Pickard et al: Nimodipine in Subarachnoid Haemorrhage (1989)

“This study provides evidence that nimodipine reduces the occurrence of cerebral infarction and poor outcome after subarachnoid haemorrhage.”

  • The British Aneurysm Nimodipine Trial (BRANT) Group

1. Publication Details

  • Trial Title: Effect of nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial
  • Citation: Pickard JD, Murray GD, Illingworth R, et al. Effect of nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989;298(6674):636-642. DOI: 10.1136/bmj.298.6674.636
  • Published: March 11, 1989, in The British Medical Journal (BMJ)
  • Author: J. D. Pickard, on behalf of the trial group
  • Funding: Bayer UK.

2. Keywords

  • Subarachnoid Hemorrhage, Cerebral Vasospasm, Nimodipine, Calcium Channel Blocker, Neurocritical Care, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with subarachnoid hemorrhage from a ruptured aneurysm (Population), does treatment with oral nimodipine (Intervention) compared to placebo (Comparison) reduce the incidence of cerebral infarction and poor outcome at 3 months (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Delayed cerebral ischemia from vasospasm is a major cause of death and disability after aneurysmal subarachnoid hemorrhage. Nimodipine, a calcium channel blocker, was thought to prevent or reverse vasospasm by dilating cerebral arteries.
  • Knowledge Gap: While physiologically plausible, the clinical efficacy of nimodipine in improving patient-centered outcomes was uncertain. Previous smaller trials had been promising but inconclusive. A large, definitive randomized controlled trial was needed.
  • Proposed Hypothesis: The authors hypothesized that nimodipine would be superior to placebo in reducing the incidence of cerebral infarction and improving functional outcomes after subarachnoid hemorrhage.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 31 neurosurgical units in the United Kingdom and Ireland.
  • Trial Period: Enrollment ran from December 1985 to September 1987.
  • Population:
    • Inclusion Criteria: Adult patients (16-70 years) with a confirmed aneurysmal subarachnoid hemorrhage who could be started on treatment within 96 hours of the bleed.
    • Exclusion Criteria: Included patients who were moribund or who had severe pre-existing medical conditions.
  • Intervention: Patients received oral nimodipine (60 mg) every 4 hours for 21 days.
  • Control: Patients received matching placebo tablets on the same schedule.
  • Management Common to Both Groups: All other aspects of care, including the timing and method of aneurysm repair (clipping), were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 540 patients would be required to have 90% power to detect a 10% absolute risk reduction in poor outcomes. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: The incidence of cerebral infarction on CT scan.
    • Secondary Outcomes: Included functional outcome at 3 months (Glasgow Outcome Scale), mortality, and the incidence of delayed ischemic deficits.

6. Key Results

  • Enrollment and Baseline: 554 patients were randomized (278 to nimodipine and 276 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: The incidence of cerebral infarction was significantly lower in the nimodipine group: 58 of 278 patients (21%) in the nimodipine group developed an infarction, compared with 92 of 276 patients (33%) in the placebo group (p=0.003).
  • Secondary Outcomes: The rate of poor functional outcome at 3 months was also significantly lower in the nimodipine group (20% vs. 33%; p=0.001). There was a trend towards lower mortality in the nimodipine group, but this was not statistically significant.
  • Adverse Events: The main adverse event was hypotension requiring a reduction in the nimodipine dose, which occurred in a small number of patients.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who developed cerebral infarction between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.003 for the primary outcome is well below the 0.05 threshold, indicating that the observed difference in cerebral infarction is highly statistically significant and very unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for poor functional outcome):
    • Absolute Risk Reduction (ARR):
      • Formula: ARR = (Risk in Control Group) – (Risk in Intervention Group)
      • Calculation: ARR = 33% – 20% = 13%.
      • Clinical Meaning: For every 100 patients treated with nimodipine, about 13 were saved from death or severe disability.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.13 = 7.7, which is rounded up to 8.
      • Clinical Meaning: You would need to treat 8 patients with nimodipine to prevent one additional poor outcome.
  • Subgroup Analyses: The benefit of nimodipine was consistent across all subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias and provided high-quality evidence.
  • Generalizability: The inclusion of 31 diverse neurosurgical centers increases the applicability of the findings.
  • Statistical Power: The study was large and adequately powered for its primary outcome.
  • Patient-Centered Outcomes: The study included the crucial patient-centered outcome of functional status at 3 months.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a low risk of bias.
  • External Validity (Generalizability): The study was conducted in an era before the widespread use of endovascular coiling, but the underlying pathophysiology of vasospasm remains the same.
  • Other: The primary outcome was a radiological finding (infarction on CT), which is a surrogate for the more important clinical outcome of functional status. However, the strong positive finding for the secondary outcome of functional status reinforces the overall conclusion.

10. Conclusion of the Authors

  • The authors concluded that nimodipine reduces the incidence of cerebral infarction and improves clinical outcomes in patients after aneurysmal subarachnoid hemorrhage.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided the definitive evidence that established oral nimodipine as the global standard of care for preventing delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage, a recommendation that has remained unchanged for over 30 years.
  • Specific Recommendations:
    • Patient Selection: For all adult patients with aneurysmal subarachnoid hemorrhage.
    • Actionable Intervention: Administer oral nimodipine (60 mg every 4 hours) for 21 days.
    • Expected Benefit: This intervention can be expected to prevent one case of death or severe disability for every 8 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that nimodipine is a cure for subarachnoid hemorrhage. It is a specific therapy to prevent one of its most deadly complications.
  • Implementation Caveats: The key is to initiate therapy as early as possible (within 96 hours) and to complete the full 21-day course. Careful blood pressure monitoring is required.

12. Context and Related Studies

  • Building on Previous Evidence: The Pickard et al. trial (1989) was the large, definitive study that confirmed the promising findings of earlier, smaller trials on calcium channel blockers in this condition.
  • Influence on Subsequent Research: The definitive positive result of this trial was so practice-changing that it has not been ethically feasible to repeat a placebo-controlled trial. Its findings were rapidly incorporated into all international guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question.
  • Future Directions: Subsequent research in subarachnoid hemorrhage has focused on other aspects of care, such as the optimal timing of aneurysm repair, the management of hydrocephalus, and the use of more advanced monitoring techniques.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a promising therapy for a devastating and common neurocritical care emergency.
  • Methods: The large, multicenter, double-blind RCT design was of high quality and appropriate for minimizing bias. The patient population was representative, and the outcomes were clinically important.
  • Results: The study reported a statistically significant and clinically profound benefit for both its primary radiological outcome and its key secondary functional outcome (NNT of 8).
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in neurocritical care that established a new and durable standard of care. Its findings are highly applicable to all patients with aneurysmal subarachnoid hemorrhage.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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