Cilostazol With Nimodipine to Improve Outcome After Aneurysmal Subarachnoid Hemorrhage

The CASH trial (Cilostazol in Aneurysmal Subarachnoid Hemorrhage) is a multicenter, randomized, double-blind, placebo-controlled Phase III clinical trial investigating whether the addition of cilostazol to standard nimodipine therapy improves long-term neurological outcomes in patients suffering from aneurysmal subarachnoid hemorrhage (aSAH).

Secondary brain injury following aSAH, particularly delayed cerebral ischemia (DCI) and vasospasm, remains a major cause of mortality and long-term disability. Currently, nimodipine is the only drug with proven efficacy in improving neurological outcomes after aSAH. However, emerging data-mostly from studies conducted in Japan-suggest that cilostazol, a selective phosphodiesterase 3 (PDE3) inhibitor with antiplatelet and vasodilatory effects, may further reduce the risk of ischemic complications and disability when added to standard care.

The cilostazol mechanism includes inhibition of platelet aggregation via cAMP enhancement, vasodilation via nitric oxide release, and endothelial protection. Experimental studies also suggest neuroprotective effects such as attenuation of cortical spreading depolarizations and inhibition of vascular smooth muscle cell proliferation.

The trial will enroll 630 adult patients admitted to intensive care units within 96 hours of a confirmed aSAH due to a ruptured aneurysm that has been secured by either surgical clipping or endovascular coiling. Patients will be randomly assigned to receive either cilostazol 100 mg twice daily for 14 days (administered orally or via gastric tube) or placebo, alongside the standard 21-day nimodipine regimen.

The primary endpoint is the neurological outcome at 6 months, assessed by the modified Rankin Scale (mRS). Secondary outcomes include cognitive performance (MoCA score), return to work, independence in daily activities, hospital and ICU stay durations, 28-day mortality, and incidence of DCI, vasospasm, and cerebral infarctions as defined by imaging or clinical criteria.

The study will be conducted over 49 months (42 months of enrollment + 6 months of follow-up), across 9 French centers, with an expected inclusion rate of 1.9 patients per center per month. Two interim analyses are planned. The study is funded by a Programme Hospitalier de Recherche Clinique (PHRC) and monitored by an independent data safety monitoring board (DSMB).

While cilostazol is generally well tolerated, especially in short-term use, potential side effects include headache, palpitations, diarrhea, arrhythmias, bleeding, and allergic reactions. Previous short-term studies suggest an acceptable safety profile in aSAH patients.

If positive, the CASH study may significantly impact clinical guidelines by supporting the inclusion of cilostazol as an adjunct therapy in the management of aneurysmal subarachnoid hemorrhage.

Inclusion criteria

• Adult patients admitted to an ICU with SAH related to a ruptured cerebral aneurysm occurring within the last 96 hours.
• Aneurysm successfully secured by surgical clipping or endovascular coiling
• Consent of the patient or, if not possible, from a proxy (emergency clause).
• Registration in a national health care system

Exclusion criteria

• - Precritical modified Rankin Scale (mRS) > 2
• Nonaneurysmal SAH
• Delayed >96h admission after first symptoms of SAH
• Coma defined by GCS of 3-5 with untreatable aneurysm will be excluded"
• Known allergy to cilostazol
• Pregnancy
• Pre-existing major hepatic, renal, pulmonary or cardiac disease
• Concomitant use of one other anti-platelet and/or anticoagulant agent
• SAH diagnosed on Lumbar puncture with no evidence of blood on CT.
• Tutelage or guardianship