Abstract
Introduction
Oral nimodipine is recommended as standard therapy for aneurysmal subarachnoid hemorrhage (aSAH) based on trials from the 1980s. Given major advances in aneurysm treatment and neuro-intensive care, its effectiveness in contemporary settings warrants reevaluation.
Methods
We retrospectively analyzed consecutive patients with aSAH treated between 2015 and 2025. Clinical, radiological, and outcome data were extracted from medical records. Patients receiving prophylactic oral nimodipine (Nimo+) were compared with those who did not (Nimo−). Propensity score matching (PSM) was applied to balance baseline characteristics. Primary outcome was neurological function at discharge and at 3 months, assessed with the Glasgow Outcome Scale (GOS). Secondary outcomes included angiographic vasospasm, cerebral infarction, and mortality.
Results
Of the 312 patients eligible for inclusion in this study, 102 received oral nimodipine and 210 did not. After PSM, 102 patients were included per group with no differences in baseline characteristics. Nimodipine was associated with lower rates of angiographic vasospasm (43% vs 64%; p < 0.001) and delayed infarction (38% vs 58%; p = 0.008) and with better GOS score at discharge (p = 0.047) and at 3 months (p = 0.008). Mortality did not differ between the two groups. Subgroup analysis showed benefits in terms of angiographic vasospasm, infarction, and functional outcome among patients receiving nimodipine ≥ 14 days, whereas shorter administration only reduced angiographic vasospasm.
Conclusion
In this contemporary propensity score-matched cohort, oral nimodipine therapy reduced vasospasm and delayed infarction and improved neurological outcome without having an impact on mortality. Sustained administration for at least 14 days appears to be crucial to achieve benefit, favoring full-course nimodipine therapy in aSAH management.
Keywords: Aneurysmal subarachnoid hemorrhage, Nimodipine, Delayed cerebral ischemia, Vasospasm, Propensity-score matching
Key Summary Points
| Why carry out this study? |
| Aneurysmal subarachnoid hemorrhage (aSAH) remains a life-threatening condition, and delayed cerebral ischemia continues to drive poor neurological outcomes despite advances in aneurysm treatment and neuro-intensive care |
| Oral nimodipine has been recommended as standard therapy for nearly four decades based on trials from the 1980s, but contemporary real-world evidence supporting its effectiveness is limited |
| Our aim was to determine whether prophylactic oral nimodipine is associated with reduced vasospasm, cerebral infarction, and improved neurological outcome in a modern cohort, and whether treatment duration influences its effectiveness |
| What was learned from the study? |
| In a propensity score–matched analysis of 204 patients, oral nimodipine was associated with lower rates of angiographic vasospasm (43% vs 64%; p < 0.001), delayed infarction (38% vs 58%; p = 0.008), and better functional outcome at discharge (p = 0.047) and at 3 months (p = 0.01), without a reduction in mortality |
| Benefits were most pronounced in patients treated for ≥ 14 days, whereas shorter courses were less effective, supporting adherence to sustained or full-course nimodipine therapy in contemporary aSAH management. These findings reinforce the continued clinical relevance of oral nimodipine in modern practice |
Introduction
Aneurysmal subarachnoid hemorrhage (aSAH) remains a severe neurological emergency, associated with high rates of mortality and poor neurologic outcome [1]. Among survivors of the initial hemorrhage, secondary brain injury—particularly delayed cerebral ischemia—continues to be a major determinant of outcome [2, 3]. The prevention and management of delayed cerebral ischemia therefore represent central therapeutic goals in the care of patients with aSAH.
Nimodipine, a dihydropyridine calcium-channel blocker, has been a cornerstone of aSAH management for nearly four decades. Its use was established following publication of results from a series of randomized controlled trials (RCTs) conducted in the 1980s, which demonstrated improved neurological outcomes in patients receiving oral nimodipine prophylaxis [4–9]. Consequently, international guidelines uniformly recommend oral nimodipine as standard therapy for all patients with aSAH at a dose of 60 mg every 4 h for 21 days [1, 10, 11]. Although numerous clinical trials have investigated novel pharmacological strategies to prevent delayed cerebral ischemia—including nicardipine, tirilazad, statins, clazosentan, and magnesium—oral nimodipine remains the only agent that has demonstrated improvement in neurological outcome after aSAH [12].
Over the past decades, the management of aSAH has advanced substantially. The advent of endovascular aneurysm treatment, refinements in microsurgical techniques, and improvements in neuro-intensive care have collectively contributed to better functional outcomes [13, 14] and reduced mortality rates [15–17]. However, contemporary evidence on the effectiveness of oral nimodipine remains scarce. Most available data originate from the above-mentioned trials conducted several decades ago, limiting their applicability to current clinical practice [1, 11]. In addition, these historical studies also constrain the feasibility and ethical justification of new RCTs [1, 18].
In the present study, our aim was to reassess the effectiveness of prophylactic oral nimodipine in a contemporary cohort of patients with aSAH, using propensity score matching (PSM). Specifically, we sought to examine the effects of oral nimodipine on angiographic vasospasm, cerebral infarction, and neurological outcome, and to explore whether these effects depend on treatment duration.
Methods
Study Design
This study is a retrospective analysis of consecutive patients who presented with aSAH at the authors’ institution within the past 10 years. Medical charts were systematically reviewed to collect demographic data (sex, age, body mass index [BMI]), clinical and imaging data (Hunt and Hess grade, Fisher group, aneurysm location, cerebrospinal fluid drainage type, treatment modality, comorbidities), and neurological outcomes. Patients who received prophylactic oral nimodipine (Nimo+) were identified and compared with those who did not (Nimo−). For analysis, Hunt and Hess grades I–III were classified as mild/moderate aSAH and grades IV–V as severe aSAH. Similarly, Fisher groups 1–2 were grouped as mild/moderate aSAH and grades 3–4 as severe aSAH.
Inclusion criteria were patients aged > 18 years with radiologically confirmed aSAH. Patients who died within the first 3 days after admission or who received nimodipine for < 5 days were excluded.
The primary endpoint was neurological outcome at discharge and at 3 months, assessed using the Glasgow Outcome Scale (GOS) [19]. A GOS score ≤ 3 was defined as a poor outcome and a GOS score ≥ 4 as a good outcome. Secondary endpoints included the occurrence of angiographic vasospasm, cerebral infarction, and mortality at discharge and at 3 months.
Ethical Approval
This study was conducted in accordance with the Declaration of Helsinki of 1964 and its later amendments. For this type of study, formal approval of the institutional ethics at the Medical School of Hannover is not required. Written informed consent was obtained from all participants, including consent for the use of anonymized clinical and biological data for research and publication purposes.
Local Standard of Procedure for aSAH Treatment
All patients were managed in a neuro-intensive care unit. Following confirmation of SAH and aneurysm on computed tomography (CT) and CT angiography images, digital subtraction angiography (DSA) was mostly performed prior to aneurysm occlusion. In patients with Hunt and Hess grade ≥ 3 aSAH or hydrocephalus, cerebrospinal fluid (CSF) diversion was achieved by placement of an external ventricular drain (EVD) using a bundle approach [20] or, alternatively, a lumbar drain (LD).
The treatment modality—microsurgical clipping or endovascular treatment—was determined by consensus between the neurosurgical and neuroradiological teams. In general, middle cerebral artery aneurysms were treated by surgical clipping, whereas posterior circulation aneurysms were primarily managed endovascularly, in accordance with previously reported protocols [21–23]. During the stay in the intensive care unit, daily transcranial Doppler ultrasonography (TCD) and neurological examinations were performed. After aneurysm clipping, a routine follow-up DSA was obtained between days 4 and 7 post-surgery. In patients treated endovascularly, magnetic resonance imaging (MRI) was conducted instead.
CT and DSA were additionally performed in the event of neurological deterioration or when mean flow velocities exceeded 120 cm/s on TCD monitoring. When angiographic vasospasm was detected, intra-arterial vasospasmolysis—defined as the local, catheter-based administration of nimodipine—was initiated and repeated as necessary according to spasm severity. Before discharge, patients were assessed for shunt dependency, and ventriculoperitoneal shunting was performed when indicated.
During the early years of the study period, prophylactic oral nimodipine was not routinely administered at our institution. This reflected local clinical practice rather than medical contraindications. Over time, oral nimodipine (60 mg every 4 h) was progressively adopted as standard therapy, as recommended by international guidelines [1, 10, 11]. Also, nimodipine was intermittently unavailable on the international market during certain periods. Consequently, our institutional database contains a substantial number of patients who did not receive oral nimodipine, enabling a retrospective comparison between treated and untreated cohorts.
Definition of Angiographic Vasospasm and Cerebral Infarction
All imaging data and reports were systematically reviewed by the study team. Angiographic vasospasm was defined as a moderate to severe arterial narrowing on DSA, as assessed by a neuroradiologist, in accordance with previously published criteria [24]. Cerebral infarction was defined as any new hypodense area on CT images not attributable to intraoperative brain retraction or manipulation. Infarctions occurring > 48 h after aneurysm occlusion were classified as delayed infarctions [25].
Data Analysis
All statistical analyses were performed using R (version 4.3.2; R Foundation for Statistical Computing, Vienna, Austria). Baseline characteristics were summarized as the means ± standard deviation (SD) for continuous variables and absolute numbers with corresponding percentages for categorical variables. Group comparisons of baseline characteristics were conducted using the t-test for continuous variables and the χ2 test or Fisher’s exact test for categorical variables, as appropriate.
All tests were two-sided and statistical significance was defined as p < 0.05.
Main Analysis
Propensity score matching was applied to minimize selection bias between the two treatment groups (Nimo+ and Nimo−) using the MatchIt package. Nearest-neighbor matching without replacement was performed with matching ratios of 1:1 or 1:2 depending on subgroup size. Nearest-neighbor matching was chosen as the primary approach because it is widely used, transparent, and readily reproducible; robustness to the matching algorithm was assessed in sensitivity analyses using optimal matching. No caliper was applied in any of the PSM procedures (nearest-neighbor or optimal matching); all matches were performed without a caliper constraint. For both, matching variables included age, sex, Hunt and Hess grade, Fisher group, treatment modality (clipping or endovascular), aneurysm location, use of intra-arterial nimodipine, presence of arterial hypertension, use of EVD/LD, and shunt placement. Covariate balance was assessed using absolute standardized mean differences (SMDs) for each covariate, with values < 0.10 considered to be indicative of good balance; values of 0.10–0.15 were considered acceptable residual imbalance. BMI was excluded from the matching process due to a high proportion of missing values (21%). No other variable contained missing data for the baseline parameters used in the matching procedure. Therefore, all eligible patients were included in the propensity score analyses. GOS at 3 months was missing in six patients due to loss to follow-up; these cases were excluded from that specific comparison but retained in all other analyses.
After PSM, group comparisons for outcomes were performed in the matched cohort using paired methods to account for within-pair dependence. For each binary outcome, we estimated treatment effects as conditional odds ratios (ORs) with 95% confidence intervals (CIs) using conditional logistic regression with matched pairs specified as strata.
Subgroup Analysis Based on Treatment Duration
To assess treatment duration effects, we categorized oral nimodipine exposure as < 14 days or ≥ 14 days. Each duration subgroup was compared separately with the Nimo− group using nearest-neighbor propensity score matching (1:2, without replacement) based on the same covariates as the primary model. Post-matching outcomes were analyzed with conditional logistic regression stratified by matched sets, reporting ORs with 95% CIs.
As a robustness check to mitigate reverse causation in duration-based comparisons, we conducted a landmark analysis at day 14 that was restricted to patients alive and infarction-free through to day 14. Within this landmark cohort, we compared no nimodipine treatment, < 14 days of oral nimodipine, and ≥ 14 days of oral nimodipine using unadjusted Fisher’s exact tests.
Sensitivity Analysis Using Optimal Matching
To assess the robustness of the primary propensity score–matched findings to the choice of matching algorithm, we performed a sensitivity analysis using optimal matching. Using the same propensity score model and covariates as in the primary analysis, patients receiving oral nimodipine (Nimo+) and those not receiving nimodipine (Nimo−) were re-matched 1:1 without replacement with the optimal matching method. Covariate balance in the optimally matched cohort was evaluated using SMDs. Post-matching outcome comparisons were then repeated using paired inference, estimating treatment effects as conditional ORs with 95% CIs from conditional logistic regression stratified by matched sets, thereby accounting for within-set dependence.
Effect Modification Analysis
To evaluate the heterogeneity of treatment effects, effect modification was assessed in the full cohort using multivariable logistic regression models that included an interaction term between nimodipine exposure and each prespecified modifier (age, sex, Hunt and Hess grade, and Fisher grade). Models were adjusted for the same covariates as in the primary adjusted analyses (age, sex, treatment modality, aneurysm location, CSF diversion, shunt dependency, and intra-arterial nimodipine administration). Age was analyzed per 10-year increment. Interaction significance was primarily evaluated using likelihood ratio tests (LRT) comparing models with and without the interaction term; interaction estimates are reported as ORs with 95% CIs.
Results
Patient Population
A total of 337 patients presented with aSAH between June 2015 and June 2025. Twenty-five patients were excluded due to early death (n = 8), age below 18 years (n = 3), or oral nimodipine administration for < 5 days (n = 14). The final study cohort therefore comprised 312 patients, including 102 receiving prophylactic oral nimodipine (Nimo+) and 210 who did not (Nimo−) (see Fig. 1).
Fig. 1.
Study flow diagram. Flowchart illustrating patient selection, treatment allocation, and formation of the propensity score–matched cohort. aSAH Aneurysmal subarachnoid hemorrhage, GOS Glasgow Outcome Scale, Nimo nimodipine, Nimo+/Nimo− patients receiving/not receiving oral nimodipine
Oral nimodipine therapy was frequently discontinued due to nimodipine-induced hypotension and vasopressor requirement to achieve arterial hypertension in patients with delayed cerebral ischemia, and several patients were discharged from the intensive care unit before completing the standard 21-day-long course. Overall, only 27% of patients received the full oral nimodipine regimen for at least 21 days. In this context, we used the duration of oral nimodipine administration as a surrogate for treatment intensity. Based on the median number of treatment days (13 days), the nimodipine group was additionally subdivided into short-course (Nimo < 14 days) and long-course (Nimo ≥ 14 days) treatment cohorts to enable further subgroup analyses.
Baseline Characteristics Before Matching
The mean age was comparable between groups (58.13 ± 14.23 years vs 58.88 ± 13.62 years; p = 0.65). There was a female predominance in both cohorts (69% vs 74%; p = 0.41).
BMI data were available in 80% and 78% of cases in the Nimo+ and Nimo− groups, respectively, and did not differ significantly (26.78 ± 5.66 vs 26.67 ± 6.31 kg/m2; p = 0.89). The prevalence of arterial hypertension was also comparable between groups (54% vs 51%; p = 0.65).
Clinically severe aSAH (Hunt and Hess grades IV–V) was observed in 35% of Nimo+ patients and 44% of Nimo− patients (p = 0.19). Radiologically severe aSAH (Fisher groups 3–4) was present in 72% and 87% of cases, respectively (p = 0.002). The aneurysm location was within the anterior circulation in 84% of the patients of both groups (p = 1.00). CSF drainage was mainly achieved via EVD (62% vs 65%; p = 0.70). More patients underwent surgical clipping compared to endovascular coiling (52% vs 63%; p = 0.18). Patients in the Nimo+ group underwent intra-arterial vasospasmolysis more frequently than those in the Nimo− group, with a higher mean number of sessions (1.92 ± 2.82 vs 1.28 ± 1.86; p = 0.02). Ventriculoperitoneal shunt placement was required in 25% of patients receiving nimodipine and in 32% of those who did not (p = 0.30). Baseline characteristics before matching are summarized in Table 1.
Table 1.
Baseline characteristics before propensity score matching (Nimo+ vs Nimo−)
| Baseline characteristics | All patients (n = 312) | Nimo+ group (n = 102) | Nimo− group (n = 210) | p-value |
|---|---|---|---|---|
| Age, mean ± SD | 58.63 ± 13.80 | 58.13 ± 14.23 | 58.88 ± 13.62 | 0.654 |
| Sex, n (%) | 0.411 | |||
| Male | 87 (27.9) | 32 (31.4) | 55 (26.2) | |
| Female | 225 (72.1) | 70 (68.6) | 155 (73.8) | |
| Procedure, n (%) | 0.184 | |||
| Clipping | 185 (59.3) | 53 (52.0) | 132 (62.9) | |
| Endovascular | 122 (39.1) | 47 (46.1) | 75 (35.7) | |
| Conservative | 5 (1.6) | 2 (2.0) | 3 (1.4) | |
| Hunt and Hess grade, n (%) | 0.190 | |||
| Mild/moderate (I–III) | 184 (59.0) | 66 (64.7) | 118 (56.2) | |
| Severe (IV–V) | 128 (41.0) | 36 (35.3) | 92 (43.8) | |
| Fisher group, n (%) | 0.002* | |||
| Mild/moderate (1–2) | 57 (18.3) | 29 (28.4) | 28 (13.3) | |
| Severe (3–4) | 255 (81.7) | 73 (71.6) | 182 (86.7) | |
| Aneurysm location, n (%) | 1.000 | |||
| Anterior | 263 (84.3) | 86 (84.3) | 177 (84.3) | |
| Posterior | 49 (15.7) | 16 (15.7) | 33 (15.7) | |
| CSF drainage, n (%) | 0.703 | |||
| EVD | 200 (64.1) | 63 (61.8) | 137 (65.2) | |
| None | 53 (17.0) | 17 (16.7) | 36 (17.1) | |
| LD | 59 (18.9) | 22 (21.6) | 37 (17.6) | |
| Arterial hypertension, n (%) | 0.652 | |||
| Yes | 161 (51.6) | 55 (53.9) | 106 (50.5) | |
| No | 151 (48.4) | 47 (46.1) | 104 (49.5) | |
| Shunt, n (%) | 0.303 | |||
| Yes | 93 (29.8) | 26 (25.5) | 67 (31.9) | |
| No | 219 (70.2) | 76 (74.5) | 143 (68.1) | |
| Intra-arterial Nimodipine, mean ± SD | 1.49 ± 2.24 | 1.92 ± 2.82 | 1.28 ± 1.86 | 0.017* |
aSAH Aneurysmal subarachnoid hemorrhage, CSF cerebrospinal fluid, GOS Glasgow Outcome Scale, EVD external ventricular drain, LD lumbar drain, Nimo nimodipine, Nimo+/Nimo− patients receiving/not receiving oral nimodipine, SD standard deviation
*Significant difference between treatment groups at p < 0.05
Propensity Score Matching
Propensity score matching substantially improved baseline comparability between the groups. Before matching, moderate imbalances were observed across several clinical and procedural variables. After matching, all covariates demonstrated adequate balance, with SMDs reduced to acceptable levels in all analyses.
In the main analysis comparing the Nimo+ and Nimo− groups, the mean SMD decreased from 0.148 to 0.086 following 1:1 nearest-neighbor matching, and from 0.119 to 0.054 in the optimal-matching sensitivity analysis. For the subgroup analyses, balance improvement was observed, with SMD reductions from 0.163 to 0.100 (Nimo− vs Nimo < 14 days) and from 0.205 to 0.106 (Nimo− vs Nimo ≥ 14 days). Detailed matching characteristics are provided in Table 2.
Table 2.
Propensity score matching overview
| Comparison | Matching method | Matching ratio (treated:control) | Sample size (n treated/n control) | Matched (n treated/n control) | Mean SMD (before → after PMS) |
|---|---|---|---|---|---|
| Nimo+ vs Nimo− | Nearest neighbor | 1:1 | 102/210 | 102/102 | 0.148 → 0.086 |
| Nimo+ vs Nimo− (sensitivity) | Optimal | 1:1 | 102/210 | 102/102 | 0.119 → 0.054 |
| Nimo < 14 vs Nimo− | Nearest neighbor | 1:2 | 54/210 | 54/108 | 0.163 → 0.100 |
| Nimo ≥ 14 vs Nimo− | Nearest neighbor | 1:2 | 48/210 | 48/96 | 0.205 → 0.106 |
Nimo Nimodipine, Nimo+/Nimo− patients receiving/not receiving oral nimodipine, Nimo < 14/≥ 14 short-course (< 14 days) /long-course (≥ days) nimodipine treatment, PSM propensity score matching, SMD standardized mean difference
Main Analysis (Nimo+ vs Nimo−)
After matching, there were no significant differences between groups in terms of the baseline characteristics (all p > 0.05).
Patients who received oral nimodipine exhibited a significantly lower incidence of angiographic vasospasm compared with those not receiving nimodipine (43% vs 64%; conditional OR 0.40, 95% CI 0.22–0.74; p = 0.004). Likewise, cerebral infarctions were less frequent in the Nimo+ group than in the Nimo− group, both for delayed cerebral ischemia (38% vs 58%; conditional OR 0.44, 95% CI 0.25–0.80; p = 0.007) and for all infarctions (57% vs 72%; conditional OR 0.45, 95% CI 0.23–0.86; p = 0.016). Compared to patients not receiving nimodipine, functional outcome was improved in patients treated with nimodipine, with higher odds of favorable GOS at discharge (51% vs 37%; conditional OR 1.82, 95% CI 1.01–3.29; p = 0.047) and at 3 months (67% vs 48%; conditional OR 2.27, 95% CI 1.23–4.16; p = 0.008). In-hospital mortality did not differ significantly between groups (conditional OR 0.53, 95% CI 0.24–1.19; p = 0.123), and no significant between-group difference was observed for 3-month mortality (conditional OR 0.52, 95% CI 0.25–1.09; p = 0.082). A detailed overview of outcomes in the post-matching groups is provided in Table 3, and results are depicted in Fig. 2.
Table 3.
Outcomes in propensity score matched cohorts (Nimo+ vs Nimo−)
| Outcome | Nimo+ group, n/N (%) | Nimo− group, n/N (%) | Paired OR (95% CI) | p value (clogit) |
|---|---|---|---|---|
| Angiographic vasospasm | 44/102 (43.1) | 65/102 (63.7) | 0.40 (0.22–0.74) | 0.004 |
| Delayed cerebral infarction | 39/102 (38.2) | 59/102 (57.8) | 0.44 (0.25–0.80) | 0.007 |
| All infarctions | 58/102 (56.9) | 74/102 (72.5) | 0.45 (0.23–0.86) | 0.016 |
| GOS at discharge (favorable) | 52/102 (51.0) | 38/102 (37.3) | 1.82 (1.01–3.29) | 0.047 |
| GOS at 3 months (favorable) | 66/102 (66.7) | 49/102 (48.0) | 2.27 (1.23–4.16) | 0.008 |
| Death at discharge | 13/102 (12.7) | 21/102 (20.6) | 0.53 (0.24–1.19) | 0.123 |
| Death at 3 months | 15/102 (14.7) | 25/102 (24.5) | 0.52 (0.25–1.09) | 0.082 |
CI Confidence interval, clogit conditional logistic regression, GOS Glasgow Outcome Scale, Nimo Nimodipine, Nimo+/Nimo− patients receiving/not receiving oral nimodipine, OR odds ratio, PSM propensity score matching
Fig. 2.
Main analysis in the propensity score-matched cohort. Forest plot showing paired odds ratios with 95% confidence intervals for angiographic vasospasm, delayed cerebral infarction, all infarctions, favorable Glasgow Outcome Scale (GOS) at discharge and at 3 months, and mortality at discharge and at 3 months, comparing treatment with prophylactic oral nimodipine (Nimo+) versus no nimodipine treatment (Nimo−) in the nearest-neighbor propensity score-matched cohort (102 matched pairs). Effect estimates were obtained using conditional logistic regression stratified by matched sets
Subgroup Analyses Based on Duration of Oral Nimodipine Therapy
In duration-stratified propensity score–matched analyses, nimodipine administered for < 14 days was not significantly associated with angiographic vasospasm (53.7% vs 68.5%; OR 0.56, 95% CI 0.30–1.08; p = 0.084), delayed cerebral ischemia (42.6% vs 59.3%; OR 0.56, 95% CI 0.30–1.03; p = 0.063), all infarctions (63.0% vs 70.4%; OR 0.74; p = 0.366), favorable GOS at discharge (40.7% vs 34.3%; OR 1.33; p = 0.417) or at 3 months (57.4% vs 45.8%; OR 1.66; p = 0.155). Mortality also did not differ (in-hospital: 22.2% vs 20.4%; OR 1.12; p = 0.782; 3-month: 24.1% vs 23.4%; OR 1.03; p = 0.948).
In contrast, nimodipine administered for ≥ 14 days was associated with significantly lower rates of angiographic vasospasm (31.2% vs 59.4%; OR 0.27, 95% CI 0.12–0.62; p = 0.0019), delayed cerebral ischemia (33.3% vs 62.5%; OR 0.29, 95% CI 0.13–0.63; p = 0.0019), and all infarctions (50.0% vs 67.7%; OR 0.45; p = 0.040), as well as higher rates of favorable functional outcome at discharge (62.5% vs 40.6%; OR 3.15; p = 0.008) and at 3 months (77.8% vs 58.9%; OR 2.78; p = 0.028). Mortality differences were also not significant, although point estimates favored the ≥14-day group (in-hospital: 2.1% vs 11.5%; OR 0.16; p = 0.088; 3-month: 4.3% vs 14.7%; OR 0.27; p = 0.096). These results are summarized in Table 4 and depicted in Fig. 3.
Table 4.
Outcomes in duration-based subgroups
| Subgroup comparison | Outcome | Nimo (%) | Nimo− (%) | OR (95% CI) | p |
|---|---|---|---|---|---|
| Nimo < 14 vs Nimo− | Angiographic vasospasm | 29/54 (53.7) | 74/108 (68.5) | 0.56 (0.30–1.08) | 0.084 |
| Delayed cerebral infarction | 23/54 (42.6) | 64/108 (59.3) | 0.56 (0.30–1.03) | 0.063 | |
| All infarctions | 34/54 (63.0) | 76/108 (70.4) | 0.74 (0.39–1.42) | 0.366 | |
| GOS at discharge (favorable) | 22/54 (40.7) | 37/108 (34.3) | 1.33 (0.67–2.63) | 0.417 | |
| GOS at 3 months (favorable) | 31/54 (57.4) | 49/107 (45.8) | 1.66 (0.83–3.32) | 0.155 | |
| Death at discharge | 12/54 (22.2) | 22/108 (20.4) | 1.12 (0.50–2.51) | 0.782 | |
| Death at 3 months | 13/54 (24.1) | 25/107 (23.4) | 1.03 (0.48–2.21) | 0.948 | |
| Nimo ≥ 14 vs Nimo− | Angiographic vasospasm | 15/48 (31.2) | 57/96 (59.4) | 0.27 (0.12–0.62) | 0.0019 |
| Delayed cerebral infarction | 16/48 (33.3) | 60/96 (62.5) | 0.29 (0.13–0.63) | 0.0019 | |
| All infarctions | 24/48 (50.0) | 65/96 (67.7) | 0.45 (0.21–0.96) | 0.040 | |
| GOS at discharge (favorable) | 30/48 (62.5) | 39/96 (40.6) | 3.15 (1.35–7.35) | 0.0081 | |
| GOS at 3 months (favorable) | 35/45 (77.8) | 56/95 (58.9) | 2.78 (1.12–6.94) | 0.028 | |
| Death at discharge | 1/48 (2.1) | 11/96 (11.5) | 0.16 (0.02–1.31) | 0.088 | |
| Death at 3 months | 2/46 (4.3) | 14/95 (14.7) | 0.27 (0.06–1.26) | 0.096 |
CI Confidence interval, GOS Glasgow outcome scale, Nimo nimodipine, Nimo− patients not receiving oral nimodipine, Nimo < 14/≥ 14 short-course (< 14 days) /long-course (≥ days) nimodipine treatment, OR odds ratio, PSM propensity score matching
Fig. 3.
Duration subgroup analyses. Forest plots of paired odds ratios (95% confidence interval) for the same outcomes as Fig. 2 from separate duration-stratified propensity score–matched analyses comparing patients without nimodipine (Nimo−) with those receiving oral nimodipine for < 14 days (Nimo < 14) and ≥ 14 days (Nimo > 14), respectively. Matching was performed using nearest-neighbor propensity score matching (1:2 treated-to-control, without replacement), and treatment effects were estimated using conditional logistic regression stratified by matched sets.
In the day-14 landmark cohort, a total of 119 patients were eligible, as defined by being alive and free of delayed cerebral infarction through to day 14. Within this cohort, 69 patients received no oral nimodipine, 23 patients received < 14 days of oral nimodipine, and 27 patients received ≥ 14 days of oral nimodipine. Post-day-14 infarction rates were 17% in patients without nimodipine, 13% in those receiving nimodipine < 14 days, and 11% in those receiving nimodipine ≥ 14 days, with no statistically significant differences between these groups in the unadjusted comparisons (all p > 0.5). Favorable GOS at discharge was 56.5% (no oral nimodipine), 65.2% (< 14 days of oral nimodipine) and 77.8% (≥ 14 days of oral nimodipine) (≥ 14 days vs no nimodipine, p = 0.063). Favorable GOS at 3 months was 72.1%, 78.3% and 95.8%, respectively; the ≥ 14-day treatment group showed higher favorable outcome rates than the Nimo− group (p = 0.019), whereas no difference was observed for the < 14-day treatment group.
Sensitivity Analysis Using Optimal Matching
In the sensitivity analysis applying optimal 1:1 PSM (102 matched pairs), the main findings were largely consistent with those of the primary nearest-neighbor matched analysis. Oral nimodipine remained associated with significantly lower odds of angiographic vasospasm (conditional OR 0.39, 95% CI 0.21–0.72; p = 0.0027), delayed cerebral ischemia (conditional OR 0.41, 95% CI 0.22–0.74; p = 0.0032), and all infarctions (conditional OR 0.40, 95% CI 0.20–0.78; p = 0.0073). Compared with the Nimo− group, functional outcome at 3 months remained significantly improved in the nimodipine treatment group (favorable GOS: conditional OR 1.94, 95% CI 1.08–3.48; p = 0.026). In contrast, the association with favorable GOS at discharge was attenuated and did not reach statistical significance (conditional OR 1.71, 95% CI 0.94–3.10; p = 0.080). No significant between-group differences were observed for in-hospital mortality (conditional OR 0.69, 95% CI 0.32–1.48; p = 0.339) or 3-month mortality (conditional OR 0.65, 95% CI 0.32–1.31; p = 0.227).
Assessment of Effect Modification for Nimodipine Treatment
In the full-cohort multivariable interaction models, there was no evidence of effect modification of the nimodipine association by age or sex for delayed cerebral ischemia (age interaction OR 1.34 per 10 years, 95% CI 0.90–2.00; p_LRT = 0.145; sex interaction OR 0.95, 95% CI 0.29–3.11; p_LRT = 0.935). In contrast, the association between nimodipine and delayed cerebral ischemia differed significantly by clinical severity, with a treatment-by-Hunt–Hess interaction (interaction OR 1.99 per grade, 95% CI 1.28–3.09; p_LRT = 0.002; see Fig. 4). Model-based estimates indicated progressive attenuation of the nimodipine-associated reduction in delayed cerebral infarction with increasing Hunt and Hess grade. A trend toward effect modification by Fisher grade was also observed for delayed cerebral ischemia (interaction OR 2.00, 95% CI 0.95–4.22; p_LRT = 0.062). For functional outcome at 3 months, no significant interactions were detected with age, sex, Hunt and Hess grade, or Fisher grade (all p_LRT > 0.17). Effect modification results are shown in Table 5.
Fig. 4.
Effect modification by clinical severity. Model-based predicted probability of delayed cerebral infarction across ordinal Hunt and Hess grades for patients treated with oral nimodipine versus those not receiving nimodipine, derived from a multivariable logistic regression model including a nimodipine × Hunt–Hess interaction term and adjusting for prespecified covariates. Shaded bands indicate 95% confidence intervals for predicted probabilities; other covariates were held constant at typical reference values during prediction
Table 5.
Effect modification analyses for nimodipine treatment
| Outcome | Effect modifier | Interaction OR (95% CI) | p (LRT) | p (Wald) |
|---|---|---|---|---|
| Delayed cerebral ischemia | Age (per 10 years) | 1.34 (0.90–2.00) | 0.145 | 0.149 |
| Sex | 0.95 (0.29–3.11) | 0.935 | 0.935 | |
| Hunt and Hess grade (ordinal, per grade) | 1.99 (1.28–3.09) | 0.002 | 0.002 | |
| Fisher grade (ordinal, per grade) | 2.00 (0.95–4.22) | 0.062 | 0.068 | |
| GOS at 3 months (favorable) | Age (per 10 years) | 0.72 (0.43–1.21) | 0.208 | 0.216 |
| Sex | 0.82 (0.20–3.35) | 0.780 | 0.781 | |
| Hunt and Hess grade (ordinal, per grade) | 0.93 (0.56–1.55) | 0.783 | 0.783 | |
| Fisher grade (ordinal, per grade) | 0.51 (0.19–1.39) | 0.171 | 0.187 |
CI Confidence interval, GOS Glasgow Outcome Scale, LRT likelihood ratio test, OR odds ratio, Wald Wald test
Discussion
In this contemporary propensity score-matched analysis of 312 patients with aSAH, prophylactic oral nimodipine was associated with a significantly lower incidence of angiographic vasospasm, delayed cerebral ischemia, and better neurological outcome, while no difference in mortality was observed. Subgroup analyses demonstrated a clear treatment duration-dependent effect: patients treated with nimodipine for ≥ 14 days experienced benefit in angiographic vasospasm, delayed cerebral ischemia, and GOS, whereas shorter treatment (< 14 days) was not associated with any benefit. Exploratory analyses further suggested that the observed treatment-associated reduction in delayed ischemic injury was less pronounced with increasing clinical severity, as reflected by higher Hunt and Hess grades.
These findings align with and expand upon results from the pivotal RCTs conducted in the 1980s [4–9]. The largest of these, the British Aneurysm Nimodipine Trial, enrolled 554 patients and demonstrated a significant reduction in cerebral infarction and poor outcome with 60 mg oral nimodipine administered every 4 h for 21 days [9]. Earlier, smaller trials also showed improved neurological outcomes [4–8] and reduced rates of cerebral infarction among treated patients [7]. Moreover, the landmark Cochrane review of calcium antagonists in aSAH demonstrated that oral nimodipine significantly reduced poor functional outcome and cerebral infarction without a corresponding reduction in mortality, a pattern that is consistent with the findings of the present study [26]. Our interaction models suggest attenuation of the nimodipine-associated reduction in delayed infarction with increasing Hunt and Hess grade. This pattern is consistent with prior observations in poor-grade cohorts, for which the benefit was apparent in patients with Hunt and Hess grades 3–4 aSAH but not grade 5 [7].
Other RCTs have investigated the efficacy of intravenous nimodipine in patients with aSAH, either compared with placebo [27, 28] or with enteral administration [29, 30]. Subsequent meta-analyses incorporating both intravenous and enteral nimodipine treatment arms suggested that the two routes of administration may confer comparable benefits with respect to the prevention of delayed cerebral ischemia and poor functional outcome in aSAH [31, 32]. In addition, intraventricular administration of nimodipine has been evaluated in an RCT (NEWTON trial), which was terminated early due to futility, as interim analyses indicated a low likelihood of achieving a significant reduction in poor outcome, despite lower rates of angiographic vasospasm and delayed cerebral ischemia in patients receiving intraventricular nimodipine [33].
The mechanisms underlying the beneficial effects of oral nimodipine in aSAH are not fully understood. Our results regarding angiographic vasospasm support the original hypothesis of a direct mitigation of large-vessel vasospasm leading to improved perfusion [9]. Other proposed mechanisms underlying nimodipine’s protective effects include the attenuation of cortical spreading depolarizations and the promotion of endogenous fibrinolytic activity, which together may help prevent the formation of cerebral microthrombi [34, 35]. In addition, experimental data indicate that nimodipine alleviates microvascular dysfunction by reducing microvasospasm and microthrombus formation—both of which contribute to delayed cerebral ischemia [36]. Also, nimodipine has demonstrated antioxidant properties that enhance cerebral oxygen metabolism and attenuate calcium overload–induced reperfusion injury, thereby limiting secondary neuronal damage [37]. However, nimodipine did not improve neurological outcomes in patients with traumatic SAH [38], suggesting that its beneficial effects in aSAH are likely mediated through mechanisms related to vasospasm reduction rather than general neuroprotection.
Despite the evidence base for nimodipine and its inclusion in international guidelines [1, 10, 11], the real-world administration of oral nimodipine remains often inconsistent. In our cohort, only 27% of patients received the full recommended regimen. Similar findings have been reported by others, with the proportion of patients receiving the complete 21-day course ranging between 1% and 44% [39–42]. The main reasons for dose reduction or discontinuation include hypotension, vasopressor requirement for induced hypertension in cases of delayed cerebral ischemia, and early referral without continued prescription, but temporarily limited nimodipine availability is also a factor.
Our findings demonstrate that patients receiving longer or complete courses of oral nimodipine had better neurological outcomes, consistent with results from previous studies focusing on treatment duration and dose reduction [42, 43]. These earlier retrospective studies have specifically examined the impact of nimodipine dose reduction or interruption of nimodipine treatment in patients with aSAH. In the first one study, including 170 patients, nimodipine treatment interruption and dose reduction were significantly associated with a higher incidence of delayed cerebral ischemia; nimodipine treatment interruption was identified as an independent predictor of delayed cerebral ischemia [43]. In the second retrospective analysis, including 270 patients, multivariable analysis demonstrated that administration of the full nimodipine dosage was independently associated with a lower risk of unfavorable clinical outcome [42], reinforcing the importance of maintaining the full 21-day regimen, as recommended by current guidelines [1, 10, 11]. However, it has been argued that retrospective studies investigating nimodipine treatment duration are prone to selection bias, since discontinuation of treatment or dose reduction often occurs in patients developing vasospasm or delayed cerebral ischemia [10]. This reverse-causation bias may confound associations between shorter treatment and poor outcome. In our analysis, this bias is partially mitigated, as we compared patients with short-term nimodipine exposure (< 14 days) directly to those who never received the drug. The absence of a difference between these groups suggests that poorer outcomes in patients with brief treatment duration cannot be fully attributed to treatment cessation during deterioration, but rather to an insufficient treatment duration to achieve benefit. Also, the results of the landmark analyses reduce the likelihood that the observed duration pattern is explained solely by early deterioration, as comparisons were restricted to patients who were alive and infarction-free through to day 14. The effect direction was consistent, with lower post-day-14 infarction rates and higher favorable GOS proportions in the Nimo > 14-day group versus the Nimo− group, whereas the Nimo < 14-day group showed no clear benefit. However, the results were mostly not statistically significant, partly due to the small cohort and limited post-landmark events. Accordingly, these findings should be interpreted as supportive robustness evidence rather than definitive causal proof.
In cases of nimodipine-induced hypotension, the American Heart Association guideline recommends counteracting nimodipine-related hypotension using “standard medical interventions,” although specific measures are not defined [1]. In patients with delayed cerebral ischemia, the authors considered vasopressor-induced hypertension to be a reasonable approach based on observational data [1]. Accordingly, the use of vasopressin may be considered in cases of nimodipine-induced hypotension to maintain adequate blood pressure and enable continuation of full-dose treatment. However, the only RCT investigating vasopressor-induced hypertension in delayed cerebral ischemia was terminated early due to lack of efficacy on cerebral perfusion and was therefore underpowered; however, the authors still reported an increased risk of serious adverse events (risk ratio 2.1) [44]. Thus, the efficacy and safety of vasopressor-supported normotension during nimodipine therapy warrant further investigation in prospective studies. Furthermore, additional antihypertensive agents could be withheld when feasible. When delayed cerebral ischemia occurs, a combination of nimodipine and vasopressor-induced hypertension could be a possible option [45]. In cases of early referral, oral nimodipine might be prescribed for the remaining treatment period to ensure guideline-compliant therapy.
This study has several limitations inherent to its retrospective, single-center design. First, treatment allocation was not randomized—the decision to administer prophylactic oral nimodipine was based on local clinical practice, which changed over time. Second, despite statistical balancing, some residual baseline differences may persist between groups, including factors not captured in the database, such as fluid management, intensive care management, or hemodynamic targets. Third, the duration of oral nimodipine treatment was not always consistent, reflecting real-world clinical variability. The analysis of subgroups according to treatment duration (Nimo < 14 days vs ≥ 14 days) was based on the observed distribution of administered days and may not fully represent biological dose–response relationships. Fourth, rationales for treatment interruptions were not systematically recorded. Fifth, radiological endpoints, such as angiographic vasospasm and cerebral infarction, were derived from routine clinical imaging and not from a uniform imaging protocol; therefore, under- or over-detection bias is possible. Also, functional outcome data at 3 months were incomplete for a subset of patients, potentially introducing attrition bias.
Conclusions
This study reaffirms the historically-established benefits of prophylactic oral nimodipine in patients with aSAH in a contemporary cohort. In our study, sustained administration for at least 14 days was associated with reduced angiographic vasospasm, delayed infarction, and improved functional outcome. Full-course treatment (60 mg every four hours for 21 days) appears to be the optimal strategy.
Acknowledgments
We thank the participants of the study.
Medical Writing/Editorial Assistance
Portions of the manuscript were edited for clarity and scientific style with the help of ChatGPT (OpenAI); the authors reviewed and approved all final content and remain fully responsible for the manuscript. The use of AI tools was funded by the authors.
Author Contribution
Harold F. Hounchonou: conceptualization; methodology; formal analysis; data curation; writing—original draft; writing—review and editing; supervision. Merle Hirsch: data curation; writing—review and editing. Josef M. Lang: writing—review and editing. Florian Wild: writing—review and editing. Omar Abu-Fares: data curation; writing—review and editing. Shadi Al-Afif: data curation; writing—review and editing; supervision. Joachim K. Krauss: conceptualization; writing—original draft; writing—review and editing; supervision.
Funding
No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.
Data Availability
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. No tables/figures/images/other material that infringe the copyright of another publisher/individual are included in the manuscript.
Declarations
Authorship
Harold F. Hounchonou, Merle Hirsch, Josef M. Lang, Florian Wild, Omar Abu-Fares, Shadi Al-Afif, and Joachim K. Krauss meet authorship criteria, have approved the final manuscript, and agree to be accountable for all aspects of the work. All co-authors are aware of the submission to this journal, and agree to allow the corresponding author to serve as the primary correspondent with the editorial office and to review and sign off on the final proofs for publication. No deserving authors have been omitted from the authorship list. All persons who made substantial contributions to the manuscript are listed as authors. This manuscript complies with all instructions to authors and has not been published elsewhere and is not under consideration by another journal. STROBE Checklist was used
Conflict of interest
Harold F. Hounchonou has nothing to disclose. Merle Hirsch has nothing to disclose. Josef M. Lang has nothing to disclose. Florian Wild has nothing to disclose. Omar Abu-Fares has nothing to disclose. Shadi Al-Afif has nothing to disclose. Joachim K. Krauss has nothing to disclose.
Ethical Approval
This study was conducted in accordance with the Declaration of Helsinki of 1964 and its later amendments. For this type of study, formal approval of the institutional ethics at the Medical School of Hannover is not required. Written informed consent was obtained from all participants, including consent for the use of anonymized clinical and biological data for research and publication purposes.
Footnotes
Harold F. Hounchonou and Merle Hirsch have contributed equally to this work and share first authorship.
Shadi Al-Afif and Joachim K. Krauss have contributed equally to this work and share last authorship.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. No tables/figures/images/other material that infringe the copyright of another publisher/individual are included in the manuscript.