;2007(3):CD000277.
doi: 10.1002/14651858.CD000277.pub3.

Calcium antagonists for aneurysmal subarachnoid haemorrhage

S M Dorhout Mees, G J E Rinkel, V L Feigin, A Algra, W M van den Bergh, M Vermeulen, J van Gijn
Meta-Analysis

Calcium antagonists for aneurysmal subarachnoid haemorrhage

S M Dorhout Mees et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: To determine whether calcium antagonists improve outcome in patients with aneurysmal SAH.

Search strategy: 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.

Selection criteria: 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.

Main results: 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.

Authors' conclusions: 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.

PubMed Disclaimer

Conflict of interest statement

The authors are currently conducting a randomised trial with magnesium sulphate (MASH‐II).

Figures

1.1
1.1. Analysis
Comparison 1 Poor outcome (death or dependence), Outcome 1 Poor outcome, according to type and route of study medication.
1.2
1.2. Analysis
Comparison 1 Poor outcome (death or dependence), Outcome 2 Poor outcome, according to timing of outcome assessment.
1.3
1.3. Analysis
Comparison 1 Poor outcome (death or dependence), Outcome 3 Poor outcome: studies with magnesium in addition of nimodipine.
2.1
2.1. Analysis
Comparison 2 Case fatality, Outcome 1 Case fatality according to type and route of study medication.
2.2
2.2. Analysis
Comparison 2 Case fatality, Outcome 2 Case fatality according to timing of outcome assessment.
2.3
2.3. Analysis
Comparison 2 Case fatality, Outcome 3 Case fatality, studies with magnesium in addition of nimodipine.
3.1
3.1. Analysis
Comparison 3 Secondary ischaemia, Outcome 1 Clinical signs of secondary ischaemia.
3.2
3.2. Analysis
Comparison 3 Secondary ischaemia, Outcome 2 Clinical signs of secondary ischaemia: studies with magnesium in addition of nimodipine.
3.3
3.3. Analysis
Comparison 3 Secondary ischaemia, Outcome 3 Cerebral infarction on CT/MR.
3.4
3.4. Analysis
Comparison 3 Secondary ischaemia, Outcome 4 Cerebral infarction on CT/MR: studies with magnesium in addition of nimodipine.
4.1
4.1. Analysis
Comparison 4 Rebleeding, Outcome 1 Rebleeding during clinical course.
4.2
4.2. Analysis
Comparison 4 Rebleeding, Outcome 2 Rebleeding: studies with magnesium in addition of nimodipine.
See this image and copyright information in PMC

Update of

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

References to studies included in this review

Allen 1983 {published data only}
    1. Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, Chou SN, et al. Cerebral arterial spasm ‐ a controlled trial of nimodipine in patients with subarachnoid hemorrhage. New England Journal of Medicine 1983;308:619‐24. - PubMed
Ferro 1990 {unpublished data only}
    1. Ferro JM, Melo TP, Oliveira V, Trindade AM, Lobo‐Antunes J, Campos JC. Prevention of vasospasm in subarachnoid hemorrhage with oral nicardipine. Unpublished study (personal communication) 1990.
Haley 1993 {published data only}
    1. Haley EC, Kassell NF, Torner JC. A randomised controlled trial of high‐dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery 1993;78:537‐47. - PubMed
    1. Haley EC, Kassell NF, Torner JC. A randomized trial of nicardipine in subarachnoid hemorrhage: angiographic and transcranial Doppler ultrasound results. Journal of Neurosurgery 1993;78:548‐53. - PubMed
    1. Haley EC, Kassell NF, Torner JC, Kongable G. Nicardipine ameliorates angiographic vasospasm following subarachnoid hemorrhage. Neurology 1991;41(Suppl 1):346.
Han 1993 {published and unpublished data}
    1. Han DH, Lee SH, Lee SH. Effect of nimodipine treatment on outcome in surgical cases of aneurysmal SAH. Journal of Neurosurgery 1993;78:346A.
Luo 1996 {published data only}
    1. Luo W, Qiu S, MA W. Clinical study of magnesium sulphate on delayed cerebral vasospasm after subarachnoid haemorrhage. Journal of Clinical Neurology 1996;9(4):244‐5.
Messeter 1987 {published data only}
    1. Messeter K, Brandt L, Ljunggren B, Svendgaard NA, Algotsson L, Romner B, et al. Prediction and prevention of delayed ischemic dysfunction after aneurysmal subarachnoid hemorrhage and early operation. Neurosurgery 1987;20:548‐53. - PubMed
Neil‐Dwyer 1987 {published data only}
    1. Mee E, Dorrance D, Lowe D, Neil‐Dwyer G. Controlled study of nimodipine in aneurysm patients treated early after subarachnoid hemorrhage. Neurosurgery 1988;22:484‐91. - PubMed
    1. Mee EW, Dorrance DE, Low D, Neil‐Dwyer G. Cerebral blood flow and neurological outcome: a controlled study of nimodipine in patients with subarachnoid haemorrhage. Journal of Neurology and Psychiatry 1986;49:469.
    1. Neil‐Dwyer G, Mee E, Dorrance D, Lowe D. Early intervention with nimodipine in subarachnoid haemorrhage. European Heart Journal 1987;8:41‐7. - PubMed
Ohman 1991 {published data only}
    1. Juvela S, Kaste M, Hillbom M. Effect of nimodipine on platelet function in patients with subarachnoid hemorrhage. Stroke 1990;21:1283‐8. - PubMed
    1. Ohman J. Surgery for ruptured intracranial aneurysms: defining the present optimal conditions. Finland: Helsingin Yliopisto, 1991.
    1. Ohman J, Heiskanen O. Effect of nimodipine on the outcome of patients after aneurysmal subarachnoid hemorrhage and surgery. Journal of Neurosurgery 1988;69(5):683‐6. - PubMed
    1. Ohman J, Servo A, Heiskanen O. Long‐term effects of nimodipine on cerebral infarcts and outcome after aneurysmal subarachnoid hemorrhage and surgery. Journal of Neurosurgery 1991;74:8‐13. - PubMed
Petruk 1988 {published data only}
    1. Disney LB. Cerebral vasospasm following subarachnoid hemorrhage: clinical investigation of oral nimodipine and factors influencing outcome (hemorrhage). Dissertation Abstracts International 1990; Vol. Volume 52/11‐B:221 pages.
    1. Petruk KC, West M, Mohr G, Weir BKA, Benoit BG, Gentili F, et al. Nimodipine treatment in poor‐grade aneurysm patients. Results of a multicentre double‐blind placebo‐controlled trial. Journal of Neurosurgery 1988;68:505‐17. - PubMed
Philippon 1986 {published data only}
    1. Philippon J, Grob R, Dagreou F, Guggiari M, Rivierez M, Viars P. Prevention of vasospasm in subarachnoid haemorrhage. A controlled study with nimodipine. Acta Neurochirurgica 1986;82:110‐4. - PubMed
Pickard 1989 {published data only}
    1. Pickard JD, Murray GD, Illingworth R, Shaw MDM, Teasdale GM, Foy PM, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ 1989;298:636‐42. - PMC - PubMed
Shibuya 1992 {published data only}
    1. Shibuya M, Suzuki Y. Treatment of cerebral vasospasm by a protein kinase inhibitor AT877 [Japanese]. No to Shinkei ‐ Brain & Nerve 1993;45:819‐24. - PubMed
    1. Shibuya M, Suzuki Y, Sugita K, Saito I, Sasaki T, Takakura K, et al. Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Results of a prospective placebo controlled double blind trial. Journal of Neurosurgery 1992;76:571‐7. - PubMed
van den Bergh 2005 {published data only}
    1. Bergh WM, Algra A, Kooten F, Dirven CM, Gijn J, Vermeulen M, et al. Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. Stroke 2005;36:1011‐5. - PubMed
Veyna 2002 {published data only}
    1. Veyna RS, Seyfried D, Burke DG, Zimmerman C, Mlynarek M, Nichols V, et al. Magnesium sulfate therapy after aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery 2002;96:510‐4. - PubMed
Wong 2006 {published data only}
    1. Boet R, Chan MTV, Poon WS, Wong GKC, Wong HT, Gin T. Intravenous magnesium sulfate to improve outcome after aneurysmal subarchnoid hemorrhage: interim report from a pilot study. Acta Neurochirurgica 2005;95(Suppl):263‐4. - PubMed
    1. Wong GKC, Chan MTV, Boet R, Poon WS, Gin T. Intravenous magnesium sulfate after aneurysmal subarachnoid hemorrhage: a prospective randomized pilot study. Journal of Neurosurgery and Anesthesiology 2006;18(2):142‐8. - PubMed
Zhu 2001 {published data only}
    1. Zhu Y. Clinical study of nimodipine in preventing and treating cerebral vasospasm after subarachnoid hemorrhage. Chinese Journal of Primary Medicine and Pharmacy 2001;8:256‐7.

References to studies excluded from this review

Cabral 1991 {published data only}
    1. Cabral ND, Scaff M. Use of nimodipine in spontaneous meningeal haemorrhage through aneurysm rupture [Uso da nimodipina em hemorragia meníngea espontânea por rotura de aneurisma]. Revista Brasileira de Neurologia 1991;27(1):21‐2.
Cadoux‐Hudson 1999 {published data only}
    1. Cadoux‐Hudson TAD. A randomised, double‐blind placebo controlled pilot trial of intravenous magnesium sulphate in subarachnoid haemorrhage. National Research Register, Issue 1, 2001.
Islekel 1999 {published data only}
    1. Islekel S, Oktar N, Yurtseven T, Ozdamar N. Effect of nimodipine on the outcome of patients after aneurysm surgery. Journal of Neurological Sciences 1999;16(1):4.
Jan 1988 {published data only}
    1. Desbordes JM, Ades PE, Guggiari M. Intravenous nimodipine in curative treatment of cerebral vasospasm after subarachnoid haemorrhage caused by rupture of intra‐cranial aneurysms: a comparative multicenter study. Agressologie 1989;30:438‐40. - PubMed
    1. Frerebeau Ph, Janny P, Taquoi G, Besson G, Buchheit F, Childs M, et al. Curative intravenous nimodipine treatment of subarachnoidal hemorrhage of vasospasm origine intracranial‐aneurysms. Neurochirurgie 1988;34:383‐8. - PubMed
    1. Jan M, Buchheit F, Tremoulet M. Therapeutic trial of intravenous nimodipine in patients with established cerebral vasospasm after rupture of intracranial aneurysms. Neurosurgery 1988;23:154‐7. - PubMed
Maldonado 1990 {published data only}
    1. Maldonado JA, Milchorena G, Lopez‐Camacho O, Madrazo I. Management with nimodipine of the cerebral vasospasm secondary to subarachnoid hemorrhage due to the rupture of an intracranial aneurysm [Manejo con nimodipina del vaso‐espasmo cerebral secundario a hemorragia subaracnoidea por ruptura de aneuisma intracraneano]. Archivos de Investigacion Medica 1990;21:179‐87. - PubMed
Prevedello 2006 {published data only}
    1. Prevedello DMS, Cordeiro JG, Morais AL, Saucedo NS, Chen IB, Araujo JC. Magnesium sulfate: role as possible attenuating factor in vasospasm morbidity. Surgical Neurology 2006;65(S1):14‐21. - PubMed
Wang 1995 {published data only}
    1. Wang H, Song D, Lu J, Jia S. Preventive effect of nimodipine on SAH and CVS. Journal of Apoplexy and Nervous Diseases 1995;12(4):237.
Xie 1994 {published data only}
    1. Xie R, Yao J. Observation on the therapeutic effect of nimodipine versus kang‐xuan‐ding versus placebo for 14 days. Journal of Clinical Neurology 1994;7(1):48‐9.
Zhu 1996 {published data only}
    1. Zhu S, Liu X, Li Y, Hou Q, Cai P. Observation of therapeutic effect of combined nimodipine and magnesium sulphate after subarachnoid haemorrhage. Stroke and Nervous Diseases 1996;3(3):163.

References to ongoing studies

IMASH {unpublished data only}
    1. Intravenous Magnesium sulfate in Aneurysmal Subarachnoid Hemorrhage. http://www.surgery.cuhk.edu.hk/imash‐trial/.
MASH‐II {unpublished data only}
    1. Major ongoing trials. Stroke 2006; Vol. 37, issue 10:e36‐44. - PubMed

Additional references

ACROSS 2000
    1. The ACROSS Group. Epidemiology of aneurysmal subarachnoid hemorrhage in Australia and New Zealand: incidence and case fatality from the Australasian Cooperative Research on Subarachnoid Hemorrhage Study (ACROSS). Stroke 2000;31(8):1843‐50. - PubMed
Barker 1996
    1. Barker II FG, Ogilvy CS. Efficacy of prophylactic nimodipine for delayed ischemic deficit after subarachnoid hemorrhage: a metaanalysis. Journal of Neurosurgery 1996;84:405‐14. - PubMed
Brilstra 2000
    1. Brilstra EH, Rinkel GJE, Algra A, Gijn J. Rebleeding, secondary ischemia and timing of operation in patients with subarachnoid hemorrhage. Neurology 2000;55:1656‐60. - PubMed
de Rooij 2006
    1. Rooij NK, Linn FHH, Plas JAP, Algra A, Rinkel GJE. Incidence of subarachnoid hemorrhage: a ten years' update of a systematic review with emphasis on role of region, gender, age and time trend. In preparation.
Deeks 2001
    1. Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta‐analysis. In: Egger M, Davey Smith G, Altman DG editor(s). Systematic reviews in health care: meta‐analysis in context. 2nd Edition. London: BMJ, 2001.
Gaab 1985
    1. Gaab MR, Haubitz I, Brawanski A, Korn A, Czech T. Acute effects of nimodipine on the cerebral blood flow and intracranial pressure. Neurochirurgia 1985;28(Suppl 1):93‐9. - PubMed
Haley 1994
    1. Haley EC Jr, Kassell NF, Torner JC, Truskowski LL, Germanson TP. A randomized trial of two doses of nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. Journal of Neurosurgery 1994;80:788‐96. - PubMed
Hop 1997
    1. Hop JW, Rinkel GJE, Algra A, Gijn J. Case fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 1997;28:660‐4. - PubMed
Ljunggren 1984
    1. Ljunggren B, Brandt L, Saveland H, Nilsson PE, Cronqvist S, Andersson KE, et al. Outcome in 60 consecutive patients treated with early aneurysm operation and intravenous nimodipine. Journal of Neurosurgery 1984;61:864‐73. - PubMed
Mascio 1994
    1. Mascio RD, Marchioli R, Tognoni G. Meta‐analysis. From pharmacological promises to controlled clinical trials to meta‐analysis and back: the case of nimodipine in cerebrovascular disorders. Clinical Trials and Meta‐Analysis 1994;29:57‐79. - PubMed
Massiou 1992
    1. Massiou H, Chaumet‐Riffaud P, Bourdeix I. Nicardipine in the prevention of spasm‐induced neurological deficits after subarachnoid hemorrhage: a dose‐ranging study. Surgical Neurology 1992;38:7‐11. - PubMed
McCalden 1989
    1. McCalden TA, Nath RG. Cerebrovascular autoregulation is resistant to calcium channel blockage with nimodipine. Experientia 1989;45:305‐6. - PubMed
Pickard 1990
    1. Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, et al. Oral nimodipine and cerebral ischaemia following subarachnoid haemorrhage. British Journal of Clinical Practice 1990;44(2):66‐7. - PubMed
Ram 1991
    1. Ram Z, Sadeh M, Shacked I, Sahar A, Hadani M. Magnesium sulfate reverses experimental delayed cerebral vasospasm after subarachnoid hemorrhage in rats. Stroke 1991;22(7):922‐7. - PubMed
Robinson 1990
    1. Robinson MJ, Teasdale GM. Calcium antagonists in the management of subarachnoid haemorrhage. Cerebrovascular & Brain Metabolism Reviews 1990;2:205‐26. - PubMed
Roos 2000
    1. Roos YB, Haan RJ, Beenen LF, Groen RJ, Albrecht KW, Vermeulen M. Complications and outcome in patients with aneurysmal subarachnoid haemorrhage: a prospective hospital based cohort study in the Netherlands. Journal of Neurology Neurosurgery and Psychiatry 2000;68(3):337‐41. - PMC - PubMed
Satoh 1992
    1. Satoh S, Suzuki Y, Harada T, Ikegaki I, Asano T, Shibuya M, et al. Possible prophylactic potential of HA1077, a Ca+2 channel antagonist and vasodilator, on chronic cerebral vasospasm. European Journal of Pharmacology 1992;220:243‐8. - PubMed
Schulz 1995
    1. Schulz K, Chalmers I, Hayes R, Altman D. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408‐12. - PubMed
Seto 1995
    1. Seto M, Shindo K, Ito K, Sasaki Y. Selective inhibition of myosin phosphorylation and tension of hyperplastic arteries by the kinase inhibitor HA1077. European Journal of Pharmacology 1995;276:27‐33. - PubMed
Shibuya 1990
    1. Shibuya M, Suzuki Y, Sugita K, Saito I, Sasaki T, Takakura K, et al. Dose escalation trial of a novel calcium antagonist, AT877, in patients with aneurysmal subarachnoid haemorrhage. Acta Neurochirurgica 1990;107:11‐5. - PubMed
Takizawa 1993
    1. Takizawa S, Hori M, Ozaki H, Karaki H. Effects of isoquinoline derivatives, HA1077 and H‐7, on cytosolic Ca+2 level and contraction in vascular smooth muscle. European Journal of Pharmacology 1993;250:431‐7. - PubMed
Tettenborn 1990
    1. Tettenborn D, Dycka J. Prevention and treatment of delayed ischemic dysfunction in patients with aneurysmal subarachnoid hemorrhage. Stroke 1990;21(Suppl IV):IV85‐IV89. - PubMed
van den Bergh 2002
    1. Bergh WM, Zuur JK, Kamerling NA, Asseldonk JT, Rinkel GJ, Tulleken CA, et al. Role of magnesium in the reduction of ischemic depolarization and lesion volume after experimental subarachnoid hemorrhage. Journal of Neurosurgery 2002;97(2):416‐22. - PubMed
van den Bergh 2003
    1. Bergh WM, Algra A, Sprenkel JW, Tulleken CA, Rinkel GJ. Hypomagnesemia after aneurysmal subarachnoid hemorrhage. Neurosurgery 2003;52(2):276‐82. - PubMed
van den Bergh 2004
    1. Bergh WM, Dijkhuizen RM, Rinkel GJ. Potentials of magnesium treatment in subarachnoid haemorrhage. Magnesium Research 2004;17(4):301‐13. - PubMed
van der Schaaf 2002
    1. Schaaf IC, Ruigrok YM, Rinkel GJE, Algra A, Gijn J. Study design and outcome measures in studies on aneurysmal subarachnoid hemorrhage. Stroke 2002;33:2043‐6. - PubMed

References to other published versions of this review

Feigin 1998
    1. Feigin VF, Rinkel GJE, Algra A, Vermeulen M, Gijn J. Calcium antagonists in patients with aneurysmal subarachnoid hemorrhage: a systematic review. Neurology 1998;50:876‐83. - PubMed
Rinkel 2005
    1. Rinkel GJE, Feigin VL, Algra A, Bergh WM, Vermeulen M, Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database of Systematic Reviews 2005, Issue 1. [Art. No.: CD000277. DOI: 10.1002/14651858.CD000277.pub3] - PubMed

MeSH terms