A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage

Abstract

A neurysmal subarachnoid hemorrhage (SAH) is a significant health care problem with high morbidity and mortality; up to 70% of patients will die or be permanently disabled.33 Prognosis is dependent on a number of factors such as age, presenting neurological status, and development of delayed cerebral ischemia (DCI). 4,6,74 Occurring in 30%-40% of patients, DCI is the most common and potentially treatable contributor to outcome. 6,57,78 Though the mechanisms underlying DCI are multifactorial, the processes considered most responsible are delayed cerebrovascular vasospasm (CVS), cerebrovascular autoregulatory dysfunction, and cortical spreading ischemia. 6,47 Unfortunately, to date few therapies have proven effective for the prevention and treatment of DCI. 4,82 A significant predictor of developing DCI is angiographic CVS of intracranial vessels. 6,7,47 Approximately abbreviatioNs cGMP = cyclic guanosine monophosphate; CVS = cerebrovascular vasospasm; DCI = delayed cerebral ischemia; DSA = digital subtraction angiography; DSMB = Data Safety Monitoring Board; eNOS = endothelial nitric oxide synthase; ICA = internal carotid artery; ICP = intracranial pressure; MAP = mean arterial pressure; MCA = middle cerebral artery; NNICU = Neurology/Neurosurgery ICU; NO = nitric oxide; PDE-V = phosphodiesterase-V; SAH = subarachnoid hemorrhage. obJective Studies show that phosphodiesterase-V (PDE-V) inhibition reduces cerebral vasospasm (CVS) and improves outcomes after experimental subarachnoid hemorrhage (SAH). This study was performed to investigate the safety and effect of sildenafil (an FDA-approved PDE-V inhibitor) on angiographic CVS in SAH patients. methods A 2-phase, prospective, nonrandomized, human trial was implemented. Subarachnoid hemorrhage patients underwent angiography on Day 7 to assess for CVS. Those with CVS were given 10 mg of intravenous sildenafil in the first phase of the study and 30 mg in the second phase. In both, angiography was repeated 30 minutes after infusion. Safety was assessed by monitoring neurological examination findings and vital signs and for the development of adverse reactions. For angiographic assessment, in a blinded fashion, pre- and post-sildenafil images were graded as "improvement" or "no improvement" in CVS. Unblinded measurements were made between pre- and post-sildenafil angiograms. results Twelve patients received sildenafil; 5 patients received 10 mg and 7 received 30 mg. There were no adverse reactions. There was no adverse effect on heart rate or intracranial pressure. Sildenafil resulted in a transient decline in mean arterial pressure, an average of 17% with a return to baseline in an average of 18 minutes. Eight patients (67%) were found to have a positive angiographic response to sildenafil, 3 (60%) in the low-dose group and 5 (71%) in the highdose group. The largest degree of vessel dilation was an average of 0.8 mm (range 0-2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%-200%). coNclusioNs The results from this Phas...

Acute Effect of Intravenous Sildenafil on Cerebral Blood Flow in Patients with Vasospasm After Subarachnoid Hemorrhage

“…Sildenafil has shown promise as a treatment for DCI in SAH-animal models, and more recently, we demonstrated sildenafil’s ability to acutely improve CVS in SAH patients [7, 8]. In this study, we analyzed the effects of intravenous sildenafil on CBF and found that despite inducing a significant acute reduction in MAP, global and regional CBF remained unchanged.…”

“…On the day following DSA (when subjects received sildenafil as previously described) [8], patients underwent PET imaging. Two PET measurements of CBF (using injection of ${\mathrm{H}}_2^{15}\mathrm{normalO}$, as described in detail elsewhere [9]) were made to obtain stable baseline followed by infusion of 30-mg of sildenafil over 30-min.…”

“…Sildenafil, a PDE-V inhibitor, has been shown in preclinical SAH models to not only attenuate CVS but also reduce neuronal cell death, and improve neurological outcomes [5–7]. We recently published evidence that sildenafil can ameliorate angiographic CVS after SAH in humans [8]. In this exploratory proof-of-principle study, we tested the acute effects of sildenafil on CBF in SAH patients at-risk for DCI.…”

Letter to the Editor: Sildenafil for cerebral vasospasm: is the proof of the pudding in the eating?

“…2 Washington et al cited this study. 4 We observed sustained reversal of CVS in 11.1% (8/72) and transient reversal in 5.5% (4/72) of patients. We did not analyze the clinical outcome and angiographic evaluation of vasospasm; our study was a safety, efficacy, and feasibility study of sildenafil in humans with postSAH vasospasm.…”

“…3 The "rigorous" methodology by Washington et al only serves to confirm the existing PoC and does not in itself become a concept. 4 We congratulate the team for evaluating the role and safety of intravenous sildenafil in patients with SAH induced CVS. We agree that transcranial Doppler flow velocities are a subjective parameter.…”