British aneurysm nimodipine trial: Nimodipine in subarachnoid hemorrhage

in

Pickard JD, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. Br med J 1989;298:636-42.

 

Clinical Question

In patients with subarachnoid hemorrhage (SAH) +/- confirmed ruptured aneurysm as the cause, does nimodipine reduce the risk of delayed cerebral infarct and improve long-term functional outcome?

 

Bottom Line

In patients with SAH (of whom only 2/3 had confirmed aneurysmal SAH), nimodipine reduced the risk of poor functional outcome (NNT 8) at 3 months without causing significant adverse events.

The benefits of nimodipine may be even larger in the current era of rapidly identifying aneurysm rupture as the cause for SAH via CTA.

 

Design

Allocation-concealed "superiority" RCT with all (patients, clinicians, investigators) blinded, no loss-to-follow-up, analyzed using the intention-to-treat population.

 

Patients and Setting

  • 4 centres in the UK
  • June 1985 - September 1987
  • Inclusion criteria:
    1. SAH confirmed by LP or CT
    2. Within 96h of onset of symptoms of SAH
    3. NOTE: No angiography (CTA or digital subtraction angiography [DSA]) confirming ruptured aneurysm required prior to enrollment into trial
  • Key exclusion criteria:
    • Pre-existing "cardiac decompensation" or myocardial infarction <6 months or major dysfunction of another organ
    • Within 1 week of another SAH that led to coma
  • 1115 screened -> 554 enrolled & randomized
    • Most common reason for exlusion was >96h since symptom onset (317 patients)
  • Average patient at baseline:
    • 47 y/o
    • 60% female
    • Previous SAH 15%
    • Clinical grade on admission (using World Federation of Neurosurgical Societies [WFNS] classification)
      • I (Glasgow Coma Scale [GCS] 15, no focal neuro deficits): 4%
      • II (GCS 15, cranial nerve palsy): 59%
      • III (GCS 13-14): 27%
      • IV (GCS 8-12): 8%
      • V (GCS 3-7): 3%
    • Time from symptom onset to CT: 1.5 days
      • Fisher grade IV (i.e. presence of intraventricular hemorrhage [IVH]): 30%
      • Hydrocephalus: 13%
    • Confirmed aneurysmal SAH (by DSA): 66%
      • Spasm present: 18%
    • Time from symptom onset to OR: 11 days
      • OR prior to enrollment: 42%

 

Intervention and Control

  • Intervention: Nimodipine 60 mg PO q4h x21 days
    • 25% stopped before 21 days, mainly due to negative DSA (i.e. no ruptured aneurysm)
    • Protocol allowed for dose reduction if hypotension occurred, though this was not required in any patient
  • Control: Matching placebo
  • Co-interventions common to both groups:
    • CT head, non-contrast at 24h after admission
    • Further imaging, surgery, other management per attending MD

 

Outcomes

  • @ 3 months
  • Efficacy: Clinically & statistically significant reduction in poor outcome (NNT 8), mainly driven by a reduction in cerebral infarct (NNT 12).
  • Safety:
    • No statistically significance increase in adverse events
    • No dosage reduction required for hypotension in either group
      • From baseline to day 21, nimodipine reduced blood pressure by ~7/4 mm Hg

Key Considerations

Generalizability: Despite major changes in various aspects of diagnosis and management of SAH, the results of this trial likely still apply to today's patients.

  •  Current management emphasizes identifying a ruptured aneurysm (CT angiography) and securing it early (<24 hours) to prevent re-rupture and re-bleed, the risk of which is 4% in the first 24h and 1.5%/day in the subsequent 2 weeks.
    • In this trial, aneurysms were identified with DSA, often longer than 4 days after symptom onset. More concerning, patients waited an average of 11 days prior to surgical clipping of their aneurysm.
      • Nimodipine was reported as equally beneficial in patients regardless of whether they underwent surgical clipping (versus no intervention).
    • Notably, endovascular coiling is another modality now available to secure aneurysms, particularly for those with narrow necks found in the posterior cerebral circulation. This procedure was not available in the era when this trial was conducted.
      • Endovascular coiling doesn't reduce delayed cerebral ischemia versus surgical clipping, & produces similar long-term functional outcomes; therefore, shouldn't impact effects of nimodipine.
  • A sizable portion of patients enrolled in this trial (44%) did not have proven aneurysmal SAH at enrollment, & up to a quarter of all patients had non-aneurysmal SAH later diagnosed by angiography.
    • The patients with non-aneurysmal SAH could not benefit from nimodipine, which likely led to the dilution of nimodipine's efficacy.
    • This means that the true absolute reduction in poor outcomes with nimodipine is likely larger than reported, & the NNT is likely smaller than 8 (which is already impressive).

Additional logistic considerations for nimodipine:

  • Nimodipine does not reduce cerebral vasospasm; this is not its underlying mechanism (which remains unknown)
    • Because of this, nimodipine should ideally be continued in patients being treated for "clinical vasospasm," unless it is impairing the ability to achieve the blood pressure goals of hypertensive therapy ("triple-H therapy")
  • Cost of a 21-day course: ~$3,100 (~$150/day)
    • Many patients recover & are well enough to go home prior to the completion of the 21-day course of nimodipine. In these patients, risk of delayed cerebral ischemia is very low, particularly beyond 10 days of symptom onset, so nimodipine should be discontinued on discharge to avoid unnecessary cost (& difficulty in adhering to q4h dosing) to the patient.

 

Summary author: Ricky Turgeon BSc(Pharm), ACPR, PharmD
Summary date: Updated 14 July 2016