Inhibidores de Los Canales de Calcio en Ictus Isquemico

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 in The Cochrane Library
2012, Issue 5
http://www.thecochranelibrary.com

Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1.
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Figure 2.
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Figure 3.
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Figure 4.
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DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 1 Primary outcome at
end of follow-up.
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.2. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 2 Death at end of
treatment period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.3. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 3 Death at end of
follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.4. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 4 Recurrence of stroke
at end of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.5. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 5 Adverse events (all)
during treatment period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.6. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 6 Hypotension during
treatment period (reason to stop treatment). . . . . . . . . . . . . . . . . . . . . . . .
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. . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.1. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 1 Primary outcome by route
of administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.2. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 2 Primary outcome by dose:
indirect comparisons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.3. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 3 Primary outcome by dose:
direct comparisons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 2.4. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 4 Primary outcome by time
of start of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.1. Comparison 3 Calcium antagonists versus control: sensitivity analysis, Outcome 1 Primary outcome in
multicenter placebo controlled trials. . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 3.2. Comparison 3 Calcium antagonists versus control: sensitivity analysis, Outcome 2 Publication status. .
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1
1
2
2
3
3
5
7
8
9
10
11
12
12
13
16
53
55
57
59
61
62
63
64
65
67
69
70
72
73
74
77
77
77
77
78
78
[Intervention Review]
Calcium antagonists for acute ischemic stroke

Jing Zhang1 , Jie Yang2 , Canfei Zhang1 , Xiaoqun Jiang1 , Hongqing Zhou1 , Ming Liu1
1 Department
of Neurology, West China Hospital, Sichuan University, Chengdu, China. 2 Department 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, China. wyplmh@hotmail.com.
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 Reviews 2012, Issue 5. Art. No.: CD001928. DOI: 10.1002/14651858.CD001928.pub2.
ABSTRACT
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 the
influence 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 four
Chinese 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.
Authors conclusions
No evidence is available using calcium antagonists in patients with acute ischemic stroke is effective.
PLAIN LANGUAGE SUMMARY

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.
BACKGROUND
Calcium antagonists may act as neuroprotective drugs by diminishing the influx of calcium ions through the voltage sensitive calcium channels. One Cochrane review published in The Cochrane
Library has already demonstrated that calcium antagonists could
reduce the risk of a primary outcome and secondary ischemia after 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. Therefore, it is necessary to test whether this kind of drug can play a
neuroprotective role and improve neurological impairment.
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 administered after cerebral ischemia may be effective in
reducing infarct volume and lead to improvements in neurological
outcome (Germano 1987; Steen 1983). After their introduction
into clinical practice it was discovered that 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.
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.
How the intervention might work

Some meta-analyses with a more limited scope (restricted to nimodipine 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 subgroup analysis (patients treated within 12 hours of stroke onset)

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 danger 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 beneficial 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 upto-date evidence for clinical practice.
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 control group receiving another active therapy that had not been factored into the randomization.
Types of outcome measures
Primary outcomes
OBJECTIVES
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 administration, different dosages and various time intervals from onset
of symptoms until start of treatment) and different trial designs
(multicenter placebo-controlled trial, publication status).
Primary outcome: defined as death (all-cause case fatality) or dependency in activities of daily living at long-term follow-up (at
least three months). For assessing dependency, we used the following available functional health scales: the Modified Rankin or Oxford Handicap Scale (dependency > 3) (Bamford 1989), Glasgow
Outcome Scale (dependency < 4) (Jennet 1975), the Barthel Index
(dependency < 60) (Mahoney 1965), Toronto Stroke Scale (dependency > 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 number of missing values (see the Characteristics of included studies
table for details).
Secondary outcomes
METHODS
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 intravenous administration) and different doses. We excluded trials
that were not truly randomized.
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.

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 arranged 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), EMBASE (1980 to December 2011) (Appendix 2) and the Cochrane
Central Register of Controlled Trials (CENTRAL) (The Cochrane
Library, 2011 issue 4) (Appendix 3). We also searched the following four Chinese databases: Chinese Biological Medicine Database
(CBM-disc) (1978 to December 2011), China National Knowledge Infrastructure (CNKI) (1980 to December 2011), Chinese
scientific periodical database of VIP information (1989 to December 2011) and Wanfang Data (http://www.wanfangdata.com/)
(1982 to December 2011).
The Cochrane Stroke Group Trials Search Co-ordinator developed
the search strategies for MEDLINE, EMBASE and CENTRAL
and we adapted the MEDLINE strategy for the Chinese databases.
Searching other resources
In an effort to identify further published, ongoing and unpublished 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 and consulted a 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 articles 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 information 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) independently assessed the selection of studies and they resolved any disagreements 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 management

Two 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 information 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), controlled
intervention (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 randomization or if any of the above data were unavailable from the publications, 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 evaluated the following
methodological qualities of all included 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 according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Allocation concealment
Assessment of reporting biases
Was allocation adequately concealed? We classified allocation concealment as low risk, high risk or unclear risk according to the
Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2011).
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.
Blinding of participants, personnel and outcome assessors
Was knowledge of the allocated interventions adequately prevented during the study? We classified blinding as low risk, high
risk or unclear risk according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Incomplete outcome data
Were incomplete outcome data adequately addressed? We classified studies as low risk, high risk or unclear risk according
to the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2011). If there were patients excluded or lost to followup 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.
Data synthesis
We performed statistical analysis using RevMan 5.1 (RevMan
2011). We reported the results as risk ratio (RR) with 95% confidence interval (CI) for dichotomous data and as mean difference
(MD) with 95% CI for continuous data. We used a random-effects 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
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 the Cochrane Handbook for Systematic Reviews of
Interventions (Higgins 2011).
Measures of treatment effect
According to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we re-analyzed the data of these multicenter studies. We also re-analyzed the data according to the publication status.
RESULTS
These measures are listed under Types of outcome measures.
Description of studies
Unit of analysis issues
None.
Dealing with missing data

See Data 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 heterogeneity.
See: Characteristics of included studies; Characteristics of excluded

studies.
Our method of independent data collection by two authors increased accuracy. Much of our data were based on original data
sets. The majority of trials were performed with 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 after randomization and outcomes were not presented in the publication (Martinez-Vila 1990; NEST 1993; Wimalaratna 1994),
while data on these patients were available from the original data
set.
However, in the trial of Heiss 1990, the number of excluded patients in the published article was not accounted for in the original

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 any
data, 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 antagonists 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.
control group. We defined severe adverse events as epilepsy, bradycardia, gastrointestinal bleeding and deep venous thrombosis.
Epilepsy occurred in three patients (3/2810, 0.11%) in the treatment 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 the
control 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 patients 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 severe to be excluded.
Excluded studies
Included studies
See Characteristics of included studies. Thirty-four trials (including 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. Most
of 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), nicardipine (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; Kornhuber 1993; Martinez-Vila 1990; Sze 1998). The main
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
We excluded 13 studies. For details see Characteristics of excluded

studies.
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; Heiss
1990; Mohr 1992; Sze 1998; VENUS 1999) used numbered boxes
as the allocation concealment method. The remaining trials did
not report the method of random sequence generation and allocation 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 compared the different results between intravenous and oral nimodipine without a placebo group (Chandra 1995), and two were open
control (Gelmers 1984; Uzunur 1995).
Five trials (Canwin 1993; Capon 1983; Lowe 1989; Uzunur 1995;
Yordanov 1984) did not report the method of blinding. Three
trials (Gelmers 1984; Martinez-Vila 1990; Sze 1998) 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 (Sze 1998). The remaining 26 trials
reported they were double-blind trials, but only one reported that
the assessors were blinded (Shibuya 2005).

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 not
obtain 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 end of long-term followup. 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. In FIST 1990, there
were 331 participants involved while in Limburg 1990, only 26
participants were involved, the latter might be the most 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.

Secondary outcomes
Death at end of treatment period
Data were available from 22 trials with 6323 participants. No difference 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 increase 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.

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
related to a worse outcome (RR 1.34, 95% CI 1.01 to 1.77). As for
the other calcium antagonists, nimodipine, isradipine, lifarizine,
PY106-608 and nicardipine, no difference was found (Analysis
1.3).
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 was no difference in the
number of events between treatment groups and control groups,
(RR 0.93, 95% CI 0.56 to1.54). However, the confidence intervals
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 intravenous administration of flunarizine (after correction for differences in the size of the active and control groups). The occurrence
of hypotension (defined as episodes leading to cessation of drug

treatment) was mentioned in only five trials and was 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 in the flunarizine group. In the rest of the studies

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 trial FIST 1990, the considerable heterogeneity could be completely reversed by removing it.
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 (sufficient 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 significant difference (Analysis 1.6).
Mean systolic blood pressure during or at end of treatment
Data were available in three trials with 630 participants. The mean
blood pressure in the treated groups was on average 2 mmHg lower.
This was a very small difference. The result was not statistically
significant (MD: -1.30, 95% CI -3.92 to 1.32) (Analysis 1.7).
There was considerable heterogeneity, which could be completely
reversed by removing Martinez-Vila 1990.
Subgroup analyses

10
Primary outcome by route of administration
Primary outcome by time start of treatment
Data were available for 23 trials: 14 trials with 5131 participants

by oral administration, eight trials with 1544 participants by intravenous administration, and one trial with 143 participants compared oral and intravenous administration directly. Intravenous
administration was associated with a worse outcome in treated
groups 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 administration of nimodipine did not support the notion that intravenous administration was associated with poorer outcome (RR
7.10, 95% CI 0.37 to 134.96) (Chandra 1995) (Analysis 2.1).
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 antagonists was associated with an increase in the odds of primary outcome, 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).
Primary outcome by dose: indirect comparisons
Primary outcome in multicenter placebo-controlled trials
Data were available for 18 trials: one trial with 529 participants
using 60 mg oral nimodipine per day, 14 trials with 4526 participants 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 intravenous 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 statistically 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 difference 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 by Bridgers 1991. Removing this trial decreased the heterogeneity but did not eliminate it.
Of the 34 included trials, 10 trials including 4012 participants

reported that their data were from multicenter placebo-controlled
trials. We did the primary outcome analysis on these 10 trials (RR
1.04, 95% CI 0.95 to 1.14) and found there was no clear difference
between it (Analysis 3.1) and the Primary outcome at the end of
follow-up (Analysis 1.1).
Sensitivity analyses
Analysis 3.6: Publication status
Data were from 22 trials, including 18 trials with 5887 participants from which we could extract the primary outcome from the
published papers, and four trials with 788 participants with unpublished 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 associated
with a deleterious effect of calcium antagonist treatment, the overall RR was 1.14 (95% CI 1.00 to 1.30) (Analysis 3.2).
DISCUSSION
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 participants 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 associated with slightly better results than 60 mg and 240 mg. A
dose-dependent relationship seemed to exist for intravenous nimodipine. For both routes, the highest doses were associated with
poorer outcome (Analysis 2.3).
This systematic review of all available data failed to demonstrate a

reduction in mortality and dependency after treatment with calcium antagonists in patients with acute ischemic stroke. Due to
the large amount of data (34 trials including 7731 patients), confidence intervals were narrow and the overall result was therefore
subject to limited statistical uncertainty.
Intravenous administration of calcium antagonists was not associated with a statistically significant increased risk of primary outcome. For nimodipine, data were available to analyze dose dependency, which appeared to be present. A higher dosage (2 mg/hour)
led to a significant increase in the risk of primary outcome compared with a dosage of 1 mg/hour, which was also associated with
a significant increased risk of primary outcome as compared with

11
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 ischemic stroke was generally good. All trials included were placebocontrolled trials except Chandra 1995, Gelmers 1984 and Uzunur
1995, and all trials used a blinding method except five trials. However, 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.
We did two sensitivity analyses: one based on the primary outcome
in multicenter placebo-controlled trials and the other on 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 by Mohr 1994, we expected to find an improved
outcome in the 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 by Mohr 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 a
larger 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 of Mohr
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 inadequate monitoring and reporting.
A strong argument in favor of the presence of publication bias
was found in our sensitivity analysis concerning the relationship
of 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.
AUTHORS CONCLUSIONS
Implications 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.
ACKNOWLEDGEMENTS
We are grateful to the following individuals who provided trial information: 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 ischemic stroke.
We thank Hazel Fraser, Managing Editor of the Cochrane Stroke
Group 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
and data selection and Miss Yan Li also for help of full text writing.
If anyone is aware of any trials that we have omitted, please contact

Professor Ming Liu.

12
REFERENCES
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 the
ASCLEPIOS programme. Drugs 1990;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 Neurology 1990;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. Stroke 1991;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 Diseases 1994;4:1946.
treatment of acute ischaemic stroke. Cerebrovascular Diseases

1994;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, placebocontrolled trial of nimodipine in acute ischemic hemishperic
stroke. Stroke 1994;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.
Capon 1983 {unpublished data only}

Nimodipine for acute ischaemic stroke (unpublished study).
Bayer AG, Wuppertal, Germany.
Limburg 1990 {published and unpublished data}

Limburg M, Hijdra A. Flunarizine in acute ischemic stroke:
a pilot study. European Neurology 1990;30:1212.
Chandra 1995 {published data only}

Chandra B. A new form of management of stroke. Journal
of Stroke and Cerebrovascular Diseases 1995;5:2413.
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 Neurology 1993;50:
85562.
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 Scandinavica 1996;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
Scandinavica 1984;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 Medicine 1988;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.
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. Stroke 1992;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 Pharmacology 1998;
42:5558.
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
Metabolism 1990;10:12732.
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 Diseases 1994;4:18993.
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
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. Stroke 1999;30:141723.

13
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. Stroke 1989;
20:6048.
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
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
Scandinavica 1989;80:2826.
Csiba {published data only (unpublished sought but not used)}

Csiba L. Hungarian Nimodipine Trial. Unpublished.
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 prospective
placebo-controlled double-blind trial. Journal of the
Neurological Sciences 2005;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
Diseases 1996;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 Scandinavica 1998;97:38692.
TRUST 1990 {published and unpublished data}
TRUST Study Group. Randomised, double-blind, placebocontrolled trial of nimodipine in acute stroke. Lancet 1990;
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. Stroke 2001;32:
4615.
Wimalaratna 1994 {published and unpublished data}
Wimalaratna HSK, Capildeo R. Nimodipine in acute
ischaemic cerebral hemisphere infarction. Cerebrovascular
Diseases 1994;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
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 India 1995;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. Stroke 1988;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 Clnica 1988;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 Neurology 1992;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 patients
with 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 Neurologia 1995;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
Neurology 1996;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. Stroke 1991;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 Medicina 1992;83(2):858.

14
Szczechowski 1994 {published data only}

Szczechowski L, Wajgt A. Ocena skutecznosci Ieczenia
ostrych udarow niedokrwiennych dozylnym wlewem
nimodypiny. Neurologia i Neurochirurgia Polska 1994;28:
299306.
Yao 1991 {published data only}
Yao J. Preliminary study of nimodipine in acute cerebral
infarction. 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 India 1989;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 nicardipine
versus 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]. Neurologia 1992;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 Metabolism 1989;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.
Additional references
Counsell 1994
Counsell CE, Clarke MJ, Slattery J, Sandercock PAG. The
miracle of DICE therapy for acute stroke: fact or fictional
product of subgroup analysis?. BMJ 1994;309:167781.
Di Mascio 1994
Di Mascio R, Marchioli R, Tognomi G. From
pharmacological promises to controlled clinical trials
to meta-analysis and back: the case of nimodipine in
cerebrovascular disorders. Clinical Trials and Meta-analysis
1994;29:5779.
Gelmers 1990
Gelmers HJ, Hennerici M. Effect of nimodipine on acute
ischemic stroke pooled results from five randomized trials.
Stroke 1990;21 Suppl IV:IV81IV84.
Germano 1987
Germano IM, Bartkowski HM, Cassel ME, Pitts LH.
The therapeutic value of nimodipine in experimental
focal cerebral ischemia. Neurological outcome and
histopathological findings. Journal of Neurosurgery 1987;67:
817.
Harders 1996
Harders A, Kakarieka A, Braakman R, the German tSAH
Study Group. Traumatic subarachnoid hemorrhage and its
treatment with nimodipine. Journal of Neurosurgery 1996;
85:829.
Heininger 1996
Heininger K, Kuebler J. Use of Nimodipine is safe. Stroke
1996;27:19112.
Higgins 2011
Higgins JPT, Green S (editors). Cochrane Handbook for
Systematic Reviews of Interventions Version 5.1.0 [updated
March 2011]. The Cochrane Collaboration. Available from
www.cochrane-handbook.org. 2011.
Jennet 1975
Jennet B, Bond M. Assessment of outcome after severe brain
damage. Lancet 1975;1(7950):4804.
Legault 1996
Legault C, Furberg CD, Wagenknecht LE, Rogers AT,
Stump DA, Coker L, et al.Nimodipine neuroprotection in
cardiac valve replacement. Report of an early terminated
trial. Stroke 1996;27:5938.
Liu 2007
Liu M, Wu B, Wang WZ, Lee LM, Zhang SH, Kong
LZ. Stroke in China: epidemiology, prevention, and
management strategies. Lancet Neurology 2007;6(5):
45664.
AHA 2007
Rosamond W, Flegal K, Friday G, Furie K, Go A,
Greenlund K, et al.Heart disease and stroke statistics - 2007
update: a report from the American Heart Association
Statistics Committee and Stroke Statistics Subcommittee.
Circulation 2007; Vol. 115, issue 5:e69171.
Mahoney 1965
Mahoney FI, Barthel DW. Functional evaluation: the
Barthel Index. Maryland State Medical Journal 1965;14:
615.
Bamford 1989
Bamford JM, Sandercock PAG, Warlow CP, Slattery J.
Interobserver agreement for the assessment of handicap in
stroke patients. Stroke 1989;20:828.
Mathew 1972
Mathew NT, Meyer JS, Rivera VH. Double blind evaluation
of glycerol treatment in acute cerebral infarction. Lancet
1972;ii:132733.

15
Mees 2008
Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den
Bergh WM, Vermeulen M, et al.Calcium antagonists for
aneurysmal subarachnoid haemorrhage. Cochrane Database
of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/
14651858.CD000277.pub3]
Mohr 1994
Mohr JP, Orgogozo JM, Harrison MJG, Hennerici M,
Wahlgren NG, Gelmers JH, et al.Meta-analysis of oral
nimodipine trials in acute ischemic stroke. Cerebrovascular
Diseases 1994;3:197202.
Norris 1982
Norris JW. Comment on Study Design of Stroke
Treatments. Stroke 1982;4:5278.
Pickard 1989
Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale
GM, Foy PM, et al.Effect of oral nimodipine on cerebral
infarction and outcome after subarachnoid haemorrhage:
British aneurysm nimodipine trial. BMJ 1989;298:63642.
RevMan 2011
Review Manager (RevMan) [Computer program]. Version
5.1. Copenhagen: The Nordic Cochrane Centre. The
Cochrane Collaboration 2011.
Siesjo 1978
Siesjo BK. Brain Energy Metabolism. New York: John Wiley
& Sons, 1978.
Siesjo 1989
Siesjo BK, Bengtsson R. Review. Calcium fluxes, calcium
antagonists, and calcium-related pathology in brain
ischemia, hypoglycemia, and spreading depression: a
unifying hypothesis. Journal of Cerebral Blood Flow and
Metabolism 1989;9:12740.
Steen 1983
Steen PA, Newberg LA, Milde JH, Michenfelder JD.
Nimodipine improves cerebral blood flow and neurologic
recovery after complete cerebral ischemia in the dog. Journal
of Cerebral Blood Flow and Metabolism 1983;3:3843.
Indicates the major publication for the study

16
CHARACTERISTICS OF STUDIES
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 resolution
within 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 Unclear risk

bias)
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 without ITT analysis
Blinding of participants and personnel Low risk

(performance bias)
All outcomes
Double-blind
Blinding of outcome assessment (detection Low risk

bias)
All outcomes
Double-blind

17
Bogousslavsky 1990
Methods
Publication status: published

Unicenter placebo-controlled trial
Random 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 infarction, pregnancy, cerebral neoplasm, other cause of brain infarction than atherothrombosis, other severe diseases, medication (concomitant use of calcium channel antagonists,
piracetam, pentoxyphylline, naftidrofuryl dehydrogenoxalate, dihydroergetoxine, alphamethyldopa)
Interventions
Treatment: oral nimodipine, 30 mg qid for 2 weeks

Outcomes
Mathew Scale score

Death
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
Authors judgement
Random sequence generation (selection Low risk

bias)
The patients received nimodipine or

placebo according to a random list
Unclear risk
Not mentioned

All outcomes
High risk
60 patients recruited but only 52 patients

had been analyzed, there was no ITT analysis

(performance bias)
All outcomes
Double-blind

bias)
Double-blind

18
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 5

days, 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
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
1 missing in the placebo group and there

was no ITT analysis

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind

19
Canwin 1993
Methods

Placebo-controlled trial
Blinding: 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) minor or 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
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
189 patients randomized into the study but

164 were suitable for statistical evaluation,
and they did do the ITT analysis
Blinding of participants and personnel Unclear risk

(performance bias)
All outcomes
Not mentioned
Blinding of outcome assessment (detection Unclear risk

bias)
All outcomes
Not mentioned

20
Capon 1983
Methods

Blinding: 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
Methods

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: transient signs, large (> 60 mL on CT) cerebral hemorrhage; no informed consent; 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

Death
Last 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

21
Chandra 1995
(Continued)
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
Unclear risk
Not mentioned

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
FIST 1990
Methods

Double-blind
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 followed by oral 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

Death
Last 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

22
FIST 1990
(Continued)
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
331 patients recruited, but only 290 analyzed, ITT analysis performed but results
not reported

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Gelmers 1984
Methods

Single-blind
Participants
Inclusion criteria: acute ischemic stroke, age > 40 years, CT scan compatible with diagnosis
Exclusion criteria: not described
Interventions
Treatment: oral nimodipine, 30 mg qid, 28 days

Placebo: none
Outcomes
Mathew Stroke Scale

Death
Last follow-up: 28 days
Dependency 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

23
Gelmers 1984
(Continued)
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
Low risk
60 patients recruited and no data loss
Selective reporting (reporting bias)
Unclear risk
Not mentioned

(performance bias)
All outcomes
Single-blind
Blinding of outcome assessment (detection High risk

bias)
All outcomes
Gelmers 1988
Methods

Random sequence generation: computer-generated lists
Concealment: numbered box
Double-blind
Participants
Inclusion criteria: age > 45 years, clinical diagnosis of complete acute ischemic stroke <
24 hours after stroke onset
Exclusion criteria: other causes than atherothrombosis (subarachnoid and intracerebral
hemorrhage), complicated migraine, severe systemic diseases
Interventions

Outcomes
Mathew Scale
Death
Dependency measurement used in review: functional-item Mathew Scale (at end of
treatment)
Missing: 18 patients in active treatment and 20 patients in placebo group

24
Gelmers 1988
(Continued)
Notes
All patients received a standard regimen of 10% depolymerized low-molecular-weight

dextran for 12 hours per day during 5 days
Risk of bias
Bias
Authors judgement

bias)
Medication was randomized in equal

blocks of 10, according to computer-generated lists
Low risk
Numbered boxes contained 1 complete

treatment or identical placebo course and
were sequentially distributed among participating general practitioners and neurologists

All outcomes
High risk
They excluded 22 patients that had been

recruited into either group and gave the reason for the exclusion but did not do ITT
analysis

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
German-Austrian 1994
Methods

Double-blind
Participants
Inclusion criteria: age 40 to 80 years, start within 48 hours, infarcts in anterior circulation (CT-confirmed), no clinical or CT-scan (within 1 week) evidence of non-ischemic
disorder, Mathew sum score < 66
Exclusion criteria: TIA, progressive stroke, vertebrobasilar ischemia, coma, intracerebral
bleeding or tumor, SAH, pregnancy, cardiac surgery within last 3 months and severe
systemic illnesses, use of other stroke treatment

25
(Continued)
Interventions

Outcomes
Modified Mathew Scale, Barthel Index

Death
Dependency measurement used in review: functional item in Mathew Scale
Missing: 89 patients in active treatment, 83 in placebo group
Notes
Data available from publication, abstracts and Bayer AG, Wuppertal, Germany
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
482 patients included and ITT analysis

performed but only 356 patients were eligible for analysis and ITT analysis was not
performed for the last 356 patients but reported that there was no significant difference for these 356 patients in both groups

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Heiss 1990
Methods

Random sequence generation: random number
Concealment: packed box
Double-blind
Participants
Inclusion criteria: age > 45 years, acute completed ischemic stroke; admission < 48 hours,
Mathew Scale Score < 66
Exclusion criteria: other causes than atherothrombosis, overt systemic disease, coma,

26
Heiss 1990
(Continued)
previous cerebral infarction

Interventions
Treatment: intravenous nimodipine, 1 mg/hour in first 2 hours, 2 mg/hour next 5 days,

followed by 30 mg oral qid days 6 to 21
Outcomes
Mathew Scale Score, Barthel Index

Death
Missing: in publication 27 patients were said to be randomized, in original data set 24:
numbers reported in publication used
Notes
All patients were treated with low-molecular-weight dextran (500 mL/day for 15 days)
and glycerol (10% for 5 days)
Risk of bias
Bias
Authors judgement

bias)
Random number
Low risk
Nimodipine or placebo was packed in a box

identified only by a random number

All outcomes
High risk
27 patients were randomly assigned, but 4

of them could not be evaluated

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind

27
INWEST 1990
Methods

Double-blind
Participants
Inclusion criteria: age > 40 years, start < 24 hours, clinical diagnosis of ischemic stroke
carotid territory, functionally independent before stroke, conscious, Mathew Scale Score
< 66 or Orgogozo score 5 to 50
Exclusion criteria: cardiac disease, any disorder interfering with assessment, life-threatening concurrent illness
Interventions
Treatment: intravenous nimodipine 1 mg/hour or 2 mg/hour for 5 days, followed by

oral nimodipine 120 mg/day days 5 to 21
Outcomes
Barthel Index, Orgogozo and Mathew Scales

Death
Missing: 4 patients in nimodipine group
Notes
Trial was terminated early after including 295 patients (planned 600) because of safety
concerns
Data available from authors manuscript, abstract and Bayer AG, Wuppertal, Germany
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
Low risk
295 patients were recruited and entered

into the treatment and control groups but
only 228 patients were valid for the primary
analysis
ITT analysis performed and there were no
statistically significant differences between
these groups

(performance bias)
All outcomes

Double-blind
28
INWEST 1990
(Continued)

bias)
All outcomes
Double-blind
Kaste 1994
Methods

Concealment: sealed envelope
Double-blind
Participants
Inclusion criteria: age 16 to 69 years, start within 48 hours, acute ischemic hemispheric
stroke, CT scan compatible with clinical diagnosis
Exclusion criteria: unconsciousness, inability to swallow, rapidly improving, dependence
before stroke, brainstem infarction, complicated migraine, pregnancy, overt renal, hepatic
or cardiac failure, severe systemic infection, serious psychiatric disturbance, terminal
malignancy
Interventions

Placebo: identical regime
Outcomes
Neurological examination
Rankin scale
Death
Dependency measurement used in review: Rankin scale
Missing: 2 living patients in placebo, 1 living patient in active treatment group
Notes
Data available from authors and publication
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Low risk
Sealed envelope

All outcomes
High risk
Data for 1 patient was lost

(performance bias)
All outcomes
Double-blind
29
Kaste 1994
(Continued)

bias)
All outcomes
Double-blind
Kornhuber 1993
Methods

Random sequence generation: special sequence generation
Double-blind
Participants
Inclusion criteria: age 50 to 85 years, start within 36 hours, clinical diagnosis of anterior
or MCA stroke
Exclusion criteria: transient signs, coma, previous cerebral infarction, severe cardiac insufficiency, acute myocardial infarction, acute pulmonary embolism, connective tissue
disease, cytostatic therapy, use of calcium antagonists or oral anticoagulation, dialysis,
dementia, intracranial hemorrhage, brain tumor, brainstem infarction, complicated migraine, flunarizine treatment within previous 4 weeks
Interventions
Treatment: intravenous flunarizine, 25 mg bid, 7 days, followed by oral 10 mg/day and

20 mg/day, days 8 to 28
Outcomes
Modified Mathew Scale

Death
Data on dependency: not available from all patients randomized, since data from 1 center
were excluded from analysis
Notes
All patients received aspirin, subcutaneous aspirin and hydroxyethyl starch for 7 days
Data available from publication and abstract
Mortality data were available from all centers
Risk of bias
Bias
Authors judgement

bias)
The study was double-blind and randomized in 32 blocks: each block contained 4
sub-blocks of 8 patients randomized at a
ratio of 1:1 and given either flunarizine or
placebo; each of these sub-block was allocated to 1 of the 4 groups
Not mentioned
Unclear risk

30
Kornhuber 1993
(Continued)

All outcomes
High risk
443 patients recruited but 11 patients had

been withdraw - reason given but ITT analysis not performed

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Lamsudin 1995
Methods

Double-blind
Participants
Inclusion criteria: acute ischemic stroke within the preceding 24 hours, either sex, all
ages, diagnosis by CT
Exclusion criteria: coma, intracranial hemorrhage, tumor, infection, trauma, serious organic brain disease
Interventions

Outcomes
Canadian Scale score, Barthel Index score

Death during study period
Missing: 15 patients
Notes
Data provided by Professor Thomas
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
15 patients excluded but did not analyze

whether they were related to the outcome

31
Lamsudin 1995
(Continued)

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Limburg 1990
Methods

Unicenter placebo-controlled trial
Double-blind
Participants
Inclusion criteria: start within 24 hours, supratentorial ischemic stroke with hemiparesis,
CT scan exclusion of other relevant pathology
Exclusion criteria: lacunar syndromes, serious underlying diseases, previous disabling
strokes, use of calcium antagonists
Interventions
Treatment: intravenous flunarizine; bolus of 0.1 mg/kg body weight, followed after 3
hours by continuous intravenous infusion 0.3 mg/kg/24 hour during 72 hours, subsequently oral administration of 10 mg/24 hours for 11 days
Outcomes
Motricity Index, Rankin scale, Barthel Index

Death
Missing: none
Notes
Data available from authors and publication
Risk of bias
Bias
Authors judgement

bias)
Random table
Unclear risk
Not mentioned

All outcomes
Low risk
Reported all the patients recruited

32
Limburg 1990
(Continued)

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Lisk 1993
Methods

Double-blind
Participants
Inclusion criteria: age 40 to 90 years, start within 72 hours, clinical diagnosis of ischemic
stroke in MCA territory, systolic BP > 170 mmHg, diastolic BP > 119 mmHg or MABP
> 139 mmHg, history of hypertension
Exclusion criteria: coma, previous serious stroke, unstable cardiac disease, history of
angioedema or collagen vascular disease, liver dysfunction, brainstem strokes
Interventions
Treatment: oral nicardipine, 20 mg tid for 3 days

Outcomes
National Institutes of Health Stroke Scale

Deaths
Data on dependency: not available
Missing: none
Notes
Data from publication

Trial compared treatment with nicardipine or captopril versus placebo, in this analysis
the captopril group was excluded
Trial designed to find differences in cerebral blood flow as measured with SPECT in
hypertensive patients with a stroke
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Not mentioned
Unclear risk

33
Lisk 1993
(Continued)

All outcomes
Low risk
They reported all the patients recruited

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Lowe 1989
Methods

Participants
Inclusion criteria: age 45 to 85 years, start within 48 hours, clinical diagnosis of acute
cerebral hemispheric infarction, Barthel Index < 66
Exclusion criteria: other cause for neurological deficits, CT scan within 7 days of ictus,
not expected to survive, women capable of child bearing, severe liver or renal failure,
recent myocardial infarction, decompensated heart failure, disability due to other causes
not separable from present illness
Interventions
Treatment: oral nimodipine, 40 mg tid for 16 weeks

Outcomes
Neurological score (MRC 10-item), Barthel Index

Deaths
Missing: none
Notes
Data available from investigators and Bayer AG, Wuppertal, Germany

For analysis on time interval after stroke onset 12 patients with missing data in nimodipine group, and 8 in placebo group
For all other analyses data from the investigators were used, without missing data
Risk of bias
Bias
Authors judgement

bias)


Random number
34
Lowe 1989
(Continued)
Unclear risk
Not mentioned

All outcomes
Unclear risk
Not mentioned

(performance bias)
All outcomes
Not mentioned

bias)
All outcomes
Not mentioned
Martinez-Vila 1990
Methods

Double-blind
Participants
Inclusion criteria: age > 44 years, start within 48 hours, clinical diagnosis of ICA territory
ischemic stroke, CT scan within 3 days
Exclusion criteria: complete recovery within 24 hours, acute myocardial infarction, renal
or liver failure, severe systemic infections, poorly controlled diabetes mellitus, systolic
arterial BP < 100 mmHg, terminal malignancy
Interventions
Treatment: oral nimodipine, 30 mg qid for 28 days

Outcomes
Mathew Scale, Toronto Stroke Scale

Deaths
Missing: 40 in active treatment group, 41 in placebo group
Notes
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Not mentioned
Unclear risk

35
Martinez-Vila 1990
(Continued)

All outcomes
High risk
164 patients in total were recruited (81 to

the treatment group and 83 to the placebo
group) but 41 patients were subsequently
excluded (23 from the treatment group and
18 from the placebo group). There were no
significant differences in severity of the remaining 123 patients (58 in the treatment
group and 65 in the placebo group)

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Mohr 1992
Methods

Double-blind
Participants
Inclusion criteria: age 20 to 90 years, start within 48 hours, clinical diagnosis of acute
ischemic stroke, CT scan without evidence of cerebral hemorrhage
Exclusion criteria: coma, intracranial hemorrhage, tumor, infection, trauma, serious
other organic brain disease, need for mechanical ventilation, calcium antagonist therapy,
pregnancy, hypotension, bradycardia, heart block, hepatic or renal dysfunction, congestive heart failure, pneumonia
Interventions
Treatment: oral nimodipine 20 mg, 40 mg or 80 mg tid for 2 weeks

(4 groups: 60 mg/day, 120 mg/day and 240 mg/day and placebo)
Outcomes
Motor strength from Stroke Data Bank, Toronto Stroke Scale, Barthel Index, Mathew
Scale
Dependency measurement used in review: Barthel Index at 21 days
Death
Last follow-up: 6 months (only deaths)
Notes
Risk of bias

36
Mohr 1992
(Continued)
Bias
Authors judgement

bias)
Not mentioned
Low risk
Study centers were provided with numbered boxes containing tablets in blister
packs of 4 each
The appearance of placebo and each drug
dose was identical

All outcomes
Low risk
All patients randomized were analyzed, the

analysis followed the ITT principle

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Nag 1998
Methods

Double-blind
Participants
Inclusion criteria: acute ischemic stroke within preceding 48 hours, acute onset of hemiplegia of either side with or without aphasia, diagnosis was confirmed by CT that showed
a hypodense lesion in the territory of either MCA
Exclusion criteria: only transient neurological deficiency (persisting < 24 hours), coma
(Glasgow Coma Scale score < 10), intracranial hemorrhage, tumor, infection, trauma,
need for assisted ventilation, pregnancy, severe hypertension (diastolic BP > 120 mmHg)
, hepatic or renal dysfunction
Interventions
Treatment: oral nimodipine 120 mg/day for 28 days

Outcomes
Mathew Scale
Mortality at the end of follow-up
Adverse effects
BP

37
Nag 1998
(Continued)
Notes
Other routine management (antihypertensive drugs, hyperlipidemic drugs, platelet antiaggregants, hemorrheological drugs, edema-reducing measures, etc.) were given in both
the groups
Data provided by Professor Thomas
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
80 patients recruited but reports of only 62

patients

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
NEST 1993
Methods

Double-blind
Participants
Inclusion criteria: age 39 to 81 years, start within 48 hours, clinical diagnosis of ischemic
stroke in MCA territory, Barthel Index 60, N-score 50, CT scan within 7 days
Exclusion criteria: stupor and coma, stroke progression before randomization, disorders
interfering with assessment, serious infection, cardiac disease, life-threatening concomitant illness
Interventions
Treatment: oral nimodipine, 30 mg qid for 21 days

Outcomes
Neurological score
Barthel Index
Death

38
NEST 1993
(Continued)

Missing: 27 patients in active treatment group, 22 in placebo group
Notes
Standard hospital regimens (hemodilution and heparin) were allowed

In paper, 195 patients were excluded from the analysis; however, data set from Bayer
included 879 patients
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
27 patients in active treatment group and

22 in placebo group missed

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
NIMPAS 1999
Methods

Double-blind
Participants
Inclusion criteria: start within 12 hours, cortical infarction in MCA territory (confirmed
by CT or clinical findings), patient able to have acute SPECT and CT
Exclusion criteria: concurrent use of dihydropyridine calcium antagonists, contraindications to calcium antagonist use, other severe disease, previous stroke, cerebral hemorrhage or non-cerebrovascular pathology on CT scan
Interventions
Treatment: oral nimodipine 30 mg qid for 14 days


39
NIMPAS 1999
(Continued)
Outcomes
Canadian Neurological Scale, Barthel Index

Death
Missing: none
Notes
Data available from investigators

Trial designed to measure the effect of nimodipine on perfusion changes after acute
stroke with SPECT
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
50 patient included and 4 had been excluded. There was no ITT analysis

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Oczkowski 1989
Methods

Double-blind
Participants
Inclusion criteria: age 45 to 80 years, start within < 48 hours, acute ischemic cerebral
infarction in MCA territory, chief symptom hemiparesis
Exclusion criteria: previous stroke, brain hemorrhage, brainstem infarction, coma, recurrent seizures, organ failure, lacunar infarction, systolic BP >165 or < 110 mmHg
Interventions
Treatment: oral PY108-608 100 mg day 1, 112.5 mg day 2, 125 mg day 3, 150 mg days
4 to 21, divided in 4 daily doses
Placebo: identical regime

40
Oczkowski 1989
(Continued)
Outcomes
Toronto Stroke Scale, Barthel Index

Deaths
Data on dependency presented in an unusable way
Missing: none
Notes
Only data from publication, no additional data from authors available
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
Low risk
Reported all patients included

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Paci 1989
Methods

Double-blind
Participants
Inclusion criteria: start within < 12 hours, sudden and persistent focal event in carotid
artery distribution
Exclusion criteria: TIA, progressing stroke, cerebral hemorrhage (confirmed by CT scan),
severe systemic disorders, recent myocardial infarction, congestive heart failure, evidence
of abnormal hepatic, pulmonary or renal functions, previous complete stroke
Interventions
Treatment: oral nimodipine 40 mg tid for 28 days


41
Paci 1989
(Continued)
Outcomes
Mathew Neurological score, Global assessment of outcome: good/fair/poor

Death
Dependency measurement used in review: functional item from Mathew score
Missing: 1 patient in active treatment and 1 patient in control group
Notes
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
1 patient in active treatment and 1 patient

in control group missed. No ITT analysis

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Sherman 1986
Methods

Double-blind
Participants
Inclusion criteria: start within 48 hours, clinical evidence of cerebral hemisphere ischemic
event
Exclusion criteria: TIA, brainstem infarction, progressing stroke, cerebral hemorrhage,
severe cardiac, renal or hepatic disease
Interventions


42
Sherman 1986
(Continued)
Outcomes
Neurological examination, mobility, functional status

Death
No data available on functional outcome
Missing: none
Notes
Data only from limited publication in book
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
Unclear risk
Not mentioned

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Shibuya 2005
Methods

Random sequence generation: random list
Double-blind
Participants
Inclusion criteria: age > 20 years, informed consent, acute ischemic stroke due to thrombosis, treatment onset < 48 hours after stroke onset, Japan Coma Scale score of 0 to 3,
motor deficit (from moderate to severe) of the arms, legs, or both
Exclusion criteria: history of severe cardiopulmonary, hepato-renal or metabolic diseases,
women of child-bearing potential, cerebral hemorrhage on CT scan, systolic BP < 90
mmHg
Interventions
Treatment: intravenous fasudil 60 mg bid for 14 days


43
Shibuya 2005
(Continued)
Outcomes
Neurological status was assessed by the Motor System of Japan Stroke Scale (JSS), modified Rankin Scale (mRS), adverse events
Notes
This article did not provide the result of poor outcome or death at the end of treatment
or follow-up, but it did provide adverse events and neurological improvement as the
result
Data were available from publication and from the database of Sichuan University,
Chengdu, China
Risk of bias
Bias
Authors judgement

bias)
A random list was prepared by an independent statistical center

Patients were randomized to fasudil or
placebo with the use of separate randomization lists balanced for each participating
center by personnel unrelated to the study
Unclear risk
Not mentioned

All outcomes
Low risk
Reported all the patients included

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
All assessments were blinded
Squire 1996
Methods

Double-blind
Participants
Inclusion criteria: first-ever ischemic stroke < 6 hours or 6 to 12 hours from onset
of symptoms, age 21 to 74 years, stable clinical signs, had written informed consent,
pretreatment motor arm or motor leg (NIH scale) of 2 or 3, treatment could be started
within 12 hours of onset of symptoms, normal plasma electrolytes prior to start of
treatment

44
Squire 1996
(Continued)
Exclusion criteria: NIH scale level of consciousness 2 or 3; previous stroke; unable to

initiate treatment within 12 hours from onset; myocardial infarction within previous 4
months; BP < 120/80 mmHg; history of ventricular arrhythmia, AV block or IVCD;
not likely to be available for 3-month assessment; premenopausal female not surgically
sterilized; pre-existing life-threatening disease or systematic illness
Interventions
Treatment: lifarizine 250 g/kg intravenous stat plus 60 mg bid orally for 5 days within
6 hours or 6 to 12 hours since stroke onset
Outcomes
Mortality at the end of treatment and follow-up

Rankin Scale, Barthel Index score
Notes
Data available Professor Thomas
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
147 patients involved but only 117 patients

evaluated

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Sze 1998
Methods

Concealment: permuted block
Double-blind
Participants
Inclusion criteria: based on brain CT scan within 14 days, clinical assessment according
to WHO definition on stroke
Exclusion criteria: cerebral hemorrhage, patient refused, acute cardiopulmonary instability, sepsis, clinical depression, Glasgow Coma Scale score < 15 and patients who did

45
Sze 1998
(Continued)
not complete the full course of treatment

Interventions
Treatment: oral nimodipine 30 mg tid between days 7 to 14 after the onset of the stroke
for 12 weeks
Outcomes
Death, Mini-Mental State Examination and Ful Object-Memory Evaluation
Notes
Data were available from publication and from the database of Sichuan University,
Chengdu, China
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Low risk
Patients were separately randomized to the

groups according to random permuted
blocks

All outcomes
High risk
14 patients excluded

(performance bias)
All outcomes
Single-blind

bias)
All outcomes
They described that the assessors were

blinded
TRUST 1990
Methods

Double-blind
Participants
Inclusion criteria: age > 40 years, start within 48 hours, clinical evidence of hemiparetic
stroke, independent before stroke, conscious, able to swallow
Exclusion criteria: intracranial hemorrhage or tumor on CT scan between days 7 to 14
(whenever possible)

46
TRUST 1990
(Continued)
Interventions
Treatment: oral nimodipine 40 mg tid for 21 days

Outcomes
Neurological examination, Orgogozo Stroke scale, Nottingham Activities of Daily Living

scale, Barthel Index
Death
Missing: 4 patients in active treatment group, 8 patients in placebo group
Notes

Some minor differences between original data set and publication - we used original data
set for analysis on time after stroke onset
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
Many patients were withdrawn and 12 patients were lost to follow-up; the article did
not provide the results of these patients and
there was no ITT analysis

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind
Uzunur 1995
Methods
Publication status: published as an abstract

Open controlled trial
Participants
Inclusion criteria: acute stroke (hemorrhage and ischemic), start within 24 hours

47
Uzunur 1995
(Continued)
Interventions
Treatment: oral nimodipine 180 mg/day. If CT demonstrated intracranial or intracerebral

hemorrhage, intravenous nimodipine 2 mg/hour
Control: no nimodipine
Outcomes
Death
BP at various time intervals
Last follow-up: discharge from hospital, maximum 40 days
Data on dependency: not available
Missing: 2 patients in active treatment, 8 patients in control group withdrawn because
of malignant hypertension
Notes
Data available from manuscript and abstract, received from principal investigator
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
Unclear risk
Not mentioned

(performance bias)
All outcomes
Not mentioned

bias)
All outcomes
Not mentioned
VENUS 1999
Methods

Random sequence generation: computer-generated lists
Double-blind
Participants
Inclusion criteria: age 18 to 85 years, start within < 6 hours, acute stroke, hemiparesis
Exclusion criteria: unconsciousness, rapidly improving, symptoms indicative for intracranial hemorrhage (Panzer criteria), dependence before stroke, pregnancy, other severe disease, hypotension, bradycardia, inability to swallow

48
VENUS 1999
(Continued)
Interventions

Outcomes
Neurological examination, Rankin scale

Death
Missing: 3 living patients in placebo, 3 living patient in active treatment group
261 patients with ischemic stroke were randomized; 133 received nimodipine and 128
received placebo
Missing: none
Notes
All data (assessed in trial) available

Inclusion by general practitioners
Data available from publication
Risk of bias
Bias
Authors judgement

bias)
Medication was randomized in equal

blocks of 10, according to computer-generated lists
Low risk
Numbered boxes contained 1 complete

treatment or identical placebo and were distributed among participating general practitioners and neurologists

All outcomes
Low risk
261 patients with ischemia recruited and

all of them reported

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind

49
Wimalaratna 1994
Methods

Double-blind
Participants
Inclusion criteria: age 45 to 85 years, start within 24 hours, Barthel Index < 65
Exclusion criteria: hemorrhage on CT scan
Interventions
Treatment: oral nimodipine 120 mg/day or 240 mg/day for 16 weeks

Outcomes
MRC-based rating system for motor scoring, Barthel Index

Death
Missing: 32 patients in active treatment group, 13 patients in placebo group
Notes
Data available from publication, manuscript, abstracts and Bayer AG, Wuppertal, Germany
Risk of bias
Bias
Authors judgement

bias)
Not mentioned
Unclear risk
Not mentioned

All outcomes
High risk
32 patients in active treatment group and

13 in placebo group were missed

(performance bias)
All outcomes
Double-blind

bias)
All outcomes
Double-blind

50
Yordanov 1984
Methods

Placebo-controlled trial?
Participants
Stroke patients, inclusion within 5 days after onset of symptoms
Interventions
Treatment: nimodipine 0.5 mg/hour intravenously for 7 days, followed by 30 mg qid for 21 days
Placebo: Identical regimen (?)
Outcomes
Toronto Stroke Scale

Deaths
Missing: none
Notes
Only limited data available from Bayer AG, Wuppertal, Germany
AV block: atrioventricular block

bid: twice per day (bis in die)
BP: blood pressure
CT: computerized tomography
ICA: internal carotid artery
ITT: intention-to-treat
IVCD: interior vena cava diameter
MABP: mean arterial blood pressure
MCA: middle cerebral artery
MRC: Medical Research Council
qid: four times per day (quarter in die)
SPECT: single-photon emission computed tomography
TIA: transient ischemic attack
tid: three times per day (ter in die)
WHO: World Health Organization
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Ameriso 1992
Nimodipine trial
Seems to be part of the another larger trial, but which one is unknown
In this report the hemorrheological data of few patients are reported

51
(Continued)
Csiba
Nimodipine trial performed in Hungary

Investigators and company are unable to retrieve data
Dalal 1995
Nimodipine trial
The treatment group is intravenous nimodipine followed by oral nimodipine, while the control group is
antithrombotic agents, anticoagulant drugs and other supportive measures
Fagan 1988
Nimodipine trial
Outcomes are BP recorded before and 30 and 60 minutes after a dose for the first 8 days that is not related
to this systematic reviews outcome measures
Marn Gmez 1988
Nicardipine trial
Spanish article: in the study 75 patients were included; unknown how many patients in which treatment
group; more than 30% of patients (24/75) were excluded after randomization, no follow-up data are provided
Matias Guiu 1992
Nicardipine trial
Aim of the study was to assess the effect on cognitive impairment after minor stroke
Molto 1994
Nicardipine trial
Included patients with TIA, Spanish article
Orgogozo
Nicardipine trial
Principal investigator could not supply data from this unpublished trial
Petrogiannopoulos 96
Nimodipine trial
Patients were included 1 to 2 months after acute ischemic stroke
Rosenbaum 1990
Nicardipine trial
Safety study without a control group
Rosselli 1992
Nimopidine trial (Italy)

Outcomes are not included in this review
Data extraction provided Dr Chiara Menichetti
Szczechowski 1994
Nimodipine trial
Treatment group given intravenous nimodipine, control group given standard treatment with dextran
Yao 1991
Nimodipine trial
Chinese report of preliminary study, no outcome data available
BP: blood pressure

TIA: transient ischemic attack

52
DATA AND ANALYSES
Comparison 1. Calcium antagonists versus control in acute ischemic stroke
Outcome or subgroup title

1 Primary outcome at end of
follow-up
1.1 Nimodipine versus control
1.2 Flunarizine versus control
1.3 Isradipine versus control
2 Death at end of treatment period
2.3 Any other agent versus
control
3 Death at end of follow-up
3.3 Isradipine versus control
control
4 Recurrence of stroke at end of
follow-up
control
5 Adverse events (all) during
treatment period
control
6 Hypotension during treatment
period (reason to stop
treatment)
control
7 Mean systolic blood pressure
during or at end of treatment
No. of
studies
No. of
participants
22
6684
Risk Ratio (M-H, Random, 95% CI)
1.05 [0.98, 1.13]
19
2
1
22
16
3
3
6093
357
234
6323
5163
790
370

1.06 [0.97, 1.14]

0.81 [0.34, 1.94]
1.01 [0.74, 1.40]
1.06 [0.93, 1.20]
1.02 [0.88, 1.19]
1.31 [0.94, 1.82]
0.98 [0.58, 1.66]
31
24
3
1
3
7483
6312
790
234
147

1.07 [0.98, 1.17]

1.05 [0.96, 1.16]
1.34 [1.01, 1.77]
1.05 [0.60, 1.85]
0.84 [0.45, 1.56]
2460
0.93 [0.56, 1.54]
6
2
1
1677
764
19

0.98 [0.45, 2.10]

0.82 [0.35, 1.97]
0.0 [0.0, 0.0]
13
5095
1.18 [0.81, 1.74]
11
1
1
4604
331
160

0.93 [0.74, 1.16]

3.16 [1.91, 5.21]
1.19 [0.52, 2.72]
1667
1.43 [0.61, 3.38]
5
1
1648
19

1.26 [0.50, 3.14]

5.50 [0.30, 101.28]
630
Mean Difference (IV, Random, 95% CI)
-1.30 [-3.92, 1.32]
630
Mean Difference (IV, Random, 95% CI)
-1.30 [-3.92, 1.32]
Statistical method

Effect size
53
Comparison 2. Calcium antagonists versus control: subgroup analysis

1 Primary outcome by route of
administration
1.1 Oral administration
1.2 Intravenous
administration
1.3 Oral versus intravenous
administration (outcome
death)
2 Primary outcome by dose:
indirect comparisons
2.1 Nimodipine 60 mg versus
control oral
2.2 Nimodipine 120 mg
versus control oral
versus control oral
2.4 Nimodipine 2 mg/hour
versus control intravenous
2.5 Nimodipine 1 mg/hour
versus control intravenous
3 Primary outcome by dose: direct
comparisons
120 mg oral
240 mg oral
versus 240 mg oral
3.4 Nimodipine 1 versus 2
mg/hour intravenous
4 Primary outcome by time of
start of treatment
4.1 Treatment started 12
hours
4.2 Treatment started > 12
hours
No. of
studies
No. of
participants
23
Statistical method
Effect size
Subtotals only
14
8
5131
1544

1.03 [0.93, 1.14]

1.11 [1.01, 1.22]
143
7.10 [0.37, 134.96]
Subtotals only
18
1
529
1.08 [0.94, 1.24]
14
4526
0.99 [0.88, 1.11]
673
1.07 [0.94, 1.22]
552
1.34 [0.93, 1.93]
329
1.09 [0.91, 1.29]
Subtotals only
4
1
533
1.08 [0.94, 1.24]
532
1.00 [0.88, 1.13]
681
0.93 [0.82, 1.06]
333
0.82 [0.71, 0.95]
18
5950
1.04 [0.96, 1.13]
18
1879
1.08 [0.96, 1.21]
14
4071
1.01 [0.90, 1.13]

54
Comparison 3. Calcium antagonists versus control: sensitivity analysis
No. of
studies
No. of
participants
10
4012
1.04 [0.95, 1.14]
22
18
6675
5887

1.06 [0.98, 1.14]

1.03 [0.94, 1.12]
788
1.14 [1.00, 1.30]
1 Primary outcome in multicenter

placebo controlled trials
2 Publication status
2.1 Primary outcome in
published trials
2.2 Primary outcome in
unpublished trials
Statistical method
Effect size
Analysis 1.1. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 1
Primary outcome at end of follow-up.
Review:
Comparison: 1 Calcium antagonists versus control in acute ischemic stroke

Outcome: 1 Primary outcome at end of follow-up
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
2/30
3/30
0.2 %
0.67 [ 0.12, 3.71 ]
Bridgers 1991
103/138
43/66
8.0 %
1.15 [ 0.94, 1.40 ]
Canwin 1993
39/96
42/93
4.0 %
0.90 [ 0.65, 1.25 ]
Gelmers 1984
2/29
12/31
0.3 %
0.18 [ 0.04, 0.73 ]
Gelmers 1988
24/93
34/93
2.5 %
0.71 [ 0.46, 1.09 ]
60/239
63/243
4.5 %
0.97 [ 0.71, 1.31 ]
5/14
4/13
0.5 %
1.16 [ 0.40, 3.41 ]
133/195
54/100
7.8 %
1.26 [ 1.03, 1.55 ]
Kaste 1994
44/176
31/174
2.8 %
1.40 [ 0.93, 2.11 ]
Lowe 1989
34/56
23/56
3.2 %
1.48 [ 1.01, 2.16 ]
Martinez-Vila 1990
18/81
22/83
1.7 %
0.84 [ 0.49, 1.44 ]
Mohr 1992
475/800
155/264
13.3 %
1.01 [ 0.90, 1.14 ]
NEST 1993
197/437
211/443
11.4 %
0.95 [ 0.82, 1.09 ]
1 Nimodipine versus control

Bogousslavsky 1990
Heiss 1990
INWEST 1990
0.1 0.2
0.5
favors treatment group
10
favors control group
(Continued . . . )
55
(. . .
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI
n/N
n/N
11/25
10/25
1.2 %
1.10 [ 0.57, 2.11 ]
2/19
5/22
0.2 %
0.46 [ 0.10, 2.12 ]
TRUST 1990
275/607
257/608
12.4 %
1.07 [ 0.94, 1.22 ]
VENUS 1999
44/133
30/128
3.0 %
1.41 [ 0.95, 2.10 ]
Wimalaratna 1994
57/146
28/69
3.6 %
0.96 [ 0.68, 1.37 ]
Yordanov 1984
70/121
62/117
6.8 %
1.09 [ 0.87, 1.37 ]
3435
2658
87.4 %
1.06 [ 0.97, 1.14 ]
NIMPAS 1999
Paci 1989
Subtotal (95% CI)
Total events: 1595 (Treatment), 1089 (Control)

Heterogeneity: Tau?? = 0.01; Chi?? = 26.57, df = 18 (P = 0.09); I?? =32%
Test for overall effect: Z = 1.30 (P = 0.19)
2 Flunarizine versus control
FIST 1990
93/166
83/165
7.9 %
1.11 [ 0.91, 1.36 ]
3/12
8/14
0.5 %
0.44 [ 0.15, 1.29 ]
178
179
8.4 %
0.81 [ 0.34, 1.94 ]
Limburg 1990
Subtotal (95% CI)


3 Isradipine versus control
ASCLEPIOS 1990
47/120
44/114
4.2 %
1.01 [ 0.74, 1.40 ]
120
114
4.2 %
1.01 [ 0.74, 1.40 ]
3733
2951
100.0 %
1.05 [ 0.98, 1.13 ]
Subtotal (95% CI)

Heterogeneity: not applicable
Total (95% CI)

Test for subgroup differences: Chi?? = 0.38, df = 2 (P = 0.82), I?? =0.0%
0.1 0.2
0.5
10

56
Analysis 1.2. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 2 Death
at end of treatment period.
Review:

Outcome: 2 Death at end of treatment period
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Risk Ratio
MH,Random,95%
CI
n/N
n/N
0/30
0/30
0.0 [ 0.0, 0.0 ]
26/96
30/93
0.84 [ 0.54, 1.30 ]
14/239
21/243
0.68 [ 0.35, 1.30 ]
3/14
1/13
2.79 [ 0.33, 23.52 ]
INWEST 1990
46/195
18/100
1.31 [ 0.80, 2.14 ]
Kaste 1994
18/176
6/174
2.97 [ 1.21, 7.29 ]
0/72
0/78
0.0 [ 0.0, 0.0 ]
Lowe 1989
14/56
12/56
1.17 [ 0.59, 2.29 ]
Martinez-Vila 1990
12/81
14/83
0.88 [ 0.43, 1.78 ]
117/800
40/264
0.97 [ 0.69, 1.34 ]
0/31
0/31
0.0 [ 0.0, 0.0 ]
61/437
65/443
0.95 [ 0.69, 1.31 ]
NIMPAS 1999
3/25
3/25
1.00 [ 0.22, 4.49 ]
Paci 1989
0/19
0/22
0.0 [ 0.0, 0.0 ]
Sherman 1986
0/11
0/11
0.0 [ 0.0, 0.0 ]
81/607
75/608
1.08 [ 0.81, 1.45 ]
2889
2274
1.02 [ 0.88, 1.19 ]

Bogousslavsky 1990
Canwin 1993
Heiss 1990
Lamsudin 1995
Mohr 1992
Nag 1998
NEST 1993
TRUST 1990
Subtotal (95% CI)


FIST 1990
40/166
28/165
1.42 [ 0.92, 2.19 ]
Kornhuber 1993
25/215
20/218
1.27 [ 0.73, 2.21 ]
2/12
4/14
0.58 [ 0.13, 2.65 ]
393
397
1.31 [ 0.94, 1.82 ]
Limburg 1990
Subtotal (95% CI)
0.1 0.2
0.5
10
(Continued . . . )

57
(. . .
Study or subgroup
Treatment
Control
n/N
n/N
Continued)
Risk Ratio
MH,Random,95%
CI
Risk Ratio
MH,Random,95%
CI

Heterogeneity: Tau?? = 0.0; Chi?? = 1.25, df = 2 (P = 0.54); I?? =0.0%
3 Any other agent versus control
ASCLEPIOS 1990
Oczkowski 1989
Squire 1996
Subtotal (95% CI)
19/120
16/114
1.13 [ 0.61, 2.08 ]
1/9
1/10
1.11 [ 0.08, 15.28 ]
4/54
8/63
0.58 [ 0.19, 1.83 ]
183
187
0.98 [ 0.58, 1.66 ]
2858
1.06 [ 0.93, 1.20 ]

Total (95% CI)
3465

0.1 0.2
0.5

10
58
Analysis 1.3. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 3 Death
at end of follow-up.
Review:

Outcome: 3 Death at end of follow-up
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Risk Ratio
MH,Random,95%
CI
n/N
n/N
29/176
22/174
1.30 [ 0.78, 2.18 ]
Nag 1998
0/31
0/31
0.0 [ 0.0, 0.0 ]
Lamsudin 1995
0/72
0/78
0.0 [ 0.0, 0.0 ]
Sze 1998
1/44
2/42
0.48 [ 0.04, 5.07 ]
Heiss 1990
5/14
4/13
1.16 [ 0.40, 3.41 ]
173/607
150/608
1.16 [ 0.96, 1.39 ]
49/239
45/243
1.11 [ 0.77, 1.59 ]
Bogousslavsky 1990
0/30
1/30
0.33 [ 0.01, 7.87 ]
Martinez-Vila 1990
15/81
20/83
0.77 [ 0.42, 1.39 ]
Gelmers 1988
16/93
27/93
0.59 [ 0.34, 1.02 ]
0/19
0/22
0.0 [ 0.0, 0.0 ]
Mohr 1992
120/800
42/264
0.94 [ 0.68, 1.30 ]
NEST 1993
105/437
103/443
1.03 [ 0.81, 1.31 ]
83/195
33/100
1.29 [ 0.93, 1.78 ]
15/56
12/56
1.25 [ 0.64, 2.42 ]
Sherman 1986
0/11
0/11
0.0 [ 0.0, 0.0 ]
Canwin 1993
29/96
33/93
0.85 [ 0.57, 1.28 ]
40/146
24/69
0.79 [ 0.52, 1.20 ]
1/30
2/30
0.50 [ 0.05, 5.22 ]
Bridgers 1991
37/138
12/66
1.47 [ 0.82, 2.64 ]
Yordanov 1984
44/121
36/117
1.18 [ 0.82, 1.69 ]
NIMPAS 1999
3/25
3/25
1.00 [ 0.22, 4.49 ]
Gelmers 1984
2/29
5/31
0.43 [ 0.09, 2.03 ]

Kaste 1994
TRUST 1990
Paci 1989
INWEST 1990
Lowe 1989
Wimalaratna 1994
Capon 1983
0.1 0.2
0.5
10
(Continued . . . )

59
(. . .
Study or subgroup
Treatment
Control
Continued)
Risk Ratio
MH,Random,95%
CI
Risk Ratio
MH,Random,95%
CI
n/N
n/N
6/50
7/50
0.86 [ 0.31, 2.37 ]
3540
2772
1.05 [ 0.96, 1.16 ]
59/166
41/165
1.43 [ 1.02, 2.00 ]
3/12
5/14
0.70 [ 0.21, 2.34 ]
25/215
20/218
1.27 [ 0.73, 2.21 ]
393
397
1.34 [ 1.01, 1.77 ]
21/120
19/114
1.05 [ 0.60, 1.85 ]
120
114
1.05 [ 0.60, 1.85 ]
12/54
17/63
0.82 [ 0.43, 1.57 ]
Oczkowski 1989
1/9
1/10
1.11 [ 0.08, 15.28 ]
Lisk 1993
0/5
0/6
0.0 [ 0.0, 0.0 ]
68
79
0.84 [ 0.45, 1.56 ]
3362
1.07 [ 0.98, 1.17 ]
Uzunur 1995
Subtotal (95% CI)


FIST 1990
Limburg 1990
Kornhuber 1993
Subtotal (95% CI)


3 Isradipine versus control
ASCLEPIOS 1990
Subtotal (95% CI)

Squire 1996
Subtotal (95% CI)


Total (95% CI)
4121

Test for subgroup differences: Chi?? = 3.11, df = 3 (P = 0.37), I?? =4%
0.1 0.2
0.5

10
60
Recurrence of stroke at end of follow-up.
Review:

Outcome: 4 Recurrence of stroke at end of follow-up
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Risk Ratio
MH,Random,95%
CI
n/N
n/N
0/30
0/30
0.0 [ 0.0, 0.0 ]
Kaste 1994
5/176
7/174
0.71 [ 0.23, 2.18 ]
Lowe 1989
4/56
1/56
4.00 [ 0.46, 34.68 ]
Mohr 1992
24/800
7/264
1.13 [ 0.49, 2.60 ]
NIMPAS 1999
0/25
3/25
0.14 [ 0.01, 2.63 ]
Paci 1989
0/19
0/22
0.0 [ 0.0, 0.0 ]
1106
571
0.98 [ 0.45, 2.10 ]

Bogousslavsky 1990
Subtotal (95% CI)


FIST 1990
3/166
3/165
0.99 [ 0.20, 4.85 ]
Kornhuber 1993
6/215
8/218
0.76 [ 0.27, 2.15 ]
381
383
0.82 [ 0.35, 1.97 ]
0/9
0/10
0.0 [ 0.0, 0.0 ]
10
0.0 [ 0.0, 0.0 ]
1496
964
0.93 [ 0.56, 1.54 ]
Subtotal (95% CI)


Oczkowski 1989
Subtotal (95% CI)

Test for overall effect: Z = 0.0 (P < 0.00001)
Total (95% CI)


0.1 0.2
0.5

10
61
Adverse events (all) during treatment period.
Review:

Outcome: 5 Adverse events (all) during treatment period
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Bogousslavsky 1990
3/30
4/30
0.75 [ 0.18, 3.07 ]
Gelmers 1988
4/93
5/93
0.80 [ 0.22, 2.89 ]
17/239
14/243
1.23 [ 0.62, 2.45 ]
Kaste 1994
5/176
0/174
10.88 [ 0.61, 195.20 ]
Lowe 1989
3/56
4/56
0.75 [ 0.18, 3.20 ]
Martinez-Vila 1990
6/81
2/83
3.07 [ 0.64, 14.79 ]
Mohr 1992
94/800
32/264
0.97 [ 0.67, 1.41 ]
NEST 1993
40/437
47/443
0.86 [ 0.58, 1.29 ]
NIMPAS 1999
0/25
0/25
0.0 [ 0.0, 0.0 ]
Paci 1989
1/19
0/22
3.45 [ 0.15, 80.03 ]
13/607
23/608
0.57 [ 0.29, 1.11 ]
2563
2041
0.93 [ 0.74, 1.16 ]
54/166
17/165
3.16 [ 1.91, 5.21 ]
166
165
3.16 [ 1.91, 5.21 ]
11/81
9/79
1.19 [ 0.52, 2.72 ]
81
79
1.19 [ 0.52, 2.72 ]
2810
2285
1.18 [ 0.81, 1.74 ]
TRUST 1990
Subtotal (95% CI)


FIST 1990
Subtotal (95% CI)

Test for overall effect: Z = 4.50 (P < 0.00001)
Shibuya 2005
Subtotal (95% CI)

Total (95% CI)
0.1 0.2
0.5
10
(Continued . . . )

62
(. . .
Study or subgroup
Treatment
Control
n/N
n/N
Continued)
Risk Ratio
MH,Random,95%
CI
Risk Ratio
MH,Random,95%
CI

0.1 0.2
0.5
10
Hypotension during treatment period (reason to stop treatment).
Review:

Outcome: 6 Hypotension during treatment period (reason to stop treatment)
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Risk Ratio
MH,Random,95%
CI
n/N
n/N
1/30
3/30
0.33 [ 0.04, 3.03 ]
3/239
3/243
1.02 [ 0.21, 4.99 ]
Martinez-Vila 1990
2/81
2/83
1.02 [ 0.15, 7.10 ]
Nag 1998
0/31
0/31
0.0 [ 0.0, 0.0 ]
7/437
2/443
3.55 [ 0.74, 16.98 ]
818
830
1.26 [ 0.50, 3.14 ]
2/9
0/10
5.50 [ 0.30, 101.28 ]
10
5.50 [ 0.30, 101.28 ]

Bogousslavsky 1990
NEST 1993
Subtotal (95% CI)


Oczkowski 1989
Subtotal (95% CI)

0.1 0.2
0.5
10
(Continued . . . )

63
(. . .
Study or subgroup
Treatment
Total (95% CI)
Control
n/N
n/N
827
840
Continued)
Risk Ratio
MH,Random,95%
CI
Risk Ratio
MH,Random,95%
CI
1.43 [ 0.61, 3.38 ]

0.1 0.2
0.5
10
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.
Review:

Outcome: 7 Mean systolic blood pressure during or at end of treatment
Study or subgroup
Treatment
Mean
Difference
Control
Weight
IV,Random,95% CI
Mean
Difference
Mean(SD)
Mean(SD)
IV,Random,95% CI
30
134 (24)
30
141 (16)
5.9 %
-7.00 [ -17.32, 3.32 ]
225
132 (4)
222
134 (4)
61.2 %
-2.00 [ -2.74, -1.26 ]
58
139 (9)
65
138 (9)
33.0 %
1.00 [ -2.19, 4.19 ]
100.0 %
-1.30 [ -3.92, 1.32 ]

Bogousslavsky 1990
Martinez-Vila 1990
Total (95% CI)
313
317

Test for subgroup differences: Not applicable
-10
-5

10
64
Analysis 2.1. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 1 Primary
outcome by route of administration.
Review:
Comparison: 2 Calcium antagonists versus control: subgroup analysis

Outcome: 1 Primary outcome by route of administration
Study or subgroup
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Bogousslavsky 1990
2/30
3/30
0.4 %
0.67 [ 0.12, 3.71 ]
Gelmers 1984
2/29
12/31
0.5 %
0.18 [ 0.04, 0.73 ]
Gelmers 1988
24/93
34/93
4.8 %
0.71 [ 0.46, 1.09 ]
60/230
63/243
8.2 %
1.01 [ 0.74, 1.36 ]
Kaste 1994
44/176
31/174
5.3 %
1.40 [ 0.93, 2.11 ]
Lowe 1989
34/56
23/56
6.0 %
1.48 [ 1.01, 2.16 ]
Martinez-Vila 1990
18/81
22/83
3.3 %
0.84 [ 0.49, 1.44 ]
Mohr 1992
475/800
155/264
19.8 %
1.01 [ 0.90, 1.14 ]
NEST 1993
197/437
211/443
17.7 %
0.95 [ 0.82, 1.09 ]
11/25
10/25
2.4 %
1.10 [ 0.57, 2.11 ]
2/19
5/22
0.5 %
0.46 [ 0.10, 2.12 ]
TRUST 1990
275/607
257/608
18.9 %
1.07 [ 0.94, 1.22 ]
VENUS 1999
44/133
30/128
5.6 %
1.41 [ 0.95, 2.10 ]
Wimalaratna 1994
57/146
28/69
6.7 %
0.96 [ 0.68, 1.37 ]
Subtotal (95% CI)
2862
2269
100.0 %
1.03 [ 0.93, 1.14 ]
1 Oral administration
NIMPAS 1999
Paci 1989
Total events: 1245 (), 884 (Control)

2 Intravenous administration
ASCLEPIOS 1990
47/120
44/114
8.6 %
1.01 [ 0.74, 1.40 ]
Bridgers 1991
103/138
43/66
21.9 %
1.15 [ 0.94, 1.40 ]
Canwin 1993
39/96
42/93
8.2 %
0.90 [ 0.65, 1.25 ]
93/166
83/165
21.6 %
1.11 [ 0.91, 1.36 ]
5/14
4/13
0.8 %
1.16 [ 0.40, 3.41 ]
133/195
54/100
21.2 %
1.26 [ 1.03, 1.55 ]
FIST 1990
Heiss 1990
INWEST 1990
0.1 0.2
0.5
10
(Continued . . . )

65
(. . .
Study or subgroup
Limburg 1990
Yordanov 1984
Subtotal (95% CI)
Control
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI
n/N
n/N
3/12
8/14
0.8 %
0.44 [ 0.15, 1.29 ]
70/121
62/117
17.0 %
1.09 [ 0.87, 1.37 ]
862
682
100.0 %
1.11 [ 1.01, 1.22 ]

3 Oral versus intravenous administration (outcome death)
Chandra 1995
Subtotal (95% CI)
3/71
0/72
100.0 %
7.10 [ 0.37, 134.96 ]
71
72
100.0 %
7.10 [ 0.37, 134.96 ]

0.1 0.2
0.5
10

66
outcome by dose: indirect comparisons.
Review:

Outcome: 2 Primary outcome by dose: indirect comparisons
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
168/265
155/264
100.0 %
1.08 [ 0.94, 1.24 ]
265
264
100.0 %
1.08 [ 0.94, 1.24 ]
1 Nimodipine 60 mg versus control oral

Mohr 1992
Subtotal (95% CI)

Bogousslavsky 1990
2/30
3/30
0.4 %
0.67 [ 0.12, 3.71 ]
Gelmers 1984
2/29
12/31
0.6 %
0.18 [ 0.04, 0.73 ]
Gelmers 1988
24/93
34/93
5.3 %
0.71 [ 0.46, 1.09 ]
60/230
63/243
8.8 %
1.01 [ 0.74, 1.36 ]
Kaste 1994
31/176
44/174
5.8 %
0.70 [ 0.46, 1.05 ]
Lowe 1989
34/56
23/56
6.5 %
1.48 [ 1.01, 2.16 ]
Martinez-Vila 1990
18/81
22/83
3.7 %
0.84 [ 0.49, 1.44 ]
Mohr 1992
157/268
155/264
17.5 %
1.00 [ 0.87, 1.15 ]
NEST 1993
197/437
211/443
17.5 %
0.95 [ 0.82, 1.09 ]
11/25
10/25
2.7 %
1.10 [ 0.57, 2.11 ]
2/19
5/22
0.5 %
0.46 [ 0.10, 2.12 ]
TRUST 1990
275/607
257/608
18.5 %
1.07 [ 0.94, 1.22 ]
VENUS 1999
44/133
30/128
6.1 %
1.41 [ 0.95, 2.10 ]
Wimalaratna 1994
29/73
28/69
6.0 %
0.98 [ 0.66, 1.46 ]
Subtotal (95% CI)
2257
2269
100.0 %
0.99 [ 0.88, 1.11 ]
90.0 %
1.08 [ 0.95, 1.24 ]
NIMPAS 1999
Paci 1989

Mohr 1992
170/267
155/264
0.1 0.2
0.5
10
(Continued . . . )

67
(. . .
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Wimalaratna 1994
28/73
28/69
10.0 %
0.95 [ 0.63, 1.42 ]
Subtotal (95% CI)
340
333
100.0 %
1.07 [ 0.94, 1.22 ]

4 Nimodipine 2 mg/hour versus control intravenous
Bridgers 1991
62/75
27/66
29.5 %
2.02 [ 1.49, 2.75 ]
Canwin 1993
39/96
42/93
28.7 %
0.90 [ 0.65, 1.25 ]
5/14
4/13
8.8 %
1.16 [ 0.40, 3.41 ]
70/95
54/100
33.0 %
1.36 [ 1.10, 1.70 ]
280
272
100.0 %
1.34 [ 0.93, 1.93 ]
Heiss 1990
INWEST 1990
Subtotal (95% CI)

5 Nimodipine 1 mg/hour versus control intravenous
Bridgers 1991
41/63
43/66
46.4 %
1.00 [ 0.78, 1.29 ]
INWEST 1990
63/100
54/100
53.6 %
1.17 [ 0.92, 1.48 ]
163
166
100.0 %
1.09 [ 0.91, 1.29 ]
Subtotal (95% CI)

0.1 0.2
0.5
10

68
outcome by dose: direct comparisons.
Review:

Outcome: 3 Primary outcome by dose: direct comparisons
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
168/265
157/268
100.0 %
1.08 [ 0.94, 1.24 ]
265
268
100.0 %
1.08 [ 0.94, 1.24 ]
168/265
170/267
100.0 %
1.00 [ 0.88, 1.13 ]
265
267
100.0 %
1.00 [ 0.88, 1.13 ]
157/268
170/267
90.0 %
0.92 [ 0.80, 1.05 ]
Wimalaratna 1994
29/73
28/73
10.0 %
1.04 [ 0.69, 1.55 ]
Subtotal (95% CI)
341
340
100.0 %
0.93 [ 0.82, 1.06 ]
1 Nimodipine 60 mg versus 120 mg oral

Mohr 1992
Subtotal (95% CI)

Mohr 1992
Subtotal (95% CI)

Mohr 1992

4 Nimodipine 1 versus 2 mg/hour intravenous
Bridgers 1991
41/63
62/75
46.0 %
0.79 [ 0.64, 0.97 ]
INWEST 1990
63/100
70/95
54.0 %
0.86 [ 0.71, 1.04 ]
163
170
100.0 %
0.82 [ 0.71, 0.95 ]
Subtotal (95% CI)

0.1 0.2
0.5
10

69
outcome by time of start of treatment.
Review:

Outcome: 4 Primary outcome by time of start of treatment
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
50/120
44/113
4.4 %
1.07 [ 0.78, 1.46 ]
Bridgers 1991
59/81
23/38
4.8 %
1.20 [ 0.90, 1.61 ]
Canwin 1993
4/10
9/14
0.8 %
0.62 [ 0.26, 1.46 ]
FIST 1990
44/78
46/88
5.0 %
1.08 [ 0.82, 1.43 ]
Gelmers 1988
11/48
18/44
1.5 %
0.56 [ 0.30, 1.05 ]
11/36
5/28
0.7 %
1.71 [ 0.67, 4.36 ]
1/1
0/1
0.1 %
3.00 [ 0.24, 37.67 ]
INWEST 1990
67/96
24/47
4.4 %
1.37 [ 1.00, 1.86 ]
Kaste 1994
17/54
9/51
1.2 %
1.78 [ 0.88, 3.63 ]
Limburg 1990
3/7
1/5
0.2 %
2.14 [ 0.30, 15.07 ]
Lowe 1989
3/5
2/3
0.5 %
0.90 [ 0.31, 2.63 ]
Mohr 1992
75/116
23/36
5.0 %
1.01 [ 0.76, 1.34 ]
NEST 1993
38/102
40/85
3.9 %
0.79 [ 0.56, 1.11 ]
11/25
10/25
1.4 %
1.10 [ 0.57, 2.11 ]
2/19
5/22
0.3 %
0.46 [ 0.10, 2.12 ]
TRUST 1990
42/87
35/78
4.1 %
1.08 [ 0.77, 1.49 ]
VENUS 1999
44/133
30/128
3.1 %
1.41 [ 0.95, 2.10 ]
Wimalaratna 1994
14/37
8/18
1.3 %
0.85 [ 0.44, 1.65 ]
Subtotal (95% CI)
1055
824
42.7 %
1.08 [ 0.96, 1.21 ]
1 Treatment started ??? 12 hours

ASCLEPIOS 1990
Heiss 1990
NIMPAS 1999
Paci 1989

2 Treatment started > 12 hours
Bridgers 1991
44/57
20/28
5.2 %
1.08 [ 0.82, 1.42 ]
Canwin 1993
35/86
32/78
3.5 %
0.99 [ 0.69, 1.43 ]
0.1 0.2
0.5
10
(Continued . . . )

70
(. . .
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI
n/N
n/N
FIST 1990
47/83
34/73
4.4 %
1.22 [ 0.89, 1.66 ]
Gelmers 1988
11/39
12/41
1.2 %
0.96 [ 0.48, 1.92 ]
27/112
49/127
3.1 %
0.62 [ 0.42, 0.93 ]
4/11
4/11
0.5 %
1.00 [ 0.33, 3.02 ]
66/99
29/52
5.0 %
1.20 [ 0.90, 1.58 ]
14/122
35/123
1.7 %
0.40 [ 0.23, 0.71 ]
0/5
7/9
0.1 %
0.11 [ 0.01, 1.62 ]
Lowe 1989
24/51
16/53
2.1 %
1.56 [ 0.94, 2.58 ]
Mohr 1992
395/684
130/228
9.6 %
1.01 [ 0.89, 1.15 ]
NEST 1993
159/334
171/358
8.6 %
1.00 [ 0.85, 1.17 ]
TRUST 1990
230/520
218/529
9.2 %
1.07 [ 0.93, 1.23 ]
Wimalaratna 1994
43/107
20/51
2.9 %
1.02 [ 0.68, 1.55 ]
Subtotal (95% CI)
2310
1761
57.3 %
1.01 [ 0.90, 1.13 ]
100.0 %
1.04 [ 0.96, 1.13 ]
Heiss 1990
INWEST 1990
Kaste 1994
Limburg 1990

Total (95% CI)
3365
2585

0.1 0.2
0.5
10

71
Analysis 3.1. Comparison 3 Calcium antagonists versus control: sensitivity analysis, Outcome 1 Primary
outcome in multicenter placebo controlled trials.
Review:
Comparison: 3 Calcium antagonists versus control: sensitivity analysis

Outcome: 1 Primary outcome in multicenter placebo controlled trials
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
Gelmers 1988
24/93
34/93
4.2 %
0.71 [ 0.46, 1.09 ]
Martinez-Vila 1990
18/81
22/83
2.8 %
0.84 [ 0.49, 1.44 ]
197/437
211/443
23.5 %
0.95 [ 0.82, 1.09 ]
60/239
63/243
7.9 %
0.97 [ 0.71, 1.31 ]
ASCLEPIOS 1990
47/120
44/114
7.2 %
1.01 [ 0.74, 1.40 ]
275/607
257/608
26.4 %
1.07 [ 0.94, 1.22 ]
93/166
83/165
15.0 %
1.11 [ 0.91, 1.36 ]
5/14
4/13
0.7 %
1.16 [ 0.40, 3.41 ]
67/96
24/47
7.7 %
1.37 [ 1.00, 1.86 ]
44/176
31/174
4.7 %
1.40 [ 0.93, 2.11 ]
2029
1983
100.0 %
1.04 [ 0.95, 1.14 ]
NEST 1993
TRUST 1990
FIST 1990
Heiss 1990
INWEST 1990
Kaste 1994
Total (95% CI)

Test for subgroup differences: Not applicable
0.1 0.2
0.5
10

72
Analysis 3.2. Comparison 3 Calcium antagonists versus control: sensitivity analysis, Outcome 2 Publication
status.
Review:
Comparison: 3 Calcium antagonists versus control: sensitivity analysis

Outcome: 2 Publication status
Study or subgroup
Treatment
Control
Risk Ratio
MH,Random,95%
CI
Weight
Risk Ratio
MH,Random,95%
CI
n/N
n/N
2/30
3/30
0.2 %
0.67 [ 0.12, 3.71 ]
39/96
42/93
4.0 %
0.90 [ 0.65, 1.25 ]
93/166
83/165
7.9 %
1.11 [ 0.91, 1.36 ]
Gelmers 1984
2/29
12/31
0.3 %
0.18 [ 0.04, 0.73 ]
Gelmers 1988
24/93
34/93
2.5 %
0.71 [ 0.46, 1.09 ]
60/230
63/243
4.5 %
1.01 [ 0.74, 1.36 ]
5/14
4/13
0.5 %
1.16 [ 0.40, 3.41 ]
133/195
54/100
7.8 %
1.26 [ 1.03, 1.55 ]
44/176
31/174
2.8 %
1.40 [ 0.93, 2.11 ]
3/12
8/14
0.5 %
0.44 [ 0.15, 1.29 ]
18/81
22/83
1.7 %
0.84 [ 0.49, 1.44 ]
Mohr 1992
475/800
155/264
13.3 %
1.01 [ 0.90, 1.14 ]
NEST 1993
197/437
211/443
11.4 %
0.95 [ 0.82, 1.09 ]
11/25
10/25
1.2 %
1.10 [ 0.57, 2.11 ]
2/19
5/22
0.2 %
0.46 [ 0.10, 2.12 ]
TRUST 1990
275/607
257/608
12.5 %
1.07 [ 0.94, 1.22 ]
VENUS 1999
44/133
30/128
2.9 %
1.41 [ 0.95, 2.10 ]
Wimalaratna 1994
57/146
28/69
3.6 %
0.96 [ 0.68, 1.37 ]
Subtotal (95% CI)
3289
2598
77.9 %
1.03 [ 0.94, 1.12 ]
1 Primary outcome in published trials

Bogousslavsky 1990
Canwin 1993
FIST 1990
Heiss 1990
INWEST 1990
Kaste 1994
Limburg 1990
Martinez-Vila 1990
NIMPAS 1999
Paci 1989

2 Primary outcome in unpublished trials
ASCLEPIOS 1990
Bridgers 1991
47/120
44/114
4.1 %
1.01 [ 0.74, 1.40 ]
103/138
43/66
8.0 %
1.15 [ 0.94, 1.40 ]
0.1 0.2
0.5
10
(Continued . . . )

73
(. . .
Study or subgroup
Treatment
Lowe 1989
Yordanov 1984
Control
Risk Ratio
MH,Random,95%
CI
Weight
Continued)
Risk Ratio
MH,Random,95%
CI
n/N
n/N
34/56
23/56
3.2 %
1.48 [ 1.01, 2.16 ]
70/121
62/117
6.8 %
1.09 [ 0.87, 1.37 ]
435
353
22.1 %
1.14 [ 1.00, 1.30 ]
100.0 %
1.06 [ 0.98, 1.14 ]
Subtotal (95% CI)

Total (95% CI)
3724
2951

0.1 0.2
0.5
10
APPENDICES
Appendix 1. Appendix 1
MEDLINE (Ovid)
1. 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. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw.
3. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or
middle cerebr$ or mca$ or anterior circulation) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw.
4. 1 or 2 or 3
5. exp Calcium Channel Blockers/
6. Calcium/ai
7. (calcium adj3 (antagonist$ or block$ or inhibitor$)).tw.
8. (amlodipine or amrinone or azelnidipine or bencyclan$ or bepridil or AT877 or AT 877 or cilnidipine or cinnarizine or conotoxin$ or
daropidine or diltiazem or efonidipine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidopine or lidoflazine or
magnesium sul$ or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine
or verapamil).tw.
9. 5 or 6 or 7 or 8
10. Randomized Controlled Trials as Topic/
11. random allocation/
12. Controlled Clinical Trials as Topic/
13. control groups/
14. clinical trials as topic/ or clinical trials, phase i as topic/ or clinical trials, phase ii as topic/ or clinical trials, phase iii as topic/ or
clinical trials, phase iv as topic/
15. double-blind method/
16. single-blind method/
74
17. Placebos/
18. placebo effect/
19. Drug Evaluation/
20. Research Design/
21. randomized controlled trial.pt.
22. controlled clinical trial.pt.
23. (clinical trial or clinical trial phase i or clinical trial phase ii or clinical trial phase iii or clinical trial phase iv).pt.
24. random$.tw.
25. (controlled adj5 (trial$ or stud$)).tw.
26. (clinical$ adj5 trial$).tw.
27. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw.
28. (quasi-random$ or quasi random$ or pseudo-random$ or pseudo random$).tw.
29. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw.
30. (coin adj5 (flip or flipped or toss$)).tw.
31. placebo$.tw.
32. sham.tw.
33. (assign$ or alternate or allocat$).tw.
34. or/10-33
35. 4 and 9 and 34
36. limit 35 to humans
EMBASE (ovid)
1. cerebrovascular disease/ or cerebral artery disease/ or cerebrovascular accident/ or stroke/ or vertebrobasilar insufficiency/ or carotid
artery disease/ or exp carotid artery obstruction/ or exp brain infarction/ or exp brain ischemia/ or exp occlusive cerebrovascular disease/
2. stroke patient/ or stroke unit/
3. (isch?emi$ adj6 (stroke$ or apoplex$ or cerebral vasc$ or cerebrovasc$ or cva or attack$)).tw.
4. ((brain or cerebr$ or cerebell$ or vertebrobasil$ or hemispher$ or intracran$ or intracerebral or infratentorial or supratentorial or
middle cerebr$ or mca$ or anterior circulation) adj5 (isch?emi$ or infarct$ or thrombo$ or emboli$ or occlus$ or hypoxi$)).tw.
5. 1 or 2 or 3 or 4
6. exp calcium antagonist/
7. (calcium adj3 (antagonist$ or block$ or inhibitor$)).tw.
8. (amlodipine or amrinone or azelnidipine or bencyclan$ or bepridil or AT877 or AT 877 or cilnidipine or cinnarizine or conotoxin$ or
daropidine or diltiazem or efonidipine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidopine or lidoflazine or
magnesium sul$ or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or perhexiline or prenylamine
or verapamil).tw.
9. 6 or 7 or 8
10. Randomized Controlled Trial/
11. Randomization/
12. Controlled Study/
13. control group/
14. clinical trial/ or phase 1 clinical trial/ or phase 2 clinical trial/ or phase 3 clinical trial/ or phase 4 clinical trial/ or controlled clinical
trial/
15. Double Blind Procedure/
16. Single Blind Procedure/ or triple blind procedure/
17. placebo/
18. drug comparison/ or drug dose comparison/
19. types of study/
20. random$.tw.
21. (controlled adj5 (trial$ or stud$)).tw.
22. (clinical$ adj5 trial$).tw.
75
23. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw.

24. (quasi-random$ or quasi random$ or pseudo-random$ or pseudo random$).tw.
25. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw.
26. (coin adj5 (flip or flipped or toss$)).tw.
27. placebo$.tw.
28. sham.tw.
29. (assign$ or alternate or allocat$).tw.
30. or/10-29
31. 5 and 9 and 30
32. limit 31 to human
The Cochrane Central Register of Controlled Trials
#1. MeSH descriptor cerebrovascular disorders this term only
#2. MeSH descriptor basal ganglia cerebrovascular disease this term only
#3. MeSH descriptor brain ischemia explode all trees
#4. MeSH descriptor carotid artery diseases this term only
#5. MeSH descriptor carotid artery thrombosis this term only
#6. MeSH descriptor intracranial arterial diseases this term only
#7. MeSH descriptor cerebral arterial diseases this term only
#8. MeSH descriptor intracranial embolism and thrombosis explode all trees
#9. MeSH descriptor stroke explode all trees
#10. (ischaemic in Title, Abstract or Keywords or ischemic in Title, Abstract or Keywords)
#11. (stroke* in Title, Abstract or Keywords or apoplex* in Title, Abstract or Keywords or (cerebral in Title, Abstract or Keywords and
vasc* in Title, Abstract or Keywords) or cerebrovasc* in Title, Abstract or Keywords or cva in Title, Abstract or Keywords or attack* in
Title, Abstract or Keywords)
#12. (#10 and #11)
#13. (brain in Title, Abstract or Keywords or cerebr* in Title, Abstract or Keywords or cerebell* in Title, Abstract or Keywords or
vertebrobasil* in Title, Abstract or Keywords or hemispher* in Title, Abstract or Keywords or intracran* in Title, Abstract or Keywords
or intracerebral in Title, Abstract or Keywords or infratentorial in Title, Abstract or Keywords or supratentorial in Title, Abstract or
Keywords or (middle in Title, Abstract or Keywords and cerebr* in Title, Abstract or Keywords) or mca* in Title, Abstract or Keywords
or (anterior in Title, Abstract or Keywords and circulation in Title, Abstract or Keywords) )
#14. (ischemi* in Title, Abstract or Keywords or ischaemi* in Title, Abstract or Keywords or infarct* in Title, Abstract or Keywords
or thrombo* in Title, Abstract or Keywords or emboli* in Title, Abstract or Keywords or occlus* in Title, Abstract or Keywords or
hypoxi* in Title, Abstract or Keywords)
#15. (#13 and #14)
#16. (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #12 or #15)
#17. MeSH descriptor Calcium Channel Blockers explode all trees
#18. MeSH descriptor calcium this term only with qualifiers: AI
#19. calcium in Title, Abstract or Keywords
#20. (antagonist* in Title, Abstract or Keywords or block* in Title, Abstract or Keywords or inhibitor* in Title, Abstract or Keywords)
#21.(#19 and #20)
#22. (amlodipine in Title, Abstract or Keywords or amrinone in Title, Abstract or Keywords or azelnidipine in Title, Abstract or
Keywords or bencyclan* in Title, Abstract or Keywords or bepridil in Title, Abstract or Keywords or AT877 in Title, Abstract or
Keywords or (AT in Title, Abstract or Keywords and 877 in Title, Abstract or Keywords) or cilnidipine in Title, Abstract or Keywords
or cinnarizine in Title, Abstract or Keywords or conotoxin* in Title, Abstract or Keywords or daropidine in Title, Abstract or Keywords
or diltiazem in Title, Abstract or Keywords or efonidipine in Title, Abstract or Keywords or felodipine in Title, Abstract or Keywords
or fendiline in Title, Abstract or Keywords or flunarizine in Title, Abstract or Keywords or gallopamil in Title, Abstract or Keywords
or isradipine in Title, Abstract or Keywords or lacidopine in Title, Abstract or Keywords or lidoflazine in Title, Abstract or Keywords
or (magnesium in Title, Abstract or Keywords and sul* in Title, Abstract or Keywords) or mibefradil in Title, Abstract or Keywords or
nicardipine in Title, Abstract or Keywords or nifedipine in Title, Abstract or Keywords or nimodipine in Title, Abstract or Keywords or
76
nisoldipine in Title, Abstract or Keywords or nitrendipine in Title, Abstract or Keywords or perhexiline in Title, Abstract or Keywords
or prenylamine in Title, Abstract or Keywords or verapamil in Title, Abstract or Keywords)
#23. (#17 or #18 or #21 or #22) #24.(#16 and #23)
WHATS NEW
Last assessed as up-to-date: 25 January 2012.
Date
Event
Description
25 January 2012
New citation required but conclusions have not changed The authorship of this review has changed. The basic
conclusion is unchanged
25 January 2012
New search has been performed
The searches were updated in January 2012. We have

added four new included trials in this update. These
four trials included approximately 423 patients. This
review now has 34 included trials with a total of 7731
participants. We have also added Risk of bias tables for
nearly all the trials included in this review. Specifically,
we have added new information to this update, but the
conclusions have not changed
HISTORY
Protocol first published: Issue 1, 1997
Review first published: Issue 1, 2000
Date
Event
Description
22 July 2008
Amended
Converted to new review format.
CONTRIBUTIONS OF AUTHORS
Jing Zhang and Jie Yang were involved in all aspects of the development of this review. They assessed all the trials, discussed and resolved
any problems, and wrote the review. Canfei Zhang, Xiaoqun Jiang and Hongqing Zhou have helped in the related trials selection
and looked for the full text of the related trials. Ming Liu was in charge of the judgement of the selection, did the evaluation for
methodological quality of trials and was in charge of the final draft of this review.

77
DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT
Internal sources
No sources of support supplied
External sources
Netherlands Heart Foundation (D93.014), Netherlands.
Janssen Pharmaceuticals, Netherlands.
Stichting De Drie Lichten, Netherlands.
INDEX TERMS
Medical Subject Headings (MeSH)
Brain Ischemia [ drug therapy]; Calcium [metabolism]; Calcium Channel Blockers [ therapeutic use]; Randomized Controlled Trials
as Topic; Stroke [ drug therapy]
MeSH check words

Humans

78

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Calcium antagonists for acute ischemic stroke (Review)

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

Calcium antagonists for acute ischemic stroke (Review)

Calcium antagonists for acute ischemic stroke (Review)

Calcium antagonists for acute ischemic stroke

Editorial group: Cochrane Stroke Group.

PLAIN LANGUAGE SUMMARY

Description of the intervention

Description of the condition

How the intervention might work

Calcium antagonists for acute ischemic stroke (Review)

suggested that early treatment was effective and might lead to a

Why it is important to do this review

Criteria for considering studies for this review

1. Death from any cause during the scheduled treatment

Calcium antagonists for acute ischemic stroke (Review)

Search methods for identification of studies

Data collection and analysis

Data extraction and management

Assessment of risk of bias in included studies

Was the allocation sequence adequately generated? We classified

Calcium antagonists for acute ischemic stroke (Review)

Assessment of reporting biases

We examined publication and other biases using a funnel plot.

Blinding of participants, personnel and outcome assessors

Incomplete outcome data

Subgroup analysis and investigation of heterogeneity

Were reports of the study free of suggestion of selective outcome

Measures of treatment effect

These measures are listed under Types of outcome measures.

Dealing with missing data

See: Characteristics of included studies; Characteristics of excluded

Calcium antagonists for acute ischemic stroke (Review)

We excluded 13 studies. For details see Characteristics of excluded

Risk of bias in included studies

Calcium antagonists for acute ischemic stroke (Review)

Incomplete outcome data

Death or dependency at end of follow-up

Data from 22 trials with 6684 participants were available. No

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

Calcium antagonists for acute ischemic stroke (Review)

Calcium antagonists for acute ischemic stroke (Review)

Death at end of follow-up

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

Recurrence of stroke at end of follow-up

Only a limited number of reports mentioned stroke recurrences

All adverse events during treatment period

Adverse events were more frequent in the intervention groups

Calcium antagonists for acute ischemic stroke (Review)

thrombophlebitis in the flunarizine group. In the rest of the studies

Hypotension during treatment period

Mean systolic blood pressure during or at end of treatment

Calcium antagonists for acute ischemic stroke (Review)

Primary outcome by route of administration

Primary outcome by time start of treatment

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

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

Primary outcome by dose: indirect comparisons

Primary outcome in multicenter placebo-controlled trials

Of the 34 included trials, 10 trials including 4012 participants

Analysis 3.6: Publication status

These direct comparisons were possible in very few trials: data

This systematic review of all available data failed to demonstrate a