Piracetam for acute ischaemic stroke (Review

)
Ricci S, Celani MG, Cantisani TA, Righetti E

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, Issue 9 http://www.thecochranelibrary.com

Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .TABLE OF CONTENTS HEADER . . . . .1. . . . . . Published by John Wiley & Sons. METHODS . . . . . . . . . . . . . . . . . . . . . i . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1. . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Outcome 1 Death at approximately 1 month. DECLARATIONS OF INTEREST . . . . . . APPENDICES . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison 2 Dependence at 12 weeks. . . . . . . . . . . . . . . . . . Comparison 1 Piracetam versus control. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . Analysis 1. . . . Comparison 1 Piracetam versus control. . . . . . . . . . . Analysis 3. . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . Outcome 1 Death or dependence at 12 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . FEEDBACK . . . . . . . . . . . . . . . . . . . . Outcome 1 Dependence at 12 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . Outcome 2 Death at 12 weeks. . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 2 3 3 4 5 5 5 6 10 11 11 12 12 12 13 14 14 14 14 15 Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. . . . . Ltd. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1. . . . . . . . Comparison 3 Death or dependence at 12 weeks. . . . . . . . . . . . . . . . . . . . .2. . . . . RESULTS . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . HISTORY . DISCUSSION . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

We also contacted the manufacturer of piracetam to identify further published and unpublished studies. DOI: 10. Issue 2). Copyright © 2012 The Cochrane Collaboration. dependence or proportion of patients dead or dependent.it. Citation: Ricci S. 1 UO ABSTRACT Background Piracetam has neuroprotective and antithrombotic effects that may help to reduce death and disability in people with acute stroke. MEDLINE (1966 to May 2011). 95% confidence interval 81% increase to 5% reduction). Selection criteria Randomised trials comparing piracetam with control. 2 Neurofisiopatologia. Celani MG. 2012. EMBASE (1980 to May 2011). Italy. UO Neurologia. Ospedale di Città della Pieve. Piracetam was associated with a statistically non-significant increase in death at one month (approximately 31% increase. 06012. Participants’ ages ranged from 40 to 85 years. and both sexes were equally represented. Editorial group: Cochrane Stroke Group. Data collection and analysis Two review authors extracted data and assessed trial quality and this was checked by the other two review authors.: CD000419. Italy. Main results We included three trials involving 1002 patients. Italy. Maria Grazia Celani2 . with at least mortality reported and entry to the trial within three days of stroke onset. Limited data showed no difference between the treatment and control groups for functional outcome. published in Issue 9. Teresa Anna Cantisani2 . 1 . Search methods We searched the Cochrane Stroke Group Trials Register (last searched 15 May 2011). Enrico Righetti3 Neurologia. Review content assessed as up-to-date: 18 May 2011. Ltd. istitaly@unipg. Issue 9.pub3. Italy Contact address: Stefano Ricci. Art. Publication status and date: New search for studies and content updated (no change to conclusions). We contacted study authors for missing information. Righetti E. Città della Pieve. This is an update of a Cochrane Review first published in 1999. This trend was no longer apparent in the large trial after correction for imbalance in stroke severity. Stroke Unit. Piracetam for acute ischaemic stroke. Published by John Wiley & Sons. No. Ltd. Perugia.[Intervention Review] Piracetam for acute ischaemic stroke Stefano Ricci1 . Cochrane Database of Systematic Reviews 2012. Objectives To assess the effects of piracetam in acute. Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration.CD000419. Adverse effects were not reported. Azienda Ospedaliera Perugia. with one trial contributing 93% of the data.1002/14651858. Cantisani TA. ASL 1 dell’ Umbria. Published by John Wiley & Sons. Via Engels. and ISI Science Citation Index (1981 to May 2011). Città di Castello. Ospedale. and previously updated in 2006 and 2009. presumed ischaemic stroke. the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011. ASL 1 dell’ Umbria. Città di Castello. 3 A USL 2 dell’Umbria.

death or dependence) at final follow-up. a few months after stroke onset). but just as an early secondary prevention treatment). Piracetam is a drug which has been marketed by drug companies in several countries for many years as a ’nootropic’ agent: a drug which has metabolic activity in the human brain. There have been a number of randomised controlled trials of piracetam given to patients within 48 hours of the onset of their stroke. and the first leading cause of long-term disability in survivors. thrombolytics) and neuroprotection of the ischaemic brain (e. when available. PLAIN LANGUAGE SUMMARY Piracetam for acute ischaemic stroke Ischaemic stroke is the third leading cause of death in developed countries. The main outcomes of interest were death from all causes and poor outcome (that is. The exact mechanism of action of piracetam is not known and several different effects (possibly as the result of an action on a very basic cell function) have been described: a neuroprotective effect (restoration of neurotransmission. The data reviewed did not provide conclusive evidence about the effects of piracetam for acute stroke. A Cochrane Review has been published on the efficacy of piracetam for ameliorating language in aphasic stroke patients (Greener 2001). in relation to both circulatory impairment (e. the drug has also been considered for acute stroke treatment (Noble 1996). 2 Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. Ltd. Moriau 1993). given within three days of stroke onset to patients with acute ischaemic stroke. . Data from three trials. on whether or not piracetam therapy increases the risk of fatal or disabling intracranial haemorrhage.g. improvement of metabolism) which is evident in the presence of hypoxia (Giurgea 1970. Experiments in animals suggest that piracetam could have beneficial effects in patients with acute stroke. sodium channel blockers). The potential effects of piracetam in chronic stroke patients is dealt with in a separate review (Greener 2001) This is an update of a Cochrane Review first published in 1999. One additional. but this may have been caused by baseline differences in stroke severity in the trials. Various strategies are currently being considered. The efficacy and safety of piracetam in patients with acute stroke have not yet been proven.Authors’ conclusions There is some suggestion (but no statistically significant result) of an unfavourable effect of piracetam on early death. but almost all came from a single study. in whom computed tomography (CT) or magnetic resonance imaging (MRI) scanning has been performed to identify intracerebral haemorrhage. large study has been conducted and interrupted by the manufacturer after some preliminary analyses were carried out. antithrombotics. Schaffler 1988) and an antithrombotic effect (improvement of microcirculation. and the first leading cause of long-term disability in survivors. and for the treatment of myoclonus. N-methylD-aspartate (NMDA) blocking agents. decrease of platelet aggregation) (Herrschaft 1978. involving 1002 patients. The aim of this review is to verify whether the available evidence from con- trolled trials is in favour of a beneficial effect of piracetam in acute ischaemic stroke. but despite this there is still no pharmacological treatment of proven efficacy or with a favourable risk/benefit ratio for the acute phase of the disease (aspirin has been shown to be effective. We wished to test the following hypothesis: a policy of immediate piracetam therapy is associated with a reduced risk of being dead or dependent in activities of daily living at the end of the final followup (that is. Published by John Wiley & Sons. Piracetam is a drug which has been marketed by drug companies in several countries for many years as a ’nootropic’ agent (a drug which has metabolic activity in the human brain). We also wished to consider (where available) any evidence of the effect of piracetam on haemorrhagic stroke and to review the evidence. but the results have not been made available to the scientific community. and previously updated in 2006 and 2009. BACKGROUND Ischaemic stroke is still the third leading cause of death in developed countries. There is not enough evidence to assess the effect of piracetam on dependence. were available for this review. OBJECTIVES The objective of this review was to determine the effectiveness and safety of piracetam.g.

If the results were expressed as scale scores (Rankin or Barthel scales). 6. these were dichotomised into dependent/independent. where P ≤ 0. We have included studies that involved patients of any age and either sex. or both. 2. was compared with control in patients with presumed acute ischaemic stroke. Published by John Wiley & Sons. and type of possible analysis (intention-to-treat or explanatory). and ISI Science Citation Index (1981 to May 2011). effects of different doses and routes of administration. We also considered the following details: the number of post-hoc exclusions. We obtained the full text of the remaining articles and the same two authors independently selected studies meeting the inclusion criteria for the review.05 was taken to indicate significant heterogeneity. In addition. Search methods for identification of studies See the ’Specialized register’ section in the Cochrane Stroke Group module published in The Cochrane Library. EMBASE (1980 to may 2011) (Appendix 2). all patients. whether method of concealment of next treatment allocation was good or poor. MEDLINE (1966 to May 2011) (Appendix 1). We used the MEDLINE search strategy (Appendix 1) to search the Cochrane Central Register of Controlled Trials and modified it for the other databases. at any dose. number of patients lost to follow up. given intravenously (iv) or orally. we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011. and the other two review authors checked the results. compared with placebo or open control. and the number of patients randomised and analysed but not treated for whatever reason. Criteria for considering studies for this review Types of studies We identified all truly unconfounded randomised trials in which treatment with piracetam. Issue 2). 2. Death from any cause at the end of the treatment period: this was the primary outcome. 3. The same two review authors independently extracted the relevant data from each trial. Ltd. we calculated pooled odds ratios (OR) and 95% confidence intervals (CI) for all the analyses using the Peto fixed-effect model. Types of outcome measures The main outcomes of interest were as follows. we excluded trials in which patients commenced treatment more than three days from stroke onset. 3. When relevant information was not available from the publication. the number of patients included without a prior CT. the patient is dependent on help from other people in activities of daily living). we tried to make direct contact with the trialists. A combination of death or dependence at the end of trial follow-up. As long as statistical heterogeneity did not exist for the outcome where it was calculated (early death). which was last searched by the Managing Editor on 15 May 2011. all trials. We searched for trials in all languages and arranged translation of relevant studies published in languages other than English or Italian. 4. We considered the following sensitivity analyses: 1. and only blinded trials. We excluded trials without true randomisation. Types of participants Since this review focuses on acute stroke. Dependence from stroke at the end of trial follow-up (that is. 5. Data collection and analysis Two review authors (SR and MGC) independently screened the titles and abstracts of the studies identified from the database searches and excluded obviously irrelevant articles. . and only patients with CT before randomisation. 1. Searching other resources We contacted the manufacturer of piracetam (UCB) to identify further published and unpublished studies. including randomisation method. We tested heterogeneity between trials using a Chi2 test. blinding.METHODS Electronic searches We searched the Cochrane Stroke Group Trials Register. Types of interventions The only agent considered in this review was piracetam. We resolved disagreement by discussion and consultation with other review authors. We also used I2 statistics. given within approximately 48 hours from stroke onset. Death from any cause at the end of trial follow-up. RESULTS 3 Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. Any major extracranial haemorrhage (fatal or requiring transfusion) at the end of the treatment period. Fatal and non-fatal intracranial haemorrhages at the end of the treatment period. 4.

These patients were included in our analysis of the single study.82) (Analysis 1.1). 95% CI 0. For the outcome of death at one month. All included trials used piracetam intravenously in the acute phase compared with placebo.67 to 1. This may well be due to an imbalance in stroke severity between the two groups.97 to 1. We decided to exclude the Creytens study (Creytens 1980) because there was no CT examination to allow stroke diagnosis and pathological subgroup diagnosis. if any. The number of participants was 1002: ages ranged from 40 to 85 and both sexes were equally represented. However. is not statistically significant. Only one study used a measure of functional disability (PASS 1997). Posterior circulation strokes were excluded as well as patients with coma (Glasgow Coma Scale less than 4) or a mass effect with a midline shift on the early scan.32 (95% CI 0. this result is almost completely based on data coming from the PASS study. The three trials showed a non-significant increase Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. Ltd. Results on functional disability were only reported in the PASS study. death or dependence) there was no difference between treatment and control (OR 1. which accounted for 93% of the data. The reasons for excluding 16 trials from the analysis are summarised in the ’Characteristics of excluded studies’ table. CT scans were carried out for all patients participating in the two small studies. Post hoc subgroup analysis of the PASS study (PASS 1997) suggests a benefit of very early piracetam use. CT scans were missing in seven patients in the PASS trial.80) (Analysis 1. four excluded because of missing data): there was a modest. there was no evidence of statistical heterogeneity (Chi2 3.32) (Analysis 3. Numbers of patients with haemorrhagic strokes or major extracranial haemorrhages were not available.Description of studies See: Characteristics of included studies. DISCUSSION The results of this review do not show any statistically significant effect of piracetam on early or late death. 95% CI 0. any important imbalance in treatment groups. and showed a haemorrhage in 31 patients (15 piracetam and 16 placebo) (PASS 1997). The planned sensitivity analyses were not possible because the required baseline data were not available or were not relevant. Although this last description was a bit unclear. as compared to 195 in the placebo group) there was no correlation identified between the treatment group and mortality.90. Information about the following aspects of trial quality that may relate to bias was not available from the examined trials: 1. it was merely stated that there was no difference between the two groups. very severe patients were not included in this study and therefore the imbalance in severity is based on a difference in a neurological scale which. The time of treatment from onset of stroke varied between 12 hours to ’preceding three days’. Overall.1).10. Only three of the 19 available studies fulfilled the entry criteria. All were truly randomised. 95% CI 0. Adverse events were not described in the trials. Published by John Wiley & Sons. However. However. using an ad hoc modified Barthel index.2). in itself. a hypotheses which has been tested in PASS II (PASS II 1998). in the odds of early death (that is. Characteristics of excluded studies. I2 = 35%) even though 93% of the data came from one single trial (PASS 1997). There was. Results on late death were only available for the PASS study. When we considered poor prognosis (that is. had adequate allocation concealment and were double blind. Effects of interventions The total number of individuals included in the three trials was 1002. In fact.96 to 1. we decided to include this study because it is reasonable to assume that only very few. When differences in stroke severity were accounted for (214 patients in the treated group had an Orgogozo scale of less than 35. df = 2. Original data have been provided to calculate dependence. at approximately one month) of 1.77 to 1. if we include early death data from this study (assuming a worst-case scenario whereby missing patients are recorded as dead) the overall result does not change. defining dependence as patients scoring less than 85 on the Barthel index. . we excluded the study by Creytens (Creytens 1980) because there was no CT examination to allow stroke diagnosis and pathological subgroup diagnosis. evaluated in only one study 4 Risk of bias in included studies We included three trials. 2. P > 0. in the analysis and summarised them in the ’Characteristics of included studies’ table. The trend towards an increased risk of early death among piracetam-allocated patients is a concern. and were closely similar to those at one month (OR 1. However. See ’Characteristics of included studies’. early case fatality was 18%. but our request was refused. we cannot include these results in this systematic review because they have not been made available. an unfavourable trend toward early death in the PASS study.20) (Analysis 2.32. If we consider data on dependence.01. non-significant reduction in the odds of being dependent with piracetam (OR 0. whereas. The manufacturer provided analysable disability data (460 and 463 patients. In the largest trial (PASS 1997) the sex ratio was almost one. the authors of this study controlled the possible imbalance of prognostic factors between the two groups with a logistic regression analysis.09. the number of patients excluded from analysis. However. as stated by the authors (PASS 1997). patients were treated after 48 hours. however. this was an ad hoc modification of the Barthel score. We attempted to obtain data from the drug company which owns the interim results. as it was an intention-to-treat analysis. which met our inclusion criteria.1).

16: 149–64. carotid territory stroke: a double-blind pilot study. Implications for research If the data from PASS II were made available. Konstantinova MV. data do not support the routine use of piracetam in the management of patients with acute ischaemic stroke. UCB sent us data on the PASS study (PASS 1997). Published by John Wiley & Sons. Hinton S. PASS 1997 {published and unpublished data} De Deyn P. Piracetam versus placebo in first. On the efficacy of piracetam in geriatric patients with acute cerebral ischemia: a clinical controlled doubleblind study. Stroke 2004. Skondia V. Stroke 1997. Kaunntz J. the available evidence does not suggest that further controlled trials of piracetam in acute stroke are justified. AUTHORS’ CONCLUSIONS ACKNOWLEDGEMENTS Implications for practice Trials of piracetam do not provide definite evidence of a beneficial or harmful effect on death in acute ischaemic stroke. It seems very unlikely that any further trial comparing piracetam with control. and this is a further limitation of these results. The effectiveness of piracetam in acute cerebral ischemia in man. . Patients with vertebrobasilar stroke were not included in any study.The metabolic therapy of acute stroke: the use of nootropil. which seeks to establish the effect of this drug in acute stroke reliably. Jekht AB. European Journal of Neurology 1997. the odds ratio is in the opposite direction but it comes close to unity when considering death plus dependence. Treatment of acute ischemic stroke with piracetam.97(10):24–8. Kartin 1979 {published data only} Kartin P.25:151–2. Symposium Piracetam. Medizinische Klinik 1988. et al. Qingkailing. non-haemorrhagic. Athens. Selikhova MV. The available We are grateful to the Cochrane Neurological Network and to the Chinese Cochrane Center for their help in translating the Chinese paper. pp 139-51.6:33–53. Vanichkyn AV. naofukang and ligustrazine for acute ischemic stroke.(PASS 1997).28:2347–52. Summa J. u chorych w podeszlym 5 References to studies excluded from this review Burd 1997 {published data only} Burd GS. Deberdt W. Vlietnick R. 29 April 1990. Burd GS. Pavlow NA. Korasakowa 1997. Orgogozo J. Gusev EI. Piracetam vs dextran 40 in acute ischaemic stroke in elderly patients [Porownanie skutecznosci piracetamu i dekstranu 40 tys. Acta Therapeutica 1979.83:667–77. Fritz V.4 Suppl 1:s51. Some new approaches in the treatment of cerebral pathology. for now. Kozubski 1998 {published and unpublished data} Kozubski W. Archives of Gerontology and Geriatrics 1993. Clinical study of piracetam in patients with subacute cerebrovascular accidents. Esser J. Karoutas 1990 {published data only} Karoutas G. Tolerability and efficacy of the combination of piracetam and citicoline in acute ischaemic stroke. Platt 1993 {published data only} Platt D. Povse M. Skvortsova VI. Acta Therapeutica 1980. Bolotov DA. it might be possible to reassess the need for further randomised controlled trials of this agent in acute stroke. Kronert E.35(6): e286. Herrschaft 1988 {published data only} Herrshaft H. Symposium Piracetam. will now be conducted.5:235–43. 1990: 135–8. A Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. Villanueva Osorio JA. The use of piracetam (nootropil) in acute hemispheric ischemic stroke (HIS). placebo controlled study of piracetam in patients with acute ischaemic cerebral infarct in carotid territory. ∗ Kozubski W. Huo 2004 {published data only} Huo Q. for members of the Piracetam in Acute Stroke Study (PASS) Group. Diaz Otero F. Zhurnal Nevrologii I Psickhiatrii imenuii S. double blind. Comparison of piracetam vs dextran 40 in ischemic stroke in elderly patients. Ltd. Greece. Creytens 1980 {published data only} Creytens G. Winterton R. Garcia Pastor 2004 {published data only} Garcia Pastor A.2 Suppl 2:27. Shimitt-Ruth R. Gusev 1997 {published data only} Gusev EI.S. European Journal of Neurology 1995. randomised comparative open study. De Reuck J. REFERENCES References to studies included in this review Ming 1990 {published data only} Ming A. A randomised. However. Gill Lunez AC. Shaanxi Journal of Traditional Chinese Medicine 2004. acute. Skwortsova VI. Horn J.

Crasborn L. CNS Drugs 1996. Issue 2. Effect of fluoxetine on treatment of post stroke depression. [DOI: 10. References to other published versions of this review Ricci 1999 Ricci S. Kozubski W.22(1):19–21. Journal of Neurology 1997.51(7-8):321–5. Chi Z.a single blind study. Wiadomosci Lekarskie 1998.122(6):484–6. Misirli A. Li Y-Z. Righetti E. Zhou JC.43:110–8. Pharmacological treatment for aphasia following stroke. PASS II 1998 {published and unpublished data} Orgogozo JM. Klausnitzer W. Citicoline capsules vs piracetam tablets in treatment of cerebral infarction. Ganglioside GM1 in treating acute cerebral infarction. Lavenne-Pardonge E.5(6): 1–12.2:235. Randomized placebo-controlled double-blind cross-over study on antihyoxidotic effects of piracetam using psychophysiological measures in healthy volunteers.wieku z niedokrwiennym udarem mozgu].1002/ 14651858. Schaffler 1988 Schaffler K. Cochrane Database of Systematic Reviews 2001. European Journal of Neurology 1997. Leemans R. Greener 2001 Greener J. Medizinische Klinik 1978. The effect of piracetam on global and regional cerebral blood flow in acute cerebral ischemia of man. Revue Neurologique (Paris) 1970.1002/ 14651858. Piracetam for acute ischaemic stroke. Wang YS. Issue 4. Primary study of jiannaojiangzhi on treatment of 309 patients with cerebral infarction. [DOI: 10. Zhang 2002 {published and unpublished data} Zhang L-L. Righetti E. Cantisani TA. Chinese Journal of Practical Internal Medicine 1998.38:288–91. Chinese Journal of New Drugs and Clinical Remedies 2003. Issue 2. Liu S. Cochrane Database of Systematic Reviews 2006. Platelet antiaggregant and rheological properties of piracetam: a pharmacodynamic study in normal subjects. Li H-Y. The value of piracetam on acute ischemic stroke. Shan 2001 {published data only} Shan P. Shi 1998 {published data only} Shi FC.CD000424] Herrschaft 1978 Herrschft H. Meng 2003 {published data only} Meng QL. Cerebrovascular Diseases 1992.18(6):348–9. Van Vleymen B. Electropharmacologic correlations in oxygen deficient Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. Altunine M.244 Suppl 3:s55. Ozge A.4 Suppl 1:152.39(3):229–30. Lebedeva N. Mouravieff-Lesuisse F.21:202–4. Piracetam Acute Stroke Study II (PASS II). Erenoglu N. Ltd. [MEDLINE: ISSN 1007-7669] anoxia of rabbits in natural or artificial respiration [Correlations electro–pharmacologiques au cours de l’anoxic oxyprive chez le lapin en respiration libre ou artificielle]. Piradov 1992 {published and unpublished data} Piradov M. Cochrane Database of Systematic Reviews 1999. Susline Z.CD000419] ∗ Indicates the major publication for the study Additional references Giurgea 1970 Giurgea C. Benfield P. Celani MG. 6 . Geng JG. Erdogan N. Piracetam: a review of its potential as a rehabilitative treatment after stroke. Ozalp K. ArzneimittelForschung 1993. Acta Academiae Medicinae Shandong 2001. Noble 1996 Noble S. Celani MG. Piracetam in acute ischaemic stroke. for the PASS II Group. Enderby P. [DOI: 10. Published by John Wiley & Sons. Whurr R. Cantisani TA. Shchunkin J. Cerebrovascular Diseases 1998. De Reuck J. Chinese Journal of New Drugs and Clinical Remedies 2002.73:195–202.8 Suppl 4:84. Moriau 1993 Moriau M. Piracetam for acute ischaemic stroke. Piracetam vs dextran 40 in acute ischemic stroke in elderly patients . Tunali 1997 {published data only} Tunali F.CD000419] Ricci 2006 Ricci S. Arzneimittel-Forschung 1988.1002/ 14651858.

dipyridamole and ticlopidine forbidden 927 patients included Inclusion criteria: age 40 to 85.8 g orally daily for other 25 days versus placebo Impairment scales (not analysed in this review) Death rate available from the study Participants Interventions Outcomes Notes Risk of bias Bias Allocation concealment (selection bias) Authors’ judgement Low risk Support for judgement A .Adequate PASS 1997 Methods Parallel multicentre RCT Follow-up at 4 and 12 weeks Low-dose heparin allowed. Orgogozo scale greater than 5 and less than 70 Piracetam 12 g iv daily for 4 days then 12 g daily for 4 weeks orally.CHARACTERISTICS OF STUDIES Characteristics of included studies [ordered by study ID] Ming 1990 Methods Parallel RCT 30 days follow-up Co-interventions (standard symptomatic treatment) 19 patients included Inclusion criteria: 40 to 80 years. haemodilution. full dose heparin allowed after 48 hours ASA not recommended during the first 24 hours Thrombolysis. clinically supratentorial ischaemic stroke within 12 hours.8 g daily orally for 8 weeks versus placebo Orgogozo scale Modified Barthel scale Death rate available from the study. Ltd. first ischaemic supratentorial stroke. arousable patients. within 48 hours. 7 . Published by John Wiley & Sons. both at 4 and 12 weeks Participants Interventions Outcomes Notes Risk of bias Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. then 4. no midline shift on CT. then 4. GCS > 4 Piracetam 12 g iv daily for 5 days.

8 . with supratentorial first ischaemic stroke within preceding 3 days (exact time not clearly stated) Exclusion criteria included cerebral oedema and contraindication of hypervolaemic haemodilution Piracetam 12 g iv daily for 2 weeks and then 4.PASS 1997 (Continued) Bias Allocation concealment (selection bias) Authors’ judgement Low risk Support for judgement A .Adequate Platt 1993 Methods Parallel RCT 28 days follow-up Co-interventions (heparin 15000 U daily and haemodilution) 56 patients included Inclusion criteria: above 65 years.8 g orally daily for 2 weeks versus placebo Cerebral flow measured by SPECT and motor neurological scales (not analysed in this review) Death rates available in the text More women were randomised to piracetam than to placebo 2 patients in the piracetam group had a haemorrhagic stroke Participants Interventions Outcomes Notes Risk of bias Bias Allocation concealment (selection bias) Authors’ judgement Low risk Support for judgement A .Adequate ASA: acetylsalicylic acid (aspirin) CT: computed tomography GCS: Glasgow Coma Scale iv: intravenous RCT: randomised controlled trial SPECT: Single Photon Emission Computed Tomography Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons. Ltd.

a new patient was enrolled into the study as a substitute. The study compares piracetam to citicoline. nor on follow-up after 30 days It is not clear from the study whether and how the study was randomised. therefore haemorrhages or cerebral neoplasms cannot be ruled out. but the time interval was not clearly defined in the reply Garcia Pastor 2004 Gusev 1997 Herrschaft 1988 Huo 2004 Karoutas 1990 Kartin 1979 Kozubski 1998 Meng 2003 PASS II 1998 Piradov 1992 Shan 2001 Shi 1998 Tunali 1997 Zhang 2002 CT: computed tomography Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. Time to randomisation was not stated.Characteristics of excluded studies [ordered by study ID] Study Burd 1997 Creytens 1980 Reason for exclusion The study appears not to be randomised. but is about post-stroke depression There is no information on case-fatality rate. No data on mortality are available There is no control group. were unsuccessful Only patients who completed the treatment were analysed. There was no control group This study compares piracetam or citicoline to GM1. Our requests for data. but piracetam + ligustrazine are compared with a Chinese drug No definition of the time interval from the event to inclusion. No more information from UCB Pharma (the manufacturer) is available The study compares piracetam to citicoline and to the combination of the 2 drugs in 70 patients with acute ischaemic stroke. When a patient stopped the treatment for any reason. Information in the original Chinese version was requested from the Chinese Cochrane Center. 9 . We wrote to the authors for clarification but have not received a reply There is no CT diagnosis of the possible cerebral ischaemia. No results were made available to the scientific community. Randomisation procedure not stated This study is not of acute stroke patients. No data on mortality are available Time interval from the ischaemic cerebral event to inclusion was 2 weeks. There is no control group This is a non-randomised comparative study Patients included up to 5 days after their stroke. made both to the main investigator and the sponsor. Published by John Wiley & Sons. Patients were selected and not randomised In this study 47 acute stroke patients were randomly allocated to piracetam plus dextran versus dextran. There is no control group This study was interrupted by the sponsor after a futility analysis. Ltd. No information from the authors was available Time interval is not stated in the English version of the paper.

95% CI) Peto Odds Ratio (Peto. Dependence at 12 weeks Outcome or subgroup title 1 Dependence at 12 weeks No. Ltd.DATA AND ANALYSES Comparison 1. Piracetam versus control Outcome or subgroup title 1 Death at approximately 1 month 2 Death at 12 weeks No.80] Comparison 2.97. 95% CI) Effect size 0. Fixed.32 [0.01 [0.67. 1. of studies 1 No. 10 . Fixed. of participants 723 Statistical method Peto Odds Ratio (Peto.90 [0. of participants 1002 927 Statistical method Peto Odds Ratio (Peto. Published by John Wiley & Sons. Fixed. 1.20] Comparison 3. of participants 923 Statistical method Peto Odds Ratio (Peto. 1. of studies 1 No.32] Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. 1. of studies 3 1 No.82] 1.77. Fixed.96. 95% CI) Effect size 1. Death or dependence at 12 weeks Outcome or subgroup title 1 Death or dependence at 12 weeks No. 95% CI) Effect size 1.32 [0.

95% CI Ming 1990 Platt 1993 PASS 1997 0/10 3/27 99/464 1.32 [ 0.1 % 0. Outcome 1 Death at approximately 1 month. 5.21).11 [ 0. df = 2 (P = 0. 1.5 1 2 5 10 Favours treatment Favours control Analysis 1. 89 (Control) Test for overall effect: Z = 1. Outcome 2 Death at 12 weeks.95% CI PASS 1997 111/464 100.2.38 [ 0.01. Review: Piracetam for acute ischaemic stroke Comparison: 1 Piracetam versus control Outcome: 2 Death at 12 weeks Study or subgroup Treatment n/N Control n/N 89/463 Peto Odds Ratio Peto. 1.97.71 (P = 0. Comparison 1 Piracetam versus control.97.Fixed.32 [ 0.92 ] Total (95% CI) 501 501 100.95% CI Weight Peto Odds Ratio Peto.0 % 1.2 0.1.09. Published by John Wiley & Sons.96.Analysis 1.1 0.0 % 1.2 0.99.80 ] 1.082) Test for subgroup differences: Not applicable 0.1 0.08 [ 0. 81 (Control) Heterogeneity: Chi?? = 3. Review: Piracetam for acute ischaemic stroke Comparison: 1 Piracetam versus control Outcome: 1 Death at approximately 1 month Study or subgroup Treatment n/N Control n/N 2/9 3/29 76/463 Peto Odds Ratio Peto.82 ] Total events: 102 (Treatment).0 % 1.74 (P = 0.3 % 3.087) Test for subgroup differences: Not applicable 0.Fixed. 1. 1.80 ] Total events: 111 (Treatment). Ltd.5 1 2 5 10 Favours treatment Favours control Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. 11 .20.86 ] 1.Fixed.6 % 95.95% CI Weight Peto Odds Ratio Peto.80 ] Total (95% CI) Heterogeneity: not applicable 464 463 100. 1. Comparison 1 Piracetam versus control.Fixed.32 [ 0. I?? =35% Test for overall effect: Z = 1.

Review: Piracetam for acute ischaemic stroke Comparison: 2 Dependence at 12 weeks Outcome: 1 Dependence at 12 weeks Study or subgroup Treatment n/N Control n/N 205/374 Peto Odds Ratio Peto.47) Test for subgroup differences: Not applicable 0.Fixed.0 % 0.32 ] Total events: 293 (Treatment).2 0. 1.5 1 2 5 10 Favours treatment Favours control Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. 1.1 0.77. Outcome 1 Dependence at 12 weeks.95) Test for subgroup differences: Not applicable 0.Fixed.0 % 1. Comparison 3 Death or dependence at 12 weeks. Published by John Wiley & Sons. 1.0 % 1.Fixed. Ltd.20 ] Total (95% CI) Heterogeneity: not applicable 349 374 100.90 [ 0. 205 (Control) Test for overall effect: Z = 0. 1.1. Comparison 2 Dependence at 12 weeks.Analysis 2.77.95% CI Weight Peto Odds Ratio Peto.32 ] Total (95% CI) Heterogeneity: not applicable 460 463 100.0 % 0.1.90 [ 0.95% CI PASS 1997 293/460 100.01 [ 0.67.20 ] Total events: 182 (Treatment).1 0.2 0.01 [ 0.06 (P = 0.5 1 2 5 10 Favours treatment Favours control Analysis 3.95% CI Weight Peto Odds Ratio Peto.67. 12 .Fixed. Review: Piracetam for acute ischaemic stroke Comparison: 3 Death or dependence at 12 weeks Outcome: 1 Death or dependence at 12 weeks Study or subgroup Treatment n/N Control n/N 294/463 Peto Odds Ratio Peto. 294 (Control) Test for overall effect: Z = 0. Outcome 1 Death or dependence at 12 weeks.95% CI PASS 1997 182/349 100.72 (P = 0.

Enderby and Whurr: Pharmacological treatment for aphasia following stroke) will only include patients with long-term post-stroke aphasia. 1 or 2 or 5 7. 7 or 8 10. 9. 5. and will only look at aphasia as an outcome measure. 6 and 9 FEEDBACK Comment Summary The reviewer has given the impression that a related Cochrane protocol (Greener.tw. MEDLINE search strategy MEDLINE (Ovid) 1. (brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation). 6 and 9 Appendix 2. 13 . 5.tw. Ltd.tw. Piracetam/ 8. (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$). 3 and 4 6. Piracetam/ 8. (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or transient isch?emic attack$ or tia$). (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or transient isch?emic attack$ or tia$). Published by John Wiley & Sons. Reply Ms Greener is right since her review of piracetam for stroke will cover the treatment of aphasia at any time after stroke while our review deals with the effects of piracetam on functional outcome when given during the acute phase of stroke. 4.tw. EMBASE search strategy EMBASE (Ovid) 1. (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$). and will include disability as an outcome measure. Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. 3. cerebrovascular disease/ or cerebral artery disease/ or cerebrovascular accident/ or stroke/ or vertebrobasilar insufficiency/ or carotid artery disease/ or exp carotid artery obstruction/ or exp brain infarction/ or exp brain ischemia/ or exp occlusive cerebrovascular disease/ or stroke patient/ 2. 7 or 8 10. cerebrovascular disorders/ or basal ganglia cerebrovascular disease/ or exp brain ischemia/ or carotid artery diseases/ or carotid artery thrombosis/ or intracranial arterial diseases/ or cerebral arterial diseases/ or exp “intracranial embolism and thrombosis”/ or exp stroke/ 2. 3. (piracetam or nootropil or nootropyl or pirazetam or pyramem or UCB.tw. 1 or 2 or 5 7. The proposed review will in fact cover patients with aphasia at any time after their stroke. (brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or middle cerebr$ or mca$ or anterior circulation). 4. 3 and 4 6.tw. 9.APPENDICES Appendix 1. (piracetam or nootropil or nootropyl or pirazetam or pyramem or UCB-6215 or 2-pyrrolidone-n-acetamide).tw.tw.6215 or 2-pyrrolidone-n-acetamide).

Date 28 May 2012 18 May 2011 Event Description New citation required but conclusions have not changed The conclusions have not changed. Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. 1997 Review first published: Issue 2. We did not identify any new relevant trials HISTORY Protocol first published: Issue 3. We found no new relevant information up to June 2005. Published by John Wiley & Sons. and a final agreement reached. 14 .Contributors Comment: Jenny Greener Reply: Stefano Ricci WHAT’S NEW Last assessed as up-to-date: 18 May 2011. possibly because these data are very old and the authors may have changed address. 1999 Date 30 September 2008 7 November 2005 Event Amended New search has been performed Description Converted to new review format. Tunali 1997) in a standardised format but have received no response from the study authors. Ltd. The PASS II study (PASS II 1998) was interrupted based on the results of a futility analysis. We requested data from the manufacturer but the answer was negative CONTRIBUTIONS OF AUTHORS S Ricci and MG Celani extracted data from the original trials and prepared a summary. this summary was discussed with E Righetti and TA Cantisani. The final revision was written according to this agreement by all the authors. We requested information on two trials (Burd 1997. New search has been performed We have updated the searches to 15 May 2011.

∗ therapeutic use]. mortality] MeSH check words Humans Piracetam for acute ischaemic stroke (Review) Copyright © 2012 The Cochrane Collaboration. mortality]. ∗ therapeutic use]. Neuroprotective Agents [adverse effects. Piracetam [adverse effects. 15 .DECLARATIONS OF INTEREST None known. INDEX TERMS Medical Subject Headings (MeSH) Acute Disease. Published by John Wiley & Sons. Brain Ischemia [drug therapy. Ltd. Stroke [∗ drug therapy.

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