A randomised trial to assess the efficacy of add on therapy with aspirin or clopidogrel to the standard medical therapy alone in patients with tubercular meningitis: ACT TBM.

Background: Benefit of antiplatelet therapy for stroke prevention or treatment among patients of Tubercular meningitis (TBM) is uncertain. We hypothesised that add-on therapy with aspirin or clopidogrel to standard treatment will be safe and effective in reducing clinical stroke and/or cerebral infarction in patients with TBM. Methods: This was a randomised, open-label, superiority trial with blinded outcome assessment. Patients with suspected TBM were randomised to receive either add-on oral aspirin 75 mg, clopidogrel 75 mg along with ATT (anti-tubercular treatment) or only ATT. Clinical follow up, MRI brain, and MR Angiogram were performed at baseline, one and three months from randomisation. Primary outcome was reduction in occurrence of clinical stroke and/or imaging-based cerebral infarction at one and three months. Safety outcome was the occurrence of major or minor bleeding. Key secondary outcomes included mortality at one and three months and modified Rankin scale (mRS) at three months. Findings: A total of 237 patients with TBM were randomised (77 in the aspirin group, 77 in the clopidogrel group, and 83 in the standard treatment group). At one month, clinical stroke outcome was available for 66 (85.7%), 72 (93.5%) and 69 (83.1%) patients and MRI brain was available for 61 (79.2%), 65 (84.4%) and 62 (74.7%) patients, respectively. Clinical stroke was observed in one (1.5%) in aspirin group, none (0.0%) in clopidogrel group, and three (4.3%) patients in standard group (across group comparison p = 0.2); imaging-based cerebral infarction was observed in six (9.8%), eight (12.3%), and seven (11.3%) patients, respectively (across group comparison p = 0.9). At three months, clinical stroke outcome in aspirin, clopidogrel and standard groups was available for 60 (77.9%), 63 (81.8%) and 59 (71.1%) patients and MRI brain was available for 57 (74.0%), 60 (77.9%) and 55 (66.3%) patients, respectively. Clinical stroke was observed in two (3.3%), one (1.6%), and two (3.4%) patients (across group comparison p = 0.8) and imaging-based infarction was observed in two (3.5%), three (5.0%), and two (3.6%) patients, respectively (across group comparison p = 0.9). Using intention-to-treat approach following a complete cases analysis method, primary outcome at one month was observed in six (9.1%) in aspirin group, eight (11.1%) in clopidogrel group, and ten (14.3%) in standard group (across group comparison p = 0.6, aspiring vs. standard: adjusted relative risk [aRR] 0.56 [95% CI 0.21-1.47], clopidogrel vs. standard: aRR 0.72 [95% CI 0.30-1.67]) and four (6.7%), four (6.1%), and three (5.1%) respectively at three months (across group comparison p = 0.9, aspirin vs. standard: aRR 0.98 [95% CI 0.20-4.82], clopidogrel vs. standard: aRR 0.43 [95% CI 0.06-2.87]). Major bleeding was observed in two patients: one each in clopidogrel (1.3%) and standard group (1.3%). Minor bleeding was observed in five patients: four (5.3%) in clopidogrel group, and one (1.2%) in the standard group. Eleven (15.1%), 8 (10.7%), and 12 (15.4%) died at three months in aspirin, clopidogrel and standard groups respectively. There was no difference in bleeding, mortality, and mRS among the groups. Interpretation: Among patients with TBM, no difference was observed by an add-on therapy of antiplatelets to the standard care compared to standard care alone on clinical stroke, imaging-based cerebral infarction, or mortality. Funding: Indian Council of Medical Research (ICMR), New Delhi, India.