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

Abstract

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: A2-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 high-dose 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 Phase I safety and proof-of-concept trial assessing the use of intravenous sildenafil in patients with CVS show that sildenafil is safe and well tolerated in the setting of SAH. Furthermore, the angiographic data suggest that sildenafil has a positive impact on human CVS.

Keywords: CVS = cerebrovascular vasospasm; DCI = delayed cerebral ischemia; DSA = digital subtraction angiography; DSMB = Data Safety Monitoring Board; 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; aneurysm; cGMP = cyclic guanosine monophosphate; cerebral vasospasm; delayed cerebral ischemia; eNOS = endothelial nitric oxide synthase; subarachnoid hemorrhage; vascular disorders.

Figures

FIG. 1.

Flowchart showing the study protocol with recruitment data. Twenty-four patients were enrolled, with 12 patients completing the study.

FIG. 2.

Timeline for patient enrollment and study completion.

FIG. 3.

A: The anteroposterior DSA image of a left carotid artery injection prior to sildenafil. B: The anteroposterior DSA image of the same left carotid artery following sildenafil infusion. C: A zoomed image of the pre-sildenafil angiogram, showing severe CVS of the left A1 and A2 segments of the anterior cerebral arteries (white arrows). D: Demonstrates areas of dilation in the proximal left A1(dotted arrow) and A2(solid arrow) segments of the anterior cerebral artery post-sildenafil.

FIG. 4.

A: The lateral DSA image of a left carotid artery injection prior to sildenafil. B: Lateral DSA image of the same left carotid artery following sildenafil infusion. C: A zoomed image of the pre-sildenafil angiogram showing a focal area of stenosis in the superior M2 division of the middle cerebral artery (arrow). D: Improvement in the vasospasm is seen in the M2 segment of the MCA following sildenafil infusion. The focal area of stenosis has resolved (arrow).