primary outcome:
Calcium antagonists for acute ischemic stroke
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).Data were available for 23 trials: 14 trials with 5131 participants used oral administration, 8 trials with 1544 participants used intravenous administration, and 1 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).Chandra 1995 performed the only direct comparison between oral and intravenous administration of nimodipine, but results did not support the notion that intravenous administration was associated with poorer outcome (RR 7.10, 95% CI 0.37 to 134.96; Analysis 2.1).Readers should interpret these observations with caution, as there was no significant difference between the subgroups.Data were available for 18 trials: 1 trial with 529 participants used 60 mg/d oral nimodipine, 14 trials with 4526 participants used 120 mg/d oral nimodipine, 2 trials with 637 participants used 240 mg/d oral nimodipine, 4 trials with 552 participants used 2 mg/h intravenous nimodipine per day (3 trials for 5 days and 1 trial for 10 days), and 2 trials with 329 participants used 1 mg/h intravenous nimodipine per day for 5 days. 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 (they did not show a difference between groups). Intravenous nimodipine of 2 mg/h showed a non‐significant increase in the risk of the primary outcome (RR 1.34, 95% CI 0.93 to 1.93), while there was no clear difference between control and the group treated intravenously with 1 mg/h (RR 1.09, 95% CI 0.91 to 1.29; Analysis 2.2).Heterogeneity existed in the analysis of nimodipine 2 mg/h 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.Readers should interpret these observations with caution, as there was no significant difference between the subgroups.These direct comparisons were possible in very few trials: data were available in six trials, including one trial with 533 participants comparing 60 mg versus120 mg oral nimodipine per day, one trial with 532 participants comparing 60 mg versus 240 mg oral nimodipine per day, two trials with 681 participants comparing 120 mg versus 240 mg oral nimodipine per day, two trials with 333 participants comparing 1 mg/h versus 2 mg/h intravenous nimodipine. This direct comparison showed no significant difference between 120 mg and 60 mg (RR 1.08, 95% CI 0.94 to 1.24) or between 120 mg and 240 mg (RR 1.00, 95% CI 0.88 to 1.13). A dose‐dependent relationship appeared to exist for intravenous nimodipine without a significant difference (RR 0.82, 95% CI 0.71 to 0.95, P = 0.57; Analysis 2.3).Readers should interpret these observations with caution, as there was no significant difference between the subgroups.Data were available for 32 trials, including 18 trials with 1879 participants whose treatment started within 12 h after stroke onset, and 14 trials with 4071 participants whose treatment started after 12 h from stroke onset. There was no significant difference in the odds of the primary outcome, comparing early treatment (within 12 h after stroke onset) with calcium antagonists to placebo (RR 1.08, 95% CI 0.96 to 1.21). Treatment after 12 h showed no effect whatsoever (RR 1.01, 95% CI 0.90 to 1.13). This analysis might be confounded by route of administration (Analysis 2.4).Readers should interpret these observations with caution, as there was no significant difference between the subgroups.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 and found there was no clear difference (RR 1.04, 95% CI 0.95 to 1.14; Analysis 3.1).