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Background and PurposeThe Intravenous Nimodipine West European Stroke Trial (INWEST) found a correlation
between nimodipine-induced reduction in blood pressure (BP) and an unfavorable outcome in acute stroke. We sought
to confirm this correlation with and without adjustment for prognostic variables and to investigate outcome in subgroups
with increasing levels of BP reduction.
MethodsPatients with a clinical diagnosis of ischemic stroke (within 24 hours) were consecutively allocated to receive
placebo (n100), 1 mg/h (low-dose) nimodipine (n101), or 2 mg/h (high-dose) nimodipine (n94). The correlation
between average BP change during the first 2 days and the outcome at day 21 was analyzed.
ResultsTwo hundred sixty-five patients were included in this analysis (n92, 93, and 80 for placebo, low dose, and high
dose, respectively). Nimodipine treatment resulted in a statistically significant reduction in systolic BP (SBP) and
diastolic BP (DBP) from baseline compared with placebo during the first few days. In multivariate analysis, a significant
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correlation between DBP reduction and worsening of the neurological score was found for the high-dose group (0.49,
P0.048). Patients with a DBP reduction of 20% in the high-dose group had a significantly increased adjusted OR
for the compound outcome variable death or dependency (Barthel Index 60) (n/N25/26, OR 10.16, 95% CI 1.02 to
101.74) and death alone (n/N9/26, OR 4.336, 95% CI 1.131 16.619) compared with all placebo patients (n/N62/92
and 14/92, respectively). There was no correlation between SBP change and outcome.
ConclusionsDBP, but not SBP, reduction was associated with neurological worsening after the intravenous adminis-
tration of high-dose nimodipine after acute stroke. For low-dose nimodipine, the results were not conclusive. These
results do not confirm or exclude a neuroprotective property of nimodipine. (Stroke. 2000;31:1250-1255.)
Key Words: blood pressure cerebral ischemia nimodipine stroke, acute
Received January 10, 2000; final revision received February 8, 2000; accepted February 25, 2000.
From the Karolinska Hospital (N.A., N.G.W.), Stroke Research Unit, Department of Neurology, Stockholm, Sweden; and Royal Institute of Technology
(P.N.), Center for Safety Research, Teknikringen, Stockholm, Sweden.
Correspondence to Dr Niaz Ahmed, Karolinska Hospital, Stroke Research Unit, 3 tr, Department of Neurology, S-171 76 Stockholm, Sweden. E-mail
niaz.ahmed@neuro.ks.se
2000 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
1250
Ahmed et al Nimodipine Effect on BP and Outcome After Stroke 1251
acute stroke, it was noted that the drug produces hypotension, measurement analysis was used to analyze time-dependent data, and
although no analysis was performed in relation to out- the prognostic power of the different variables was compared with
multiple regression analysis. Peto methods25 were used to calculate
come.19,20 The aim of the present study was to confirm the
the OR and 95% CI for unadjusted data, and multiple logistic
association between nimodipine-induced lowering of BP and regression analysis were performed to adjust for other prognostic
outcome after acute stroke with and without adjustment for factors. Analyses were carried out by use of SAS and Statistica
several prognostic variables and to investigate the outcome in software.
subgroups of patients with increasing levels of BP reduction.
Results
Subjects and Methods Recruitment and Baseline Characteristics
A complete description of the subjects and methods is given Of the 295 patients recruited for the INWEST, 100 were
elsewhere14; a short summary is given here. A total of 295 patients allocated to receive placebo, 101 to receive 1 mg/h nimodip-
were enrolled. Ethics committee approval was obtained at each study
center, and all patients or their representatives gave informed ine (low dose), and 94 to receive 2 mg/h nimodipine (high
consent. Patients with a clinical diagnosis of a recent (within 24 dose). For evaluation of efficacy, 228 patients who fulfilled
hours) ischemic stroke in the carotid artery territory were eligible for the validation criteria were included. In this follow-up anal-
inclusion in the trial if they were 40 years old and functionally ysis, 265 patients were eligible for evaluation of the effect of
independent before the stroke. intravenous nimodipine on BP and outcome (92, 93, and 80 in
placebo, low-dose, and high-dose groups, respectively). Pa-
Treatment Regimens
Patients received intravenous treatment for 5 days, followed by oral
tients with cerebral hemorrhage (n15), serious infection or
other life-threatening concurrent illness (n6), no CT scan or
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Figure 2. For nimodipine, death or dependency (defined as a Barthel index score of 60) at day 21. Peto OR and 95% CI in
nimodipine-treated subgroups with different levels of DBP changes (n indicates death or dependency events; N, total number of
patients). Subgroup 1, no change or increased DBP from baseline; subgroup 2; DBP reduction to 10% from baseline; subgroup 3;
DBP reduction in 10% to 20% from baseline; and subgroup 4, DBP reduction in 20% from baseline.
group 1, no change or increased DBP from baseline; sub- neurological and functional outcome at 21 days after adjust-
group 2; DBP reduction to 10% from baseline; subgroup 3; ment for several prognostic variables. Unadjusted subgroup
DBP reduction in 10% to 20% from baseline; and analyses indicated that an increase in the OR for death or
subgroup 4, DBP reduction in 20% from baseline. The dependency in the high-dose nimodipine group at day 21
unadjusted OR values for death or dependency at day 21 for occurred for the moderate-to-profound DBP reduction sub-
the nimodipine groups and for each nimodipine-treated sub- groups (10% reduction). After adjustment for other prog-
groups compared with all placebo patients are illustrated in nostic factors, the OR for the compound outcome variable
Figure 2. Multiple logistic regression analysis was performed death or dependency and for death alone increased signifi-
to adjust for age, sex, baseline severity, concomitant antihy- cantly for the profound DBP reduction subgroup (20%
pertensive agents (including prehospital antihypertensive reduction) treated with high-dose nimodipine. The relation-
agents), SBP changes, new cardiac manifestations, and his- ship between DBP reduction and outcome persisted even
tory of hypertension, diabetes, or IHD. The only significant after adjustment for concomitant antihypertensive medica-
higher OR for death or dependency occurred in the high-dose tions (including prehospital treatments).
group with a DBP reduction of 20% (OR 10.158, 95% CI A decrease in BP during the first days after entry occurred
1.02 to 101.735). Case series analysis of the neurological in all treatment groups, but the pattern of reduction differed
outcome on day 3 in the high-dose nimodipine group revealed
between the placebo group and the 2 nimodipine groups. The
a higher incidence of neurological deterioration if average
gradual decline in BP in the placebo group is known from
DBP was reduced 20% (occurring in 18 of 26 patients)
previous studies and has been attributed to recovery from
during the first 2 days than in those with a lower degree of
mental stress due to the emergency and other mechanisms.1 6
DBP reduction (occurring in 18 of 54 patients, P0.005).
There were no significant differences in BP between the
Death was analyzed separately. A total of 50 (18.9%)
patients were dead at day 21. The distribution was 14 (15.2%) treatment groups during the oral phase of the treatment period
in the placebo group and 20 (21.5%) and 16 (20%) in the low- as reported previously.14 The higher BP reduction in the
and high-dose groups, respectively. The difference and ad- nimodipine-treated patients compared with the placebo group
justed OR between treatment groups was not statistically in this analysis is consistent with previous intravenous and
significant. However, high-dose nimodipinetreated patients high-dose oral (240 mg/d) nimodipine studies19,20,26 but not
with a 20% DBP reduction had a mortality rate of 34.6% (9 with lower-dose oral (120 mg/d) nimodipine studies.26 28
of 26) and the adjusted OR (4.336, 95% CI 1.131 16.619) was The difference in BP reduction between the nimodipine
significantly higher compared with placebo at day 21. A groups and the placebo group was more pronounced during
comparison of the baseline and demographic data between the first few days of the intravenous period; thereafter, the
the subgroups shows no significant difference within the difference became successively smaller. This might be due to
groups, except for age in the high-dose nimodipine group. stabilization of the BP reduction sensitivity by nimodipine
with time and continuous decline in the placebo. A reduction
Discussion in the nimodipine infusion rate in response to hypotensive
This follow-up analysis confirmed an association between reactions may contribute to a smaller difference at the end of
DBP reduction with high-dose intravenous nimodipine and the intravenous period. Differences in BP between the treat-
1254 Stroke June 2000
ment groups were unintended, and investigators were in- ever, a DBP drop to 60 mm Hg was associated with a bad
structed to reduce the titration rate if the DBP dropped below outcome in the low-dose group.
50 mm Hg. The first 2 days of average BP change were selected for
While examining the relationship between BP reduction analysis of neurological and functional outcome because the
and outcome, we found that DBP reduction was related to BP difference between the treatment groups was profound in
outcome in the high-dose nimodipine group but not in the this period. It was also a reasonable decision from a patho-
placebo or low-dose group or for SBP in any group. Because physiological aspect, because ischemia is reversible only for
both SBP and DBP were reduced in all 3 groups, the relative a few hours up to about 24 hours.31,32 After 48 hours,
effect of nimodipine on DBP and SBP can be illustrated by reversible ischemia is not likely to occur. In the subgroup
observing the pulsatility of BP, as defined in Methods. A analysis of DBP change, all placebo-treated patients were
higher pulsatility from the baseline value in the nimodipine- considered as the control group because the placebo group
treated groups indicated a greater reducing effect of nimo- consisted of patients with a natural decline in BP. The
dipine on DBP compared with SBP. The interpretation is that baseline characteristics and mechanism of BP reduction in
the impact of nimodipine was greater on DBP than on SBP, placebo-treated subgroups were not comparable to the corre-
suggesting a lowering of peripheral resistance,18 which is a sponding nimodipine-treated subgroups. A higher suscepti-
phenomenon related to DBP reduction. Placebo- and bility for BP reductions among the elderly patients could be
nimodipine-treated patients consequently seemed to differ in one of the explanations for the imbalance in age between
the BP decrease pattern. In contrast, BP reduction after the subgroups.
In conclusion, DBP, but not SBP, reduction was associated
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Effect of Intravenous Nimodipine on Blood Pressure and Outcome After Acute Stroke
Niaz Ahmed, Per Nsman and Nils Gunnar Wahlgren
Stroke. 2000;31:1250-1255
doi: 10.1161/01.STR.31.6.1250
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