Monday, April 29, 2013

Nimodipine Shortage: What About Nicardipine


Drug shortages continue to wreak havoc on health care in US hospitals.  It seems every day there is yet another drug, more critical to medicine than the last, that’s unavailable due to shortages. Over the past few weeks, nimodipine has been going, going, gone.  Now reaching for alternatives, in this case, is proving difficult as a result of limited data on alternatives leaving many in a troubling situation.  Nicardipine, diltiazem, magnesium and other investigational agents are now being considered.  This discussion implies other treatment modalities are consistent with normal practices (ie, surgical intervention, triple-H therapy).

It’s important to consider the therapeutic goals of these treatments: reducing the occurrence of cerebral vasospasm after subarachnoid hemorrhage.  Though nimodipine has not conclusively been shown to prevent vasospasm, it has demonstrated reduction in cerebral ischemia and reduction in the incidence of poor neurological outcome at 3 months.1 Thus, when reviewing the data supporting these other treatments; cerebral vasospasm is essentially a surrogate marker for secondary cerebral ischemia and poor neurological outcomes.

Nicardipine would seem logical as an alternative to nimodipine. From the same class of CCB, similar pharmacokinetics and the availability of an IV dosage form in the US.  However, the clinical, randomized data has not shown an improvement in neurological outcome in SAH patients. In a randomized-placebo controlled trial conducted in the early 1990’s, nicardipine reduced the incidence of symptomatic vasospasm vs placebo.2 At three months, there was no difference in GOS and NIHSS.  While this study didn’t show an overall benefit for nicardipine, it is important to note that the study was stopped early and therefore underpowered, because nimodipine became commercially available in the USA during enrollment. The resulting power of the study was not the original 0.9, but 0.7. In addition, fewer patients in the nicardipine arm received adjuvant therapy for symptomatic vasospasm vs placebo, potentially reflecting under-treatment of those patients.  What I walk away with from this study is that nicardipine 1) does not worsen outcomes vs placebo and 2) has not been adequately studied to say there is no benefit. At worse, it is certainly an option if nimodipine is not available. A follow up study was published, but only compared high vs low dose nicardipine, with no placebo (or nimodipine) arm.3

It’s been postulated that nimodipine may have some other, yet to be identified, effect other than its calcium channel blockade.4 This could be an explanation why nicardipine has not shown a similar benefit.  A newer CCB of the same class, clevidipine, has not been studied in the setting of SAH, and it is not know whether it would have outcomes resembling nimodipine, or nicardipine; certainly an area for future study.

After SAH, there are multiple pathophysiologic events that lead to cerebral vasospasm. With the old clich√©, that ‘the exact mechanism is poorly understood,’ it seems that vasospasm results from depletion of nitric oxide, or the existence of extravasated oxyhemoglobin disrupting vascular endothelium-smooth muscle communication causing the production of endothelin-1 as well as a myriad of inflammatory cytokines.4  To me, it would seem that rather than address each pathophysiological derangement individually (statins, ET-1 antagonists, methylene blue??); there might be more appropriate ‘global’ therapies that may play a role. 

Ultimately, there is no good answer to the nimodipine shortage with our current understanding and existing data.  I can’t help but consider the situation we are in now with nimodipine and what is to come with other medications with unique actions and therapeutic niches.  Why can’t there be an IV acetaminophen shortage?

Reference:
  1. Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P, et al.: Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid hemorrhage: British aneurysm nimodipine trial. BMJ 1989, 298:636-642
  2. Haley EC Jr, Kassell NF, Torner JC, Truskowski LL, Germanson TP. A randomized trial of two doses of nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg. 1994 May;80(5):788-96
  3. Haley EC Jr, Kassell NF, Torner JC. A randomized controlled trial of high-dose intravenous nicardipine in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg. 1993 Apr;78(4):537-47
  4. Siasios I, Kapsalaki EZ, Fountas KN. Cerebral Vasospasm Pharmacological Treatment: An Update. Neurology Research International;13: 1-20