Triple Therapy: A Safe, Cost-Effective Regimen of Heparin, Aspirin and Clopidogrel for Managing Intracranial Vessel Occlusions in Patients With Acute Ischemic Stroke Who Are Ineligible for Intravenous Thrombolytics and Endovascular Thrombectomy

BACKGROUND: Endovascular thrombectomy (EVT) has transformed the management of acute ischemic stroke, but remains inaccessible to many patients due to anatomic, clinical, or logistical limitations. Treatment strategies for patients with intracranial occlusions who are ineligible for intravenous thrombolysis and EVT remain undefined. We evaluated the safety of short-term triple therapy (TT; heparin, aspirin, and clopidogrel) in this unique population. METHODS: This retrospective single-center hypothesis-generating study included patients who presented to a comprehensive stroke center between July 2019 and December 2024, aged 18 to 90 years, with an acute onset of symptoms within 24 hours, had radiologically confirmed intracranial occlusion on computed tomography angiography or magnetic resonance angiography, a National Institutes of Health Stroke Scale score ≤10, and documented ineligibility for intravenous thrombolysis. Comparisons were made between patients treated with TT (heparin, aspirin, and clopidogrel for a predefined period of 48–72 hours) and those treated with EVT, which served as intrinsic controls. The prespecified primary outcomes were hemorrhagic complications (symptomatic intracranial hemorrhage, any intracranial hemorrhage, extracranial hemorrhage), and 30-day mortality. Secondary outcomes included recanalization, change in National Institutes of Health Stroke Scale, length of stay in the intensive care unit, length of hospital stay, and modified Rankin Scale at discharge and at 90 days. RESULTS: Forty-seven patients with consecutive acute ischemic stroke who met the above criteria were analyzed. The median age was 63 years; 43% were female; 25 received TT and 22 underwent EVT. A critical methodological disparity was noted: the TT group presented with a significantly lower mean National Institutes of Health Stroke Scale score (2.44±2.79) compared with the EVT group (6.59±2.77; P <0.001). No symptomatic hemorrhages occurred with TT, compared with 2 (9.1%) with EVT ( P =0.20). Rates of any ICH were low (8% TT versus 27.3% EVT; P =0.11). Any extracranial hemorrhages were low (4% TT versus 4.5% EVT; P =1.00), and there were no reports of mortality in either group within 30 days. EVT achieved significantly higher complete recanalization rates (defined as TICI 2c or 3) at 77.3% compared with recanalization on follow-up imaging in the TT group (28%; P <0.001). Despite this significant radiological difference, clinical efficacy outcomes, including mean change in National Institutes of Health Stroke Scale at 72 hours (TT, 0.20±4.22 versus EVT, 0.29±8.85; P =0.98) and mean modified Rankin Scale score at discharge (TT, 1.20±1.22 versus EVT, 2.19±1.97; P =0.06), were statistically comparable. There was a high rate of patients lost to follow-up, with modified Rankin Scale score at 90 days available for only 6 of the 25 TT patients and 15 of the 22 patients with EVT, thus making this data statistically not comparable. CONCLUSIONS: Short-term TT demonstrated low rates of hemorrhage, with zero symptomatic intracranial hemorrhages, and may represent a safe, cost-effective option for managing select patients with ischemic stroke with intracranial occlusions who are ineligible for intravenous thrombolysis or EVT. However, the observed clinical outcomes may be confounded by the discrepancy between the 2 populations’ baseline stroke severity. Further prospective studies are necessary to validate the role of TT and optimize its integration into clinical practice.