inhibidores de los canales de calcio en ictus isquemico

8/21/2019 Inhibidores de los canales de Calcio en Ictus Isquemico

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Calcium antagonists for acute ischemic stroke (Review)

Zhang J, Yang J, Zhang C, Jiang X, Zhou H, Liu M

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published inThe Cochrane Library2012, Issue 5

http://www.thecochranelibrary.com

Calcium antagonists for acute ischemic stroke (Review)

Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/


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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

53DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 1 Primary outcome atend of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Analysis 1.2. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 2 Death at end of

treatment period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Analysis 1.3. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 3 Death at end of

follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Analysis 1.4. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 4 Recurrence of stroke

at end of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Analysis 1.5. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 5 Adverse events (all)

during treatment period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Analysis 1.6. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 6 Hypotension during

treatment period (reason to stop treatment). . . . . . . . . . . . . . . . . . . . . . . . 63

Analysis 1.7. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 7 Mean systolic blood

pressure during or at end of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . 64Analysis 2.1. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 1 Primary outcome by route

of administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Analysis 2.2. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 2 Primary outcome by dose:

indirect comparisons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Analysis 2.3. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 3 Primary outcome by dose:

direct comparisons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Analysis 2.4. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 4 Primary outcome by time

of start of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Analysis 3.1. Comparison 3 Calcium antagonists versus control: sensitivity analysis, Outcome 1 Primary outcome in

multicenter placebo controlled trials. . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Analysis 3.2. Comparison 3 Calcium antagonists versus control: sensitivity analysis, Outcome 2 Publication status. . 73

74APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

77DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iCalcium antagonists for acute ischemic stroke (Review)



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[Intervention Review]

Calcium antagonists for acute ischemic stroke

Jing Zhang1, Jie Yang2, Canfei Zhang1, Xiaoqun Jiang1, Hongqing Zhou1, Ming Liu1

1Department of Neurology, West China Hospital, Sichuan University, Chengdu, China. 2Department of Neurology, Nanjing First

Hospital, Nanjing Medical University, Nanjing, China

Contact address: Ming Liu, Department of Neurology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu,

Sichuan, 610041, [email protected].

Editorial group:Cochrane Stroke Group.

Publication status and date:New search for studies and content updated (no change to conclusions), published in Issue 5, 2012.

Review content assessed as up-to-date: 25 January 2012.

Citation: Zhang J, Yang J, Zhang C, Jiang X, Zhou H, Liu M. Calcium antagonists for acute ischemic stroke.Cochrane Database of

Systematic Reviews2012, Issue 5. Art. No.: CD001928. DOI: 10.1002/14651858.CD001928.pub2.


A B S T R A C T

Background

The sudden loss of blood supply in ischemic stroke is associated with the increase of calcium ions within neurons. Inhibiting this

increase could protect neurons and hence might reduce neurological impairment, disability and handicap after stroke.

Objectives

To determine whether calcium antagonists reduce the risk of death or dependency after acute ischemic stroke. To investigate theinfluence of different drugs, dosages, routes of administration, time intervals after stroke and trial design on the risk of a primary

outcome.

Search methods

We searched the Cochrane Stroke Group Trials Register (January 2012), MEDLINE (1950 to December 2011), EMBASE (1980 to

December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011 issue 4) and fourChinese databases (December 2011): Chinese Biological Medicine Database (CBM-disc), China National Knowledge Infrastructure

(CNKI), Chinese scientific periodical database of VIP information and Wanfang Data. We also contacted trialists and researchers.

Selection criteria

All truly randomized trials comparing a calcium antagonist with control in patients with acute ischemic stroke.

Data collection and analysis

Two authors assessed all trials and extracted the data. We used death or dependency at the end of long-term follow-up (at least three

months) in activities of daily living as the primary outcome. Analyses were, if possible, intention-to-treat.

Main results

We included 34 trials including 7731 patients.There was no effect of calcium antagonists on the primary outcome (risk ratio (RR)1.05; 95% confidence interval (CI) 0.98 to 1.13), or on death at the end of follow-up (RR 1.07, 95% CI 0.98 to 1.17). Comparisons

of different doses of nimodipine suggested that the highest doses were associated with poorer outcome.

1Calcium antagonists for acute ischemic stroke (Review)

mailto:[email protected]:[email protected]


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Authors conclusions

No evidence is available using calcium antagonists in patients with acute ischemic stroke is effective.

P L A I N L A N G U A G E S U M M A R Y

Calcium antagonists for acute ischemic stroke

The majority of ischemic strokes are due to blockage of an artery in the brain by a blood clot. The area of brain supplied by that artery

rapidly becomes damaged. Some of the damage to brain cells occurs because of a build-up of calcium ions inside the cells. Calcium

antagonists might reduce the damage by preventing calcium ions entering the cells. We searched for trials which assessed the effects

of calcium antagonists (given either by mouth or by intravenous injection) in patients with ischemic stroke. We found 34 studies,

including 7731 patients, that were suitable for inclusion in the review. There was no difference in deaths or survival free of disability

between patients who received calcium antagonists and those who did not. Patients who received calcium antagonists by intravenous

injection were slightly worse overall than those who received the drugs by mouth. In conclusion, the authors of this Cochrane review

found no evidence that giving calcium antagonists after acute ischemic stroke could save lives or reduce disability.

B A C K G R O U N D

Calcium antagonists may act as neuroprotective drugs by dimin-

ishing the influx of calcium ions through the voltage sensitive cal-

cium channels. One Cochrane review published in The CochraneLibraryhas already demonstrated that calcium antagonists couldreduce the risk of a primary outcome and secondary ischemia af-

ter aneurysmal subarachnoid hemorrhage (SAH) (Mees 2008).Of

course, there is a difference between the treatment of ischemic

stroke and the treatment of SAHs. At the same time, in stroke,

medication will be started after the onset of ischemia instead of

being given before. In view of the evidence on the existence of

an ischemic penumbra (Siesjo 1978), where brain tissue may

survive in ischemic periods of variable and as yet not precisely

determined duration, a therapeutic effect may be present when

administration starts up to several hours after stroke onset. There-

fore, it is necessary to test whether this kind of drug can play a

neuroprotective role and improve neurological impairment.

Description of the condition

Stroke is the second more common cause of death and the leading

cause of disability worldwide (Liu 2007). Approximately 87% of

all strokes are ischemic (i.e. due to a blockage of an artery in the

brain) (AHA 2007), which leads to the affected area being starved

of oxygen. Massive calcium influx entering into the cells is a final

common pathway that leads to cell death (Siesjo 1989). Therefore,

it is necessary to test any promising strategy that could help brain

cells recover by blocking calcium ions.

Description of the intervention

Calcium antagonists reduce the influx of calcium into the cell

through blocking calcium channels. Thus, a rationale for the use

of calcium antagonists for preventing secondary ischemia is based

on the notion that these drugs can counteract the influx of calcium

into the vascular smooth-muscle cell, thereby decreasing the rate

of vasospasm. Animal experiments have indicated that calcium

antagonists administeredafter cerebral ischemia may be effective inreducing infarct volume andlead to improvements in neurological

outcome (Germano 1987;Steen 1983). After their introduction

into clinical practice it was discoveredthat calcium antagonists also

had neuroprotective properties (Mees 2008). Calcium antagonists

reduce the risk of primary outcome and secondary ischemia after

SAH (Mees 2008), and nimodipine, a typical calcium antagonist,

has been shown to be effective in decreasing the occurrence of

death and disability (primary outcome) after SAH and traumatic

SAH in humans (Di Mascio 1994;Harders 1996;Pickard 1989).

We wondered whether calcium antagonists could have the same

effects in ischemic stroke patients.

How the intervention might work

Some meta-analyses with a more limited scope (restricted to ni-

modipine and completed before some recent trials were available)

have been performed (Di Mascio 1994; Gelmers 1990; Mohr

1994). In these meta-analyses, a beneficial effect of nimodipine

was not demonstrated, except in one subgroup analysis. This sub-

group analysis (patients treated within 12 hours of stroke onset)




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suggested that early treatment was effective and might lead to a

38% reduction in the odds of the primary outcome occurring

(Mohr 1994). Any subgroup analysis showing a beneficial effect

should be interpreted with caution, since there is always the dan-

ger that it might be a chance finding (Counsell 1994).

Why it is important to do this review

Calcium antagonists could protect neurons and hence might

reduce neurological impairment, disability and handicap after

stroke. Many calcium antagonists have been tested in randomized

controlled trials (RCTs) in patients with acute ischemic stroke,

but none of these trials have demonstrated a convincing benefi-

cial effect. However, the sample size might be too small to show

a result or significant clinical effect. For this reason a systematic

review was necessary. The last version of this Cochrane review was

published in 2000. Since then more trials have been published.

Therefore, we conducted this updated review to provide more up-to-date evidence for clinical practice.

O B J E C T I V E S

To determine whether using of calcium antagonists in patients

with acute ischemic stroke could (1) reduce the number of patients

who, at the end of follow-up, are either dead or severely disabled,

(2) reduce the risk of death during the treatment period or at the

end of follow-up and to make comparisons for different calcium

antagonist regimens (different drugs, oral or intravenous admin-istration, different dosages and various time intervals from onset

of symptoms until start of treatment) and different trial designs

(multicenter placebo-controlled trial, publication status).

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included all RCTs of calcium antagonists versus control

(placebo or standard medical treatment alone). We also included

trials comparing different routes of administration (oral versus in-

travenous administration) and different doses. We excluded trials

that were not truly randomized.

Types of participants

Patients with presumed or definite acute ischemic stroke that were

randomized within 14 days after stroke onset. All were confirmed

through computerized tomography (CT) or magnetic resonance

(MR)scanning.Two studies (Chandra 1995; Lowe 1989) included

some hemorrhagic stroke patients (255 patients included in total)but, since we could not extract the information for the ischemic

stroke patients only, we included all randomized patients.

Types of interventions

We included all types of calcium antagonists, given in any dose, by

the intravenous or oral route. These were defined as agents whose

principal mode of action is to inhibit the influx of calcium into

cells by way of the voltage-sensitive calcium channels.

We excluded trials that were confounded by the treatment or con-

trol group receiving another active therapy that had not been fac-

tored into the randomization.

Types of outcome measures

Primary outcomes

Primary outcome: defined as death (all-cause case fatality) or de-

pendency in activities of daily living at long-term follow-up (at

least three months). For assessing dependency, we used the follow-

ing available functional health scales: the Modified Rankin or Ox-

ford Handicap Scale (dependency > 3) (Bamford 1989), Glasgow

Outcome Scale (dependency < 4) (Jennet 1975), the Barthel Index

(dependency < 60) (Mahoney 1965), Toronto Stroke Scale (de-

pendency > 3) (Norris 1982) or the disability item in the Mathew

Impairment Scale (dependency = 7) (Mathew 1972). If more than

one scale was available, we selected the one with the smallest num-

ber of missing values (see theCharacteristics of included studies

table for details).

Secondary outcomes

1. Death from any cause during the scheduled treatment

period.

2. Death from any cause during long-term follow-up (at least

3 months).

3. Recurrent stroke during long-term follow-up.

4. Adverse effects of the drug (e.g. impairment of kidney

function, impairment of liver function, skin irritation, local

infusion-related irritation, nausea, etc) during the scheduled

treatment period.

5. Hypotension: substantial fall in blood pressure during the

scheduled treatment period.

6. Mean systolic blood pressure during the treatment period.

We recorded these events if they were mentioned as such in the

original paper, thus the definitions of the investigators were used.




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Search methods for identification of studies

See the Specialized register section in the Cochrane Stroke

Group module. We searched for trials in all languages and ar-

ranged translation of studies published in languages other than

English.

Electronic searches

We searched the Cochrane Stroke Group Trials Register (January

2012), MEDLINE (1950 to December 2011) (Appendix 1), EM-

BASE (1980 to December 2011) (Appendix 2) and the Cochrane

Central Register of Controlled Trials (CENTRAL) (The CochraneLibrary, 2011 issue 4) (Appendix 3). We also searched the follow-ingfour Chinese databases: Chinese BiologicalMedicine Database

(CBM-disc) (1978 to December 2011), China National Knowl-

edge Infrastructure (CNKI) (1980 to December 2011), Chinese

scientific periodical database of VIP information (1989 to Decem-

ber 2011) and Wanfang Data (http://www.wanfangdata.com/)

(1982 to December 2011).The Cochrane Stroke Group Trials SearchCo-ordinatordeveloped

the search strategies for MEDLINE, EMBASE and CENTRAL

andwe adapted theMEDLINE strategy forthe Chinese databases.

Searching other resources

In an effort to identify further published, ongoing and unpub-

lished trials we contacted trialists and researchers in the field.

Data collection and analysis

Two authors (JZ, JY) read the titles, abstracts and keywords of all

records identified from the searches of the electronic bibliographic

databases and excluded studies that were clearly irrelevant. We

obtained the full text of the remaining studies and the same two

authors selected trials for inclusion based on our defined criteria

and extracted the relevant data. The two review authors resolved

any disagreements by discussion andconsulteda third author (ML)

if necessary.

Selection of studies

To identify studies for further evaluation, we scanned the titles,

abstracts and keywords of every record found. We eliminated ar-

ticles on initial screening if we could determine from the title and

abstract that the article was not a report of an RCT or the trial did

not address the effect of calcium antagonists for acute ischemic

stroke. If there was any doubt about these criteria from the infor-

mation given in the title and abstract, we obtained the full text for

clarification. We developed an inclusion/exclusion form to assist

with the selection of trials. Two review authors (JZ, JY) indepen-

dently assessed the selection of studies and they resolved any dis-

agreements through consultation with a third review author (ML).

If they could not resolve disagreements in this way, they added the

article to those awaiting assessment and we contacted the study

authors for clarification.

Data extraction and managementTwo review authors (JZ, JY) independently extracted data on

methods, patients, interventions, outcomes and results, and

recorded the information on a data extraction form. The key in-

formation extracted was as follows.

1. General information: published/unpublished, title, authors,

reference/source, contact address, country, language of

publication, year of publication, duplicate publications, sponsor,

setting.

2. Trial characteristics: design, duration of follow-up, method

of randomization, allocation concealment, blinding (patients,

people administering treatment, people assessing outcome).

3. Interventions: intervention (dose, route, frequency,

duration, time interval from the stroke onset), controlledintervention (dose, route, frequency, duration), comedication(s)

(dose, route, frequency, duration).

4. Patients: inclusion/exclusion criteria, diagnostic criteria,

total number and number in each groups, age, baseline

characteristics, similarity of groups at baseline (including any

comorbidity), assessment of compliance, withdrawals (reasons/

description), subgroups.

5. Outcomes: outcomes specified above, any other outcomes

assessed, other events, length of follow-up, quality of reporting of

outcomes.

The same two review authors cross-checked all extracted data and

resolved any disagreements by discussion. If they could not reach

consensus, the third review author (ML) made the final decision.When patients were excluded or lost to follow-up after random-

ization or if any of the above data were unavailable from the pub-

lications, we sought further information by contacting the study

authors. If such information remained unavailable, all the review

authors decided whether or not to include the trial in the review.

Assessment of risk of bias in included studies

Two review authors (JZ, JY) independently evaluatedthe following

methodological qualities of allincluded studies. They resolved any

disagreements by discussion. If they could not reach consensus,

they asked another review author (ML) to make the final decision.

Sequence generation

Was the allocation sequence adequately generated? We classified

allocation sequence as low risk, high risk or unclear risk ac-

cording to theCochrane Handbook for Systematic Reviews of Inter-ventions(Higgins 2011).


http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.htmlhttp://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.htmlhttp://www.wanfangdata.com/http://www.wanfangdata.com/http://www.wanfangdata.com/http://www.wanfangdata.com/http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.htmlhttp://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.htmlhttp://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.html


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Allocation concealment

Was allocation adequately concealed? We classified allocation con-

cealment as low risk, high risk or unclear risk according to the

Cochrane Handbook for SystematicReviews of Interventions(Higgins2011).

Blinding of participants, personnel and outcome assessors

Was knowledge of the allocated interventions adequately pre-

vented during the study? We classified blinding as low risk, high

risk or unclear risk according to the Cochrane Handbook for Sys-tematic Reviews of Interventions(Higgins 2011).

Incomplete outcome data

Were incomplete outcome data adequately addressed? We clas-

sified studies as low risk, high risk or unclear risk according

to theCochrane Handbook for Systematic Reviews of Interventions(Higgins 2011). If there were patients excluded or lost to follow-

up after randomization or if any of the follow-up data were not

available from the publication, we sought further information by

contacting the study authors.

Selective outcome reporting

Were reports of the study free of suggestion of selective outcome

reporting? We classified studies as low risk, high risk or unclear

risk according to theCochrane Handbook for Systematic Reviews ofInterventions(Higgins 2011).

Measures of treatment effect

These measures are listed underTypes of outcome measures.

Unit of analysis issues

None.

Dealing with missing data

SeeData extraction and management.

Assessment of heterogeneity

We tested heterogeneity among trial results using the I2 statistic.

We considered a value greater than 50% as substantial heterogene-

ity.

Assessment of reporting biases

We examined publication and other biases using a funnel plot.

We plotted effect size against sample size, resulting in a graphical

display that gave some indication of whether or not some studies

had not been published or located.

Data synthesis

We performed statistical analysis using RevMan 5.1 (RevMan

2011). We reported the results as risk ratio (RR) with 95% confi-

dence interval (CI) for dichotomous data and as mean difference

(MD) with 95% CI for continuous data. We used a random-ef-

fects model to combine individual results regardless whether there

was significant heterogeneity or not.

Subgroup analysis and investigation of heterogeneity

For the subgroup analyses we collected information about route of

drug administration, dose and time interval of start of treatment.Heterogeneity might arise from a wide variety of factors, such

as the design of the trials, the type of patients included and so

on. We also examined the influence of exclusion of the trials on

heterogeneity.

Sensitivity analysis

According to the Cochrane Handbook for Systematic Reviews of In-terventions(Higgins 2011), we re-analyzed the data of these multi-center studies. We also re-analyzed the data according to the pub-

lication status.

R E S U L T S

Description of studies

See: Characteristicsof included studies; Characteristicsof excluded

studies.

Our method of independent data collection by two authors in-

creased accuracy. Much of our data were based on original data

sets. The majorityof trialswere performedwith nimodipine. Bayer

Germany provided results of various trials. The original data sets

were often more complete than the published data. For example,

in three trials a significant number of patients were excluded af-

ter randomization and outcomes were not presented in the pub-

lication (Martinez-Vila 1990;NEST 1993;Wimalaratna 1994),

while data on these patients were available from the original data

set.

However, in the trial ofHeiss 1990, the number of excluded pa-

tients in the published article was not accounted for in the original




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data set. We did the calculations based on the original data set.

Thus, there might be a slight difference from those data in the

published article.

In this update, we added four new included studies (Nag

1998;Shibuya 2005;Squire 1996;Sze 1998). One other study

(Tanahashi 2007) was unpublished and we could not access anydata, hence we included it in the review as an ongoing study.

Results of the search

From a total of 8003 articles generated by the electronic searches

and handsearches, we identified 53 studies using calcium antag-

onists in patients with acute ischemic stroke and included 34 in

this review. The total number of included patients was 7944: we

subsequently excluded 213 patients from VENUS 1999, which

were included in the previous version of this review, as they had

hemorrhagic stroke.

Included studiesSee Characteristics of included studies. Thirty-four trials (in-

cluding 7731 patients) met the inclusion criteria (ASCLEPIOS

1990;Bogousslavsky 1990;Bridgers 1991;Canwin 1993;Capon

1983;Chandra 1995;FIST 1990;Gelmers 1984;Gelmers 1988;

German-Austrian 1994; Heiss 1990; INWEST 1990; Kaste 1994;

Kornhuber 1993; Lamsudin 1995; Limburg 1990; Lisk 1993;

Lowe 1989;Martinez-Vila 1990;Mohr 1992;Nag 1998;NEST

1993; NIMPAS 1999; Oczkowski 1989; Paci 1989; Sherman

1986; Shibuya 2005; Squire 1996; Sze 1998; TRUST 1990;

Uzunur 1995; VENUS 1999; Wimalaratna 1994; Yordanov

1984).

The age of patients in the included studies ranged from 18 to 85

years, with the average age ranging from 52.3 to 74.6 years. Mostof the trials included more males than females, which is consistent

with the fact that stroke is more common among men worldwide.

In the 34 included trials, nimodipine was used as the treatment in

26 trials, flunarizine in three trials (FIST 1990;Kornhuber 1993;

Limburg 1990), and isradipine (ASCLEPIOS 1990), nicardip-

ine (Lisk 1993), PY108-608 (Oczkowski 1989), fasudil (Shibuya

2005), and lifarizine (Squire 1996) in one trial respectively. These

calcium antagonists were administered intravenously or orally in

different dosage and different time intervals from stroke onset,

therefore we did subgroup analyses according to these different

dosages and time intervals from stroke onset.

Most trials reported that antiplatelet and anticoagulate therapy

were added to both treatment and control groups.

Death was reported in 31 trials, but only six of which reported

details of the causes of death (Capon 1983;Gelmers 1988;Kaste

1994; Kornhuber1993; Martinez-Vila1990; Sze1998). Themain

causes of death in these six trials were stroke recurrence, cardiac

infarction, cardiac failure and pneumonia.

Only 13 trials reported adverse events.There were 251/2810

(8.93%) in the treatment group and 157/2285 (6.87%) in the

control group. We defined severe adverse events as epilepsy, brady-

cardia, gastrointestinal bleeding and deep venous thrombosis.

Epilepsy occurred in three patients (3/2810, 0.11%) in the treat-

ment group and in two patients (2/2285, 0.09%) in the control

group, bradycardia occurred in two patients (2/2810, 0.07%) in

the treatment group and in two patients (2/2285, 0.09%) in thecontrol group, gastrointestinal bleeding occurred in two patients

(2/2810, 0.07%) in the treatment group and in two patients (2/

2285, 0.09%) in the control group, and deep venous thrombosis

occurred in four patients (4/2810, 0.14%) in the treatment group

and in one patient (1/2285, 0.04%) in the control group. The pa-

tients who suffered from severe hypotension (reported in six trials

with 1667 participants) were 15/827 (1.81%) in the treatment

group and 10/840 (1.2%) in the control group, and were too se-

vere to be excluded.

Excluded studies

We excluded 13 studies. For details see Characteristics of excludedstudies.

Risk of bias in included studies

Allocation

Five trials(Heiss 1990; Limburg 1990; Lowe 1989; Shibuya 2005;

Wimalaratna 1994) allocated participants by random table, one

trial (Bogousslavsky 1990) by random list, and one trial (Gelmers

1988) used a different method. Five trials (Gelmers 1988;Heiss1990; Mohr1992; Sze1998; VENUS1999) used numberedboxes

as the allocation concealment method. The remaining trials did

not report the method of random sequence generation and alloca-

tion concealment, hence we graded random sequence generation

and allocation concealment for these trials as unclear risk.

Blinding

All the trials used placebo as the control except three: one com-

pared the different results between intravenous and oral nimodip-

ine without a placebo group (Chandra 1995), and two were open

control (Gelmers 1984;Uzunur 1995).

Five trials(Canwin 1993; Capon1983; Lowe 1989; Uzunur 1995;

Yordanov 1984) did not report the method of blinding. Three

trials(Gelmers1984; Martinez-Vila1990; Sze1998) reported they

were single blind trials - two did not describe which participants

were blinded (Gelmers 1984;Martinez-Vila 1990), one reported

that the assessors were blinded (Sze1998). The remaining 26 trials

reported they were double-blind trials, but only one reported that

the assessors were blinded (Shibuya 2005).




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Incomplete outcome data

Only seven trials (Gelmers 1984;Lisk 1993;Lowe 1989;Mohr

1992;Oczkowski 1989;Shibuya 2005;VENUS 1999) reported

no patient losses at follow-up. One trial (INWEST 1990) reported

there were some patients lost but there was no difference after

an intention-to-treat (ITT) analysis of the results. We could notobtain any information about incomplete outcome data in six

trials (Capon 1983;Chandra 1995;Lowe 1989;Sherman 1986;

Uzunur 1995;Yordanov 1984); we categorized the remaining 20

trials as high risk for incomplete data since they all had data loss

and no ITT analysis.

Selective reporting

None of the trial protocols were available but it was clear from

the published reports that none included the primary outcome for

this review of death or dependency at the endof long-term follow-

up. Therefore, there was insufficient information for us to make

a judgement on selective reporting.

Other potential sources of bias

None

Effects of interventions

Primary outcome

Death or dependency at end of follow-up

Data from 22 trials with 6684 participants were available. No

difference was found between patients using calcium antagonists

or not. If anything, there may be a small but detrimental effect

(RR 1.05, 95% CI 0.98 to 1.13). For these 22 trials, there were

three drugs involved, nimodipine in 19 trials, flunarizine in two

trials and isradipine in one trial. The indirect comparisons of the

different drugs did not show clear evidence of differences between

different drugs (Analysis 1.1).

Heterogeneity was present (P = 0.09, I2 = 64%, df = 1) in the

analysis of Flunarizine versus control, in which only two trials

(FIST 1990;Limburg 1990) were included. InFIST 1990, therewere 331 participants involved while in Limburg 1990, only 26

participants were involved, the lattermight be themost substantial

cause of the heterogeneity.

A funnel plot showed obvious publication bias existed (Figure 1).

Figure 1. Funnel plot of comparison: primary outcome at end of follow-up.




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Secondary outcomes

Death at end of treatment period

Data were available from 22 trials with 6323 participants. No dif-ference was found for death at the end of treatment period (RR

1.06, 95% CI 0.93 to 1.20). In patients treated with intravenous

flunarizine we also found there was no statistically significant in-

crease in mortality, although it was related to a worse outcome

(RR 1.31, 95% CI 0.94 to 1.82) (Analysis 1.2).

A funnel plot showed there was obvious publication bias (Figure

2).

Figure 2. Funnel plot of comparison: death at end of treatment period.




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Death at end of follow-up

Data were available from 31 trials with 7483 participants. In this

analysis there was no difference found for death (RR 1.07, 95%

CI 0.98 to 1.17). In patients treated with intravenous flunarizine,

there was a statistically significant increase in mortality, which was

relatedto a worse outcome (RR 1.34, 95% CI1.01 to 1.77). Asfor

the other calcium antagonists, nimodipine, isradipine, lifarizine,

PY106-608 and nicardipine, no difference was found (Analysis

1.3).

A funnel plot showed there was obvious publication bias (Figure

3).

Figure 3. Funnel plot of comparison: death at end of follow-up.

Recurrence of stroke at end of follow-up

Only a limited number of reports mentioned stroke recurrences

(nine trials with 2460 participants). There wasno difference in the

number of events between treatment groups and control groups,

(RR0.93,95% CI 0.56 to1.54). However, the confidenceintervals

were wide (Analysis 1.4).

All adverse events during treatment period

Adverse events were more frequent in the intervention groups

(8.9% versus 6.9%). About half of the excess of adverse events in

the treatment groups were caused by thrombophlebitis due to in-

travenous administration of flunarizine (after correction for differ-

ences in the size of the active and control groups). The occurrence

of hypotension (defined as episodes leading to cessation of drug




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treatment) wasmentioned in only fivetrials andwas more frequent

in the treatment group (1.8% versus 1.2%). Very limited data on

mean systolic blood pressure in three trials supported this. The

difference was statistically significant, but very small. Bias might

play a role here, as studies would be more likely to present blood

pressure data if imbalances occurred.In the largest flunarizine trial there was a clear increase of adverse

events in the treated group (33% versus 10%, RR 3.16, 95% CI

1.91 to 5.21). This was mainly due to an excess of superficial

thrombophlebitis inthe flunarizine group.In therest of thestudies

there was no difference in adverse events. The overall result was a

RR of 1.18 (95% CI 0.81 to 1.74) (Analysis 1.5).

Heterogeneity was strongly present in this analysis, caused by the

results of the intravenous flunarizine trialFIST 1990, the consid-

erable heterogeneity could be completely reversed by removing it.A funnel plot showed there was obvious publication bias (Figure

4).

Figure 4. Funnel plot of comparison: adverse events (all) during treatment period.

Hypotension during treatment period

In six trials with 1667 participants episodes of hypotension (suf-ficient to stop treatment) were mentioned. Hypotensive episodes

were more frequent in the treatment groups (1.8% versus 1.2%,

RR 1.43, 95% CI 0.61 to 3.38), but there was no statistically sig-

nificant difference (Analysis 1.6).

Mean systolic blood pressure during or at end of treatment

Data were available in three trials with 630participants. The mean

bloodpressure inthe treated groupswas onaverage 2 mmHg lower.

This was a very small difference. The result was not statisticallysignificant (MD: -1.30, 95% CI -3.92 to 1.32) (Analysis 1.7).

There was considerable heterogeneity, which could be completely

reversed by removingMartinez-Vila 1990.

Subgroup analyses




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Primary outcome by route of administration

Data were available for 23 trials: 14 trials with 5131 participants

by oral administration, eight trials with 1544 participants by intra-

venous administration, and one trial with 143 participants com-

pared oral and intravenous administration directly. Intravenous

administration was associated with a worse outcome in treatedgroups compared with placebo controls (RR 1.11, 95% CI 1.01

to 1.22). In the orally treated groups no difference was present

(RR 1.03, 95% CI 0.93 to 1.14) (Analysis 2.1).

The only direct comparison between oral and intravenous admin-

istration of nimodipine did not support the notion that intra-

venous administration was associated with poorer outcome (RR

7.10, 95% CI 0.37 to 134.96) (Chandra 1995) (Analysis 2.1).

Primary outcome by dose: indirect comparisons

Data were available for 18 trials: one trial with 529 participants

using 60 mg oral nimodipine per day, 14 trials with 4526 par-ticipants using 120 mg oral nimodipine per day, two trials with

637 participants using 240 mg oral nimodipine per day, four trials

with 552 participants using 2 mg/hour intravenous nimodipine

per day, and two trials with 329 participants using 1 mg/hour in-

travenous nimodipine per day. The indirect comparisons did not

show a clear dose-dependent treatment effect. Nimodipine, given

orally at 60 mg, 120 mg and 240 mg versus control yielded the

following risk ratios: 1.08, 0.99 and 1.07 (i.e. did not show sta-

tistically significant difference). Intravenous nimodipine of 2 mg/

hour showed a non-significant increase in the odds of the primary

outcome (RR 1.34, 95% CI 0.93 to 1.93), the significant differ-

ence in the group treated intravenously with 1 mg/hour was not

clear (RR 1.09, 95% CI 0.91 to 1.29) (Analysis 2.2).Heterogeneity existed in the analysis of nimodipine 2 mg/hour

versus control in the primary outcome by dose, and it was largely

caused byBridgers 1991. Removing this trial decreased the het-

erogeneity but did not eliminate it.

Primary outcome by dose: direct comparisons

These direct comparisons were possible in very few trials: data

were available in six trials, including one trial with 533 partic-

ipants comparing 60 mg and 120 mg oral nimodipine per day,

one trial with 532 participants comparing 60 mg and 240 mg oral

nimodipine per day, two trials with 681 participants comparing

120 mg and 240 mg oral nimodipine per day, two trials with 333

participants comparing 1 mg/hour and 2 mg/hour intravenous

nimodipine. This direct comparison showed that 120 mg was as-

sociated with slightly better results than 60 mg and 240 mg. A

dose-dependent relationship seemed to exist for intravenous ni-

modipine. For both routes, the highest doses were associated with

poorer outcome (Analysis 2.3).

Primary outcome by time start of treatment

Data were available for 32 trials, including 18 trials with 1879

participants whose treatment started within 12 hours after stroke

onset and 14 trials with 4071 participants whose treatment started

after 12 hours from stroke onset. This comparison showed early

treatment ( 12 hours after stroke onset) with calcium antago-nists was associated with an increase in the odds of primary out-

come, compared with placebo (RR 1.08, 95% CI 0.96 to 1.21).

Treatment after 12 hours gave no effect whatever (RR 1.01, 95%

CI 0.90 to 1.13). This analysis might be confounded by route of

administration (Analysis 2.4).

Sensitivity analyses

Primary outcome in multicenter placebo-controlled trials

Of the 34 included trials, 10 trials including 4012 participants

reported that their data were from multicenter placebo-controlledtrials. We did the primary outcome analysis on these 10 trials (RR

1.04, 95%CI 0.95 to 1.14) and found there wasno clear difference

between it (Analysis 3.1) and the Primary outcome at the end of

follow-up (Analysis 1.1).

Analysis 3.6: Publication status

Data were from 22 trials, including 18 trials with 5887 partici-

pants from which we could extract the primary outcome from the

published papers, and four trials with 788 participants with un-

published data. The published trials did not show an overall effect

of active treatment (RR 1.03, 95% CI 0.94 to 1.12) on primary

outcome. On the contrary, the unpublished trials were associatedwith a deleterious effect of calcium antagonist treatment, the over-

all RR was 1.14 (95% CI 1.00 to 1.30) (Analysis 3.2).

D I S C U S S I O N

This systematic review of all available data failed to demonstrate a

reduction in mortality and dependency after treatment with cal-

cium antagonists in patients with acute ischemic stroke. Due to

the large amount of data (34 trials including 7731 patients), con-

fidence intervals were narrow and the overall result was therefore

subject to limited statistical uncertainty.

Intravenous administration of calcium antagonists was not asso-

ciated with a statistically significant increased risk of primary out-

come. For nimodipine, data were available to analyze dose depen-

dency, which appeared to be present. A higher dosage (2 mg/hour)

led to a significant increase in the risk of primary outcome com-

pared with a dosage of 1 mg/hour, which was also associated with

a significant increased risk of primary outcome as compared with




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placebo. When comparing different oral dosages of nimodipine,

60 mg and 240 mg were associated with a non-significant increase

in primary outcome; 120 mg did not show any clear effect.

The quality of the included trials of calcium antagonists for is-

chemic stroke wasgenerally good. Alltrials included were placebo-

controlled trials except Chandra 1995, Gelmers 1984and Uzunur1995, and all trials used a blinding method except fivetrials. How-

ever, there were still two main drawbacks: (1) only seven trials

reported the methods of random sequence generation and only

five trials reported the method of allocation concealment, which

might lead to selection bias, and (2) we categorized incomplete

outcome as low risk in only eight trials, and as most participants

were excluded in the treatment period and lost at follow-up, this

might lead to reporting bias.

Wedid two sensitivity analyses: one based on the primary outcome

in multicenterplacebo-controlled trials and the otheron published

trials, while drawing the same conclusions.

The findings were intriguing regarding the time interval between

stroke onset and the start of treatment. Based on the previous

meta-analysis byMohr 1994, we expected to find an improved

outcome inthe early-treated group (defined as those treated within

12 hours after stroke onset). However, this was not the case. On

the contrary, early treatment was associated with a non-significant

increase in the risk of primary outcome or death. When patients

were treated late (more than 12 hours after stroke onset), no effect

of nimodipine was seen on either the primary outcome or death

alone. Our results do not confirm the positive effect reported in

the meta-analysis byMohr 1994. For the primary outcome and

mortality alone we found no effect of nimodipine. Because more

studies have become available, our study contains data from alarger number of patients. Direct comparison of the results of the

two meta-analyses was hampered by the absence of exact patient

numbers in the various outcome categories in the paper ofMohr

1994.

There has been some debate about antithrombotic properties of

some calcium antagonists (Heininger 1996; Legault 1996). We

found no influence of calcium antagonists on stroke recurrence

or myocardial infarction. However, the number of trials reporting

these data adequately was small. This might be a result of inade-

quate monitoring and reporting.

A strong argument in favor of the presence of publication bias

was found in our sensitivity analysis concerning the relationshipof publication status and treatment effect. While the published

trials showed no effect on primary outcome, unpublished trials

without exception were associated with a statistically significantly

worse outcome in the treatment group. It was quite conceivable

that more trials had remained unpublished, with perhaps similarly

negative results.

A U T H O R S C O N C L U S I O N SImplications for practice

From our review it became clear that no evidence is available to

justify the routine use of calcium antagonists in patients with acute

ischemic stroke.

Implications for research

There is no need to perform any further studies to justify the effect

of calcium antagonists in patients with ischemic stroke.

A C K N O W L E D G E M E N T S

We are grateful to the following individuals who provided trial in-

formation: Prof G Lowe, Glasgow, UK; Beverly Bowyer, Toronto,

Canada; Tina Haller, Bayer, Canada; Dr B Infeld from Melbourne,

Australia; Prof JP Mohr, New York, USA; Prof JM Orgogozo,

Bordeaux, France; Dr H Palomaki from Helsinki, Finland; Dr J

Smakman from Janssen Pharmaceutica BV, Tilburg, Netherlands;

and Dr G Uzuner, from Eskisehir, Turkey. We also thank Prof K

Heininger and Dr J Kuebler of Bayer AG, Wuppertal, Germany

who provided tabulated data of trials of nimodipine in acute is-

chemic stroke.

We thank Hazel Fraser, Managing Editor of the Cochrane StrokeGroup for lists of relevant trials from the Cochrane Stroke Group

Trials Register and Brenda Thomas, Cochrane Stroke Group Trials

Search Co-ordinator, for developing the search strategies. Dr Carl

Counsell, Prof Peter Sandercock, Dr Berge and Ashma Krishan

have also been of tremendous help.

The protocol and earlier version of the review were written by Dr

Horn and Dr Limburg. We express our gratitude to them.

We also thank Dr Chiara Menichetti (Italy) for translation and

data extraction, Dr Fangbin Zhang for help with data extraction

anddata selection andMiss Yan Li also forhelp of full text writing.

If anyone is aware of anytrials that we have omitted, pleasecontact

Professor Ming Liu.




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R E F E R E N C E S

References to studies included in this review

ASCLEPIOS 1990 {unpublished data only}

Azcona A, Lataste X. Isradipine in patients with acute

ischemic cerebral infarction. An overview of theASCLEPIOS programme.Drugs1990;40 Suppl 2:527.

Bogousslavsky 1990 {published and unpublished data}

Bogousslavsky J, Regli F, Zumstein V, Kobberling W.

Double-blind study of nimodipine in non-severe stroke.

European Neurology1990;30:236.

Bridgers 1991 {published and unpublished data}

Bridgers SL, Koch G, Munera C, Karwon M, Kurtz NM.

Intravenous nimodipine in acute stroke: interim analysis of

randomized trials. Stroke1991;22:153.

Canwin 1993 {published and unpublished data}

Norris JW, LeBrun LH, Anderson BA, The Canwin Study

Group. Intravenous nimodipine in acute ischaemic stroke.

Cerebrovascular Diseases1994;4:1946.Capon 1983 {unpublished data only}

Nimodipine for acute ischaemic stroke (unpublished study).

Bayer AG, Wuppertal, Germany.

Chandra 1995 {published data only}

Chandra B. A new form of management of stroke. Journal

of Stroke and Cerebrovascular Diseases1995;5:2413.

FIST 1990 {published and unpublished data}

Franke CL, Palm R, Dalby M, Hantson L, Eriksson B,

Lang-Jenssen L, et al.Flunarizine in stroke treatment (FIST).

A double-blind, placebo-controlled trial in Scandinavia and

the Netherlands. Acta Neurologic Scandinavica1996;93:

5660.

Gelmers 1984 {published and unpublished data}Gelmers HJ. The effects of nimodipine on the clinical course

of patients with acute ischemic stroke. Acta Neurologica

Scandinavica1984;69:2329.

Gelmers 1988 {published and unpublished data}

Gelmers HJ, Gorter K, De Weerdt CJ, Wiezer HJA. A

controlled trial of nimodipine in acute ischemic stroke.New

England Journal of Medicine1988;318:2037.

German-Austrian 1994 {published and unpublished data}

Kramer G, Tettenborn B, Schmutzhard E, Aichner

F, Schwartz A. Nimodipine in acute ischemic stroke.

Results of the nimodipine German-Austrian stroke trial.

Cerebrovascular Diseases1994;4:1828.

Heiss 1990 {published and unpublished data}

Heiss WD, Holthoff V, Pawlik G, Neveling M. Effect of

nimodipine on regional cerebral glucose metabolism in

patients with acute ischemic stroke as measured by positron

emission tomography. Journal of Cerebral Blood Flow and

Metabolism1990;10:12732.

INWEST 1990 {published and unpublished data}

Wahlgren NG, MacMahon DG, De Keyser J, Ryman T,

INWEST Study Group. Intravenous nimodipine West

European Stroke Trial (INWEST) of nimodipine in the

treatment of acute ischaemic stroke. Cerebrovascular Diseases1994;4:20410.

Kaste 1994 {published and unpublished data}

Kaste M, Fogelholm R, Erila T, Palomaki H, Murros K,Rissanen A, et al.A randomized, double-blind, placebo-

controlled trial of nimodipine in acute ischemic hemishperic

stroke.Stroke1994;25:134853.

Kornhuber 1993 {published data only}

Kornhuber HH, Hartung J, Herrlinger JD, Hertel G,

Hulser P-J, Prange H, et al.Flunarizine in ischemic stroke: a

randomised, multicentre, placebo-controlled, double blind

study. Neurology Psychiatry and Brain Research 1993;1:

17380.

Lamsudin 1995 {published data only}

Lamsudin HR. A randomized, double-blind, placebo

controlled multicenter trial with nimodipine in acute

ischaemic stroke. Unpublished.

Limburg 1990 {published and unpublished data}

Limburg M, Hijdra A. Flunarizine in acute ischemic stroke:

a pilot study. European Neurology1990;30:1212.

Lisk 1993 {published data only}

Lisk D, Grotta J, Lamki L, Tran H, Taylor J, Molony D,

et al.Should hypertension be treated after acute stroke? A

randomized controlled trial using single photon emission

computed tomography. Archives of Neurology1993;50:

85562.

Lowe 1989 {unpublished data only}

Lowe G. Nimodipine in acute cerebral hemispheric

infarction. Unpublished (University of Glasgow).

Martinez-Vila 1990 {published and unpublished data}Martinez-Vila E, Guillen F, Villanueva JA, Matias-Guiu J,

Bigorra J, Gil P, et al.Placebo-controlled trial of nimodipine

in the treatment of acute ischemic cerebral infarction. Stroke

1990;21:10238.

Mohr 1992 {published and unpublished data}

American Nimodipine Study Group. Clinical trial of

nimodipine in acute ischemic stroke. Stroke1992;23:38.

Nag 1998 {published data only}

Nag D, Garg RK, Varma M. A randomized double-blind

controlled study of nimodipine in acute cerebral ischemic

stroke.Indian Journal of Physiology and Pharmacology1998;

42:5558.

NEST 1993 {published and unpublished data}Hennerici M, Kramer G, North PM, Schmitz H,

Tettenborn D, Nimodipine European Stroke Trial Group

(NEST). Nimodipine in the treatment of acute MCA

ischemic stroke. Cerebrovascular Diseases1994;4:18993.

NIMPAS 1999 {published and unpublished data}

Infeld B, Davis SM, Donnan GA, Yasaka M, Lichenstein

M, Mitchell PJ, et al.Nimodipine and perfusion changes

after stroke. Stroke1999;30:141723.




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Oczkowski 1989 {published data only}

Oczkowski WJ, Hachinski VC, Bogousslavsky J, Barnett

HJ, Carruthers SG. A double-blind, randomized trial of PY

108-068 in acute ischemic cerebral infarction. Stroke1989;

20:6048.

Paci 1989 {published data only}

Paci A, Ottaviano P, Trenta A, Iannone G, De Santis L,Lancia G, et al.Nimodipine in acute ischemic stroke:

a double-blind controlled study. Acta Neurologica

Scandinavica1989;80:2826.

Sherman 1986 {published data only}

Sherman DG, Easton JD, Hart RG, Sherman CP.

Nimodipine in acute cerebral infarction. A double-blind

study of safety and efficacy. In: Battistini N, Fiorani P,

Courbier R, Plum F, Fieschi C editor(s). Acute Brain

Ischaemia: Medical and Surgical Therapy. New York: Raven

Press, 1986:25762.

Shibuya 2005 {published data only}

Shibuya M, Hirai S, Seto M, Satoh S, Ohtomo E. Effects

of fasudil in acute ischemic stroke: results of a prospectiveplacebo-controlled double-blind trial. Journal of the

Neurological Sciences2005;238:319.

Squire 1996 {published data only}

Squire IB, Lees KR, Pryse-Phillip W, Kertesz A, Bamford

J, Lifarizine Study Group. The effects of lifarizine in acute

cerebral infarction: a pilot safety study. Cardiovascular

Diseases1996;6:15660.

Sze 1998 {published data only}

Sze KH, Sim TC, Wong E, Cheng S, Woo J. Effect of

nimodipine on memory after cerebral infarction. Acta

Neurologica Scandinavica1998;97:38692.

TRUST 1990 {published and unpublished data}

TRUST Study Group. Randomised, double-blind, placebo-

controlled trial of nimodipine in acute stroke. Lancet1990;

336:12059.

Uzunur 1995 {published and unpublished data}

Uzuner N, Ozdemir G, Gucuyener D. The interaction

between nimodipine and systemic blood pressure and pulse

rate. Proceedings of the WHO Pan-European Consensus

Meeting on Stroke Management, Helsingborg, Sweden.

November 1995.

VENUS 1999 {published and unpublished data}

Horn J, De Haan RJ, Vermeulen M, Limburg M. Very

Early Nimodipine Use in Stroke (VENUS): a randomized,

double-blind, placebo-controlled trial. Stroke2001;32:

4615.

Wimalaratna 1994 {published and unpublished data}Wimalaratna HSK, Capildeo R. Nimodipine in acute

ischaemic cerebral hemisphere infarction. Cerebrovascular

Diseases1994;4:17981.

Yordanov 1984 {unpublished data only}

Nimodipine for acute ischaemic stroke (unpublished study).

Bayer AG, Wuppertal, Germany.

References to studies excluded from this review

Ameriso 1992 {published data only}

Ameriso SF, Wenby RB, Meiselman HJ, Fisher M.

Nimodipine and the evolution of hemorheological

variables after acute ischemic stroke. Journal of Stroke and

Cerebrovascular Diseases1992;2:225.

Csiba{published data only (unpublished sought but not used)}

Csiba L. Hungarian Nimodipine Trial. Unpublished.

Dalal 1995 {published data only}

Dalal PM, Dalal KP. Use of calcium channel blockers

in acute ischemic cerebrovascular disease. Journal of the

Association of Physicians of India1995;43(6):3947.

Fagan 1988 {published data only}

Fagan SC, Gengo FM, Bates V, Levine SR, Kinkel WR.

Effect of nimodipine in blood pressure in acute ischemic

stroke in humans. Stroke1988;19:4012.

Marn Gmez 1988 {published data only}

Marn Gmez N, Soto Mas JA, Aguilar Martnez JL,

Bermdez Garca JM, Salim A, Ramos Jimnez A, et al.A

controlled double blind clinical trial of nicardipine versus

placebo in acute focal cerebral ischaemia [Ensayo clinico

controlado a doble ciego: nicardipina frente a placebo en la

isquemia cerebral focal aguda]. Medicina Clnica1988;90:

6902.

Matias Guiu 1992 {published data only}

Matias-Guiu J, Molto JM, Galiano L, Insa R, Falip R,

Martin R. Pilot double-blind placebo controlled trial of

nicardipine versus placebo for cognitive impairment in

minor stroke patients. Journal of Neurology1992;239 Suppl

2:S39.

Molto 1994 {published data only}

Molto JM, Falip R, Martin R, Insa R, Pastor I, Matias

Guiu J. Comparative study of nicardipine versus placebo

in the prevention of cognitive deterioration in patientswith transient ischemic attacks [Estudio comparativo de

nicardipina frente a placebo en la prevencion del deterioro

cognitivo en los pacientes con accidentes isquemicos

transitorios].Revista de Neurologia1995;23:548.

Orgogozo {published data only (unpublished sought but not used)}

Nicardipine Stroke Trial. Unpublished work.

Petrogiannopoulos 96 {published data only}

Petrogiannopoulos G, Zaharof A, Tzoumani A, Poulikakos

J. Efficacy of long term treatment with nimodipine on brain

function after acute ischemic stroke. European Journal of

Neurology1996;3 Suppl 5:35.

Rosenbaum 1990 {published data only}

Rosenbaum DM, Zabramski JM, Fry J, Yatsu F, Marler J,Spetzler RF, et al.Early treatment of ischemic stroke with a

calcium antagonist. Stroke1991;22:43741.

Rosselli 1992 {published data only}

Rosselli A, Landini G, Castagnoli A, Vannucchi L,

Mugnaini C, Calacoci S, et al.The nimodipine therapy of

acute focal cerebral ischemia (minor stroke). A clinical

study with an assessment of regional cerebral blood flow by

SPECT.Recenti Progressi in Medicina1992;83(2):858.




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Szczechowski 1994 {published data only}

Szczechowski L, Wajgt A. Ocena skutecznosci Ieczenia

ostrych udarow niedokrwiennych dozylnym wlewem

nimodypiny. Neurologia i Neurochirurgia Polska1994;28:

299306.

Yao 1991 {published data only}

Yao J. Preliminary study of nimodipine in acute cerebralinfarction. Chinese Journal of Nervous & Mental Diseases

1991;17(1):47.

References to studies awaiting assessment

Davalos 1989 {published data only}

Davalos A, Cendra E, Gonzalez B, Genis D, Teruel J, Ruibal

A. Double-blind randomized clinical trial of nicardipine

versus placebo in acute ischemic stroke: clinical, radiological

and biochemical evaluation of the ischemic area. Preliminay

results.Neurology India1989;37 Suppl:283.

Davalos Errando 1992 {published data only}

Davalos Errando E, De Cendra E, Geris D, Teruel J, Ruibal

A, Musoles S. Double blind controlled trial of nicardipineversus placebo in the treatment of the acute phase of

cerebral infarction [Ensayo clinico controlado a doble ciego

de nicardipino frente a placebo en el tratamiento de la fase

aguda del infarto cerebral]. Neurologia1992;7:157.

Garcia Tigeria{published data only}

Garcia Tigera J, Alvarez LG, Hernandez MO. Treatment

with calcium channels blockers (nifedipine) of patients with

acute brain infarction. Unpublished.

Hakim 1989 {published data only}

Hakim AM, Evans AC, Berger L, Kuwabara H, Worsley K,

Marchal G, et al.The effect of nimodipine on the evolution

of human cerebral infarction studied by PET.Journal of

Cerebral Blood Flow and Metabolism1989;9:52334.

References to ongoing studies

AIIMS trial {unpublished data only}

Behari M, Prasad K. Nimodipine in acute stroke, AIIMS

trial of nimodipine in acute stroke. Unpublished.

Tanahashi 2007 {unpublished data only}

Tanahashi N. Phase Ill clinical trial for AT-877 (i.v.) in

patients with acute ischemic stroke. Placebo-controlled,

double-blind add-on therapy to antiplatelet drugs.

Unpublished.

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19/80

C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

ASCLEPIOS 1990

Methods Publication status: unpublished

Multicenter placebo-controlled trial

Random sequence generation: unclear

Concealment: unclear

Double-blind

Exclusions during trial: unclear

Losses to follow-up: 4

Participants Inclusion criteria: age: 45 to 85 years, start within 12 hours, probable MCA infarction,

CT scan within 72 hours

Exclusion: massive hemispherical infarction, Orgogozo score > 65, clinical resolutionwithin 24 hours

Interventions Treatment: intravenous isradipine, 28 days, 80 microgram/hour for 72 hours, followed

orally with 2.5 mg bid

Placebo: identical regimen

Outcomes Barthel Index

Deaths

Last follow-up: 3 months

Dependency measurement used in review: Barthel Index

Missing: 4 patients in isradipine group

Notes Data available from principal investigator (JM Orgogozo)

Risk of bias

Bias Authors judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Not mentioned

Allocation concealment (selection bias) Unclear risk Not mentioned

Incomplete outcome data (attrition bias)

All outcomes

High risk Missing 4 patients in isradipine group with-

out ITT analysis

Blinding of participants and personnel

(performance bias)

All outcomes

Low risk Double-blind

Blinding of outcome assessment (detection

bias)

All outcomes





20/80

Bogousslavsky 1990

Methods Publication status: published

Unicenter placebo-controlled trialRandom sequence generation: random list


Double-blind

Exclusions during trial: 8


Participants Inclusion criteria: age 40 to 85 years, start within 48 hours, acute ischemic stroke of

mild-to-moderate severity (Mathew Scale score 50 to 75), diagnosis on CT scan and

clinical evaluation

Exclusion criteria: rapid improvement < 24 hours, loss of consciousness, brainstem in-

farction, pregnancy, cerebral neoplasm, other causeof brain infarction than atherothrom-

bosis, other severe diseases, medication (concomitant use of calcium channel antagonists,

piracetam, pentoxyphylline, naftidrofuryl dehydrogenoxalate, dihydroergetoxine, alpha-methyldopa)

Interventions Treatment: oral nimodipine, 30 mg qid for 2 weeks


Outcomes Mathew Scale score

Death

Last follow-up: 4 months

Dependency measurement used in review: functional item Mathew Scale scale

Missing: 1 patient in placebo group

Notes Data available from publication and database of Bayer AG, Wuppertal, Germany

Risk of bias



bias)

Low risk The patients received nimodipine or

placebo according to a random list



All outcomes

High risk 60 patients recruited but only 52 patients

had been analyzed, there was no ITT anal-

ysis


(performance bias)

All outcomes



bias)





21/80

Bogousslavsky 1990 (Continued)

All outcomes

Bridgers 1991

Methods Publication status: published as abstract




Double-blind



Participants Inclusion criteria: acute stroke, moderate to severe, < 24 hours after stroke onset

Exclusion criteria: unknown

Interventions Treatment: intravenous nimodipine, 2 active groups: 1 mg/hour or 2 mg/hour for 5days, followed by oral nimodipine 120 mg/day days 5 to 21


Outcomes Barthel Index, Glasgow Outcome Scale and Mathew Scale

Deaths

Last follow-up: 21 days (?not completely clear)

Dependency measurement used in review: Glasgow Outcome Scale

Missing: 1 missing in placebo group

Notes Data available from published abstract and Bayer AG, Wuppertal

Trial was stopped after inclusion of 204 of planned 720 patients because of deleterious

effect in high dosage group

Risk of bias



bias)




All outcomes

High risk 1 missing in the placebo group and there

was no ITT analysis


(performance bias)

All outcomes



bias)

All outcomes





22/80

Canwin 1993


Placebo-controlled trial


Concealment: unclearBlinding: unclear



Participants Inclusion criteria: age 45 to 85 years, start within 48 hours, hemiplegia, CT-confirmed

hemispheric cerebral infarction, Toronto Stroke Scale scores > 20

Exclusion: coma, no motor weakness, brainstem strokes or previous strokes, CT scan

not compatible with ischemic stroke, use of calcium antagonists, concurrent terminal

illness

Interventions Treatment: intravenous nimodipine; days 1 to 10 at 2 mg/hour, days 11 to 6 months at

180 mg/day orally


Outcomes Toronto Stroke Scale

Functional disability using 3 categories:(1) minoror no disability, (2) moderate disability,

(3) severely disabled or bedridden

Death

Last follow-up: 1 year

Dependency measurement used in review: Toronto Stroke Scale

Missing: 5 in active treatment group, 11 in control group

Notes Data available from publication, principal investigator, Bayer Canada and Bayer AG,

Wuppertal, Germany

Risk of bias



bias)




All outcomes

High risk 189 patients randomized into the study but

164 were suitable for statistical evaluation,

and they did do the ITT analysis


(performance bias)

All outcomes



bias)

All outcomes





23/80

Capon 1983

Methods Publication status: unpublished



Concealment: unclearBlinding: unclear


Losses to follow-up: unclear

Participants Stroke patients, criteria unknown

Interventions Treatment: nimodipine oral, 30 mg qid for 56 days


Outcomes Death

Last follow-up: at end of treatment

No dependency measurement available

Notes Very limited data available from Bayer AG, Wuppertal, Germany. No published data

Chandra 1995


Blinded comparison of oral versus intravenous administration of nimodipine



Double-blind



Placebo-controlled

Participants Inclusion criteria: sudden focal neurologic deficit, admission within 6 hours

Exclusion: transientsigns, large (> 60 mLon CT) cerebral hemorrhage; no informed con-

sent; recent myocardial infarction; congestive heart failure; abnormal renal, pulmonary

or hepatic function

Interventions Treatment: oral versus intravenous treatment: arm 1: oral nimodipine 30 mg qid and

intravenous placebo; arm 2: nimodipine 2.5 mg/hour intravenous and oral placebo

Treatment period 10 days, followed by oral nimodipine for all

Outcomes Unmodified Mathew Scale, Barthel Index

DeathLast follow-up: day 14

Dependency: data reported in unusable way

Missing: none

Notes Data from original publication, only average scores on functional items available, hence

not used in meta-analysis

This trial is only used for direct comparison of route of administration




24/80

Chandra 1995 (Continued)

Risk of bias



bias)




All outcomes



(performance bias)

All outcomes



bias)

All outcomes


FIST 1990





Double-blind

Exclusions during trial: 32Losses to follow-up: 5

Participants Inclusion criteria: clinical diagnosis of ischemic stroke in MCA territory, disabling motor

deficit, total Glasgow Coma Score > 3, < 24 hours of stroke onset

Exclusion criteria: brain tumor, intracranial hemorrhage or lacunar infarction on CT

scan, previous disabling stroke, other severe disorder, poor physical or mental condition

Interventions Treatment: intravenous flunarizine: days 1 to 7 at 25 mg bid fol lowedbyoral flunarizine:

days 8 to 14 at 21 mg/day; days 15 to 28 at 7 mg/day


Outcomes Modified Rankin scale, Orgogozo scale, Modified Barthel Index

DeathLast follow-up: 24 weeks

Dependency measurement used in review: Modified Rankin scale

Missing: 4 in active treatment, 1 in placebo group

Notes Other stroke therapies were not allowed

Data were available from publication and from Janssen Pharmaceutica BV, Tilburg,

Netherlands




25/80

FIST 1990 (Continued)

Risk of bias



bias)




All outcomes

High risk 331 patients recruited, but only 290 ana-

lyzed, ITT analysis performed but results

not reported


(performance bias)

All outcomes



bias)

All outcomes


Gelmers 1984





Single-blindExclusions during trial: 0


Participants Inclusion criteria: acute ischemic stroke, age > 40 years, CT scan compatible with diag-

nosis

Exclusion criteria: not described

Interventions Treatment: oral nimodipine, 30 mg qid, 28 days

Placebo: none

Outcomes Mathew Stroke Scale

Death

Last follow-up: 28 daysDependency measurement used in review: functional item in Mathew Scale

Missing: none

Notes All patients standard treatment with 10% depolymerized dextran for 12 hours/day for

5 days

Data available from publication and Bayer AG, Wuppertal, Germany




26/80

Gelmers 1984 (Continued)

Risk of bias



bias)




All outcomes

Low risk 60 patients recruited and no data loss

Selective reporting (reporting bias) Unclear risk Not mentioned


(performance bias)

All outcomes

Low risk Single-blind


bias)

All outcomes

High risk

Gelmers 1988



Random sequence generation: computer-generated lists

Concealment: numbered boxDouble-blind



Participants Inclusion criteria: age > 45 years, clinical diagnosis of complete acute ischemic stroke 45 years,acute completed ischemic stroke; admission < 48 hours,

Mathew Scale Score < 66

Exclusion criteria: other causes than atherothrombosis, overt sys

inhibidores de los canales de calcio en ictus isquemico

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