By Jocelyn Owusu-Guha, PharmD, BCCCP and Pamela L. Buschur, PharmD, BCPS, OhioHealth Riverside Methodist Hospital, Columbus Ohio
Nimodipine, a lipophilic calcium channel antagonist, has been established as a standard of care in the management of aneurysmal subarachnoid hemorrhage (SAH). Approved by the Food and Drug Administration in 1988, nimodipine has been shown in multiple clinical trials to decrease the incidence of delayed cerebral ischemia and improve neurological outcomes.1-2 The current American Heart Association and American Stroke Association guidelines recommend the administration of nimodipine to all patients with aneurysmal SAH.3 The conventional dosing strategy for nimodipine is 60 mg every 4 hours for 21 days based on the regimen that was employed in clinical trials to adequately treat during the highest risk for developing cerebral vasospasm. However, the benefit of nimodipine therapy appears to be from neuroprotection and not directly related to the prevention of vasospasm. Controversy also exists surrounding the necessity of nimodipine therapy in patients with less severe aneurysmal SAH. Emerging literature challenges the 21-day duration of nimodipine and questions whether a shorter course may be equally as safe and efficacious.
The median length of hospital stay for patients with aneurysmal SAH is 17 days requiring nimodipine therapy to be completed outpatient in a significant number of patients.4 Potential issues with nimodipine continuation after discharge include compliance with a six times daily regimen, cost, and adverse effects including hypotension. The safety of outpatient nimodipine administration was summarized in a case report by Chen et al.4 The authors describe a 67 year old male admitted for severe headaches and hypertensive crisis found to have a SAH. Even though computed tomography angiography, magnetic resonance imaging, and diagnostic catheter cerebral angiography were all inconclusive for etiology, the patient was administered nimodipine for a full 21-day course which was concluded as an outpatient. Subsequently, the patient presented to the emergency department for severe hypotension requiring fluid administration and discontinuation of nimodipine therapy. The authors conclude that continuation of the full 21-day course of nimodipine outpatient may be detrimental to patients given the risk for hypotension.
The duration of nimodipine therapy often varies in clinical practice without evidence suggesting consequences of utilizing an abbreviated course. In a study published in 1999, Toyota sought to evaluate the effectiveness of a shortened duration of nimodipine treatment.5 In this study, 95 consecutive patients with good-grade aneurysmal SAH, defined as a Hunt and Hess Grade I through III, were treated with nimodipine for 15 days or less. The average length of hospitalization was 12.2 days and the median duration of nimodipine therapy was 11 days. Of the 90 patients with available follow-up data, no patients experienced a clinical deterioration after nimodipine was stopped as measured by Glasgow Outcome Scale score at discharge and a median of 18 weeks. The authors concluded that in good-grade aneurysmal SAH, nimodipine therapy can be discontinued early without consequence and that further studies are needed to determine the subset of patients that will benefit from nimodipine therapy.
In 2016, Cho and colleagues conducted a retrospective single-center cohort study to evaluate neurological outcomes between patients who had previously received a 21-day course of nimodipine (n = 164) compared with patients who received a 14-day course of nimodipine (n = 35) during a national drug shortage.6 The severity of bleed was similar between groups based on Hunt and Hess score as well as Fisher grade. In this study, a shortened duration of nimodipine was not associated with worse neurological outcome at hospital discharge as measured by the modified Rankin Scale (mRS). There were also no differences observed between the groups in hypotension-related dosage changes, hospital length of stay, or mortality rates.
Sokolowski et al evaluated an abbreviated nimodipine course in a single center retrospective study comparing the outcomes of 195 patients receiving nimodipine therapy for ≤ 14 days, 15-20 days, or ≥ 21 days.7 Nimodipine courses ≤ 14 days were attributed to a discontinuation of nimodipine therapy at discharge and courses > 21 days were attributed to hospital length of stays exceeding a 21-day duration. Good functional outcome at follow-up, defined by mRS 0-2, was the primary objective evaluated in this study. Secondary objectives included mRS at discharge and follow-up, discharge disposition, and readmission for stroke or vasospasm. Good functional outcome in the ≤ 14 day and 15–20-day groups was not lower than in the ≥ 21-day group. These findings persisted when the authors adjusted for differences in baseline characteristics suggesting a shorter course of nimodipine therapy may be efficacious for patients with aneurysmal SAH.
In summary, there is a paucity of literature evaluating abbreviated courses of nimodipine therapy. Available literature indicates that a shortened nimodipine duration does not lead to adverse clinical consequences. However, inconsistencies in disease severity, small sample sizes, and the lack of reproducible methods diminish the broad acceptance of shortened nimodipine courses. In addition, drug shortages, limited outpatient availability, and the out-of-pocket cost of nimodipine therapy may warrant further research of a shorter course option. Quantifying the frequency and outcomes of shortened nimodipine courses, capturing outpatient compliance rates, and determining cost-effectiveness are essential steps towards establishing the optimal length of nimodipine therapy.
- Allen GS, Ahn HS, Preziosi TJ, Battye R, Boone SC, Boone SC, et al. Cerebral arterial spasm--a controlled trial of nimodipine in patients with subarachnoid hemorrhage. N Engl J Med. 1983 Mar 17;308(11):619-24. PMID: 6338383.
- Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989 Mar 11;298(6674):636-42. PMID: 2496789Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012 Jun;43(6):1711-37. PMID: 22556195.
- Chen CJ, Turnage C, Sokolowski JD, Kumar JS, Kalani MY, Park MS. Dangers of outpatient nimodipine use after spontaneous subarachnoid hemorrhage in accordance with the Comprehensive Stroke Center guidelines. J Clin Neurosci. 2018 Jun;52:151-152. Apr 11. PMID: 29656002.
- Toyota BD. The efficacy of an abbreviated course of nimodipine in patients with good-grade aneurysmal subarachnoid hemorrhage. J Neurosurg. 1999 Feb;90(2):203-6. PMID: 9950489.
- Cho S, Bales J, Tran TK, Korab G, Khandelwal N, Joffe AM. Effects of 14 Versus 21 Days of Nimodipine Therapy on Neurological Outcomes in Aneurysmal Subarachnoid Hemorrhage Patients. Ann Pharmacother. 2016 Sep;50(9):718-24. PMID: 27273676.
- Sokolowski JD, Chen CJ, Soldozy S, Mastorakos P, Burke RM, Nguyen JM, et al. Nimodipine after aneurysmal subarachnoid hemorrhage: Fourteen-day course for patients that meet criteria for early hospital discharge. Clin Neurol Neurosurg. 2021 Jan;200:106299. PMID: 33092929.