Evidence for the use of nimodipine in SAH

In the broad sense, prevention and management of vasospasm were asked about in Question 10 from the first paper of 2007, and again in Question 5 from the first paper of 2013. None of these specifically made nimodipine the focus. It came up as one of the topics of  Question 24 from the second paper of 2017, which asked the candidates to "briefly discuss" various strategies, including discredited approaches like the "Triple H" therapy. The aim of this chapter is to bring together all the evidence for nimodipine so that it is accessible in one place. An ideal starting point for reading about nimodipine and vasospasm in general is Oliver Flower's LITFL article on this topic.

In order to tailor this chapter to CICM SAQ revision, it has been organised into a familiar framework, as if to answer a question like "critically evaluate the use of nimodipine in cerebral vasospasm".

Rationale for the use of nimodipine

• Nimodipine is a dihydropyridine calcium channel blocker which is thought to be selective for cerebral vessels. It was developed in the early 1980s, with a lot of enthusiasm about its selectivity. In vivo, it was found to dilate cerebral vessels predominantly, with a much less pronounced effect on the peripheral vessels.
• Cerebral vasospasm of some clinical significance may occur in up to 40% of SAH patients, and can result in significant morbidity. It is difficult to detect clinicaly, and once it is confirmed it may already have done some damage. Ergo, one should make some attempt to prevent vasospasm.

Methods of using nimodipine for prevention of vasospasm

• 60mg po q4h
• Treatment is commenced within 96 hours of the bleed
• Treatment is continued for 21 days
• This recommendation comes from the BRANT trial (1989).

Arguments for the use of nimodipine

• Multiple RCTs and meta-analysis reviews all confirm an improvement in functional outcome for the nimodipine-treated group.
• There is also probably a trend towards improved mortality.
• Even patients with severe (Hunt and Hess Grade III and IV) SAH seem to benefit  Petruk et al (1988)
• It is easy to administer (NG or oral route, q4h)
• It is not an expensive drug
• In spite of the potential for hypotension, at routinely used doses it is reasonably safe (in the BRANT trial, only 124 pts on nimodipine had any sort of side effects, vs. 10 among the placebo group)
• In a 1998 meta-analysis (Feigin et al), as well as a 2008 meta-analysis (Mees et al)
  • NNT = 8 (to prevent ischaemic neurodeficit)
  • NNT = 13 (to prevent "poor outcome" in general)
• The 2012 AGA guidelines for management of SAH make a strong recommendation for the routine use of nimodipine, making it the standard of care.

Arguments to caution against wanton abuse of nimodipine

• It does not seem to help patients with Grade V SAH.
• It causes fluctuations of blood pressure, and could cause hypotension
• This results in the increased need for invasive monitoring
• A constant IV nimodipine infusion could be used to ameliorate this effect, but most of the studies have been done on oral or NG nimodipine.
• A 60mg dose is effective, but it is unclear whether a 90mg dose is more effective, or whether a 35mg dose is less effective.
• The main premise that it somehow prevents vasospasm is probably invalid, because most of the studies have failed to demonstrate a significant difference in angiographic vessel diameter. Some other mechanism probably plays a role, and we don't know what that is.

In detail, the evidence in support of routine nimodipine use

Allen et al (1983): multicenter RCT; 125 patients randomised to nimodipine or placebo

• Treatment was started within 96 hours: 60mg of nimodipine orally every 4 hours.
• 8 in 60 placebo patients developed severe deficit or died of vasospasm in the placebo group, compared to 1 in 56 of the nimodipine group.
• CT analysis showed that nimodipine-treated patients whose subarachnoid blood volume increased (i.e. from re-bleeding) did not go on to develop any "extra" vasospasm, suggesting that nimodipine had some sort of a protective effect.
• There were no side-effects from nimodipine.
• However, the selection of patients was very careful The investigators excluded the comatose SAH victims. In order to qualify, you needed to be conscious (or at worst drowsy but well-oriented) and with a normal neurological examination, except for isolated cranial nerve palsies.
• Furthermore, the effect was only seen among the group of patients who had developed neurological symptoms (i.e. the group in whom vasospasm was defined) - when taken as a whole, the population did not demonstrate a treatment effect)

Philippon et al (1986):  RCT; 70 patients randomised to nimodipine or placebo. 

• Treatment was started within 72 hours following the bleed.
• Same outcomes measured as Allen et al; of the treated patients only one developed severe symptomatic vasospasm or died, whereas 10 among the placebo group went that way.
• Weirdly, angiographic evidence of vasospasm was no different in frequency or severity between groups. There was however a reduction in the incidence of "diffuse" vasospasm, which was defined as "three or more arterial sites showing reduction[ in diameter]".
• The study was small, but the difference in mortality and morbidity was large, which means it still had sufficient power.
• Again, the patient selection was a disappointment. The age group was 18-65, and the severity of vasospasm was again mild: in order to qualify, one needed to be a Grade I, II aor II on the Hunt and Hess classifictaion (essentially free from any neurological signs). Comatose patients again missed out.
• Furthermore, the study investigators excluded patients who had hypertension (thus of 170 eligible patients only 81 were enrolled, because of course the SAH patients are all hypertensive).

Petruk et al (1988): multicentre RCT of 188 patients, this time only those with "poor grade SAH"

• Thus study addressed concerns that only "good" patients were being enrolled in nimodipine trials, and that these patients were going to do well anyway, amplifying the treatment effect. The study selected patients of Hunt and Hess Grade III or worse.
• Again, the protocol was to treat within 96 hours, with either oral or NG nimodipine.
• One criticism was a massive number of protocol violations: 32 of the 188 enrolled patients were disqualified in this manner. Only 154 patients qualified for analysis.
• In spite of this, the study demonstrated that there was an outcome benefit: permanent deficit was significantly less likely in the nimodipine group for Grade III and IV patients(6.9% vs 26.8% at 3 months).
• Significantly, Grade V patients did not seem to benefit.
• Of the study group, the majority (124 patients) underwent routine Day 4 angiography. Again, the investigators found that "there was no significant difference in the incidence of moderate or severe diffuse spasm, which was seen in 64.3% of nimodipine-treated patients and 66.2% of placebo-treated patients". They were forced to conclude that the outcome benefit "occurs by a mechanism other than prevention of large-vessel spasm as visualized on angiography", which means that the original justification for the use of nimodipine was actualy a false premise. Who the hell knows what precisely was helping these patients? Perhaps the effect of giving an antihypertensive was somehow protective.

Pickard et al (1989) - the BRANT trial: multicentre RCT of 554 patients

• A "pragmatic" RCT: to be excluded, you had to be late to the party (i.e. beyond 96 hours).
• Again, encouraging findings:
  • Incidence of cerebral infarction was reduced from 33% to 22% ( a 34% reduction)
  • Incidence of "poor outcome" was reduced from 33% to 20% (a 40% reduction)
  • Mortality was essentially unchanged (5% vs 6%)

Many trials were done in the subsequent decade. Rather than eroding his neurons into nubs trying to analyse them all, this author has yielded to the expertise of Feigin et al (1998) who had put together a meta-analysis and systematic review of the then-available evidence. By this stage, 10 trials totalling 2756 patients were available.The salient findings of this meta-analysis were as follows:

• Relative risk reduction for death: 10%
• Relative risk reduction for ischaemia: 33%
• Relative risk reduction for CT-documented stroke: 20%
• NNT to prevent "poor outcome" = 13
• NNT to prevent cerebral ischaemia with neurological deficit = 8
• Again, there was no strong evidence that nimodipine does anything to prevent angiographically detectable vasospasm.

At the time of writing, in late 2015, the most recent meta-analysis is a 2008 Cochrane review by Mees et al. Again, ten years had passed since the last systematic review. This time, sixteen trials totalling 3361 patients were available. To spare the revising candidate trawling through more statistics, it will suffice to say that the abovelisted benefits were redemonstrated.  The authors concluded that though the efficacy of nimodipine "is not beyond all doubt", the relatively high safety of this drug merits a recommendation for its routine use.

In correlation with these findings, the AHA has (in its 2012 guidelines statement) quoted the abovementioned meta-analysis and made a Class I, Level A recommendation that "Oral nimodipine should be administered to all patients with aSAH". In fact, looking through that guidelines statement, this is the strongest recommendation made by the AHA regarding the management of  subarachnoid haemorrhage - even intra-arterial vasodilator therapy merited only a lukewarm Class IIa Level B recommendation. 

In short, there is widespread support for the use of (oral or IV) nimodipine, and it is the standard of care for SAH survivors.