by Simone Salemme
For our June paper of the month we have chosen Anderson CS, Chow CK, Asita de Silva H, et al; The Trident Research Group; Three Low-Dose Antihypertensive Agents in a Single Pill after Intracerebral Hemorrhage. N Engl J Med 2026;394:1571-1582, doi: 10.1056/NEJMoa2515043.
Spontaneous intracerebral haemorrhage (ICH) remains a high-risk condition with limited proven options for secondary prevention. In TRIDENT, investigators tested a pragmatic strategy: adding a single once-daily ‘triple pill’ (telmisartan 20mg, amlodipine 2.5mg, indapamide 1.25mg) to standard antihypertensive care, with the aim of achieving better blood-pressure control and reducing recurrent stroke.
TRIDENT was a multinational, double-blind, randomised, placebo-controlled trial conducted at 61 sites in 12 countries. Adults with prior spontaneous ICH were eligible if clinically stable and with seated systolic blood pressure 130–160 mm Hg at baseline. Importantly, all screened patients entered a two-week active run-in phase on the triple pill (with background therapies continued as indicated) to ensure tolerability and adherence; participants with a ≥20% rise in serum creatinine during run-in/follow-up were excluded per a regulatory requirement. After run-in, eligible participants were randomised 1:1 to continue the triple pill or switch to matching placebo, alongside standard care targeting systolic blood pressure <130 mm Hg or <140 mm Hg per local guidelines.
A total of 1670 patients underwent randomisation (833 triple pill; 837 placebo). Mean age was 57.8 years, 33.7% were women, and 72.6% were Asian (with 66.7% residing in Sri Lanka). Over a median follow-up of 2.5 years, the primary outcome—first recurrent stroke—occurred in 4.6% of the triple-pill group versus 7.4% of the placebo group (hazard ratio 0.61; 95% CI 0.41–0.92; P=0.02). Mean systolic blood pressure during follow-up was 127 mm Hg with the triple pill versus 138 mm Hg with placebo, corresponding to an estimated between-group difference of 9 mm Hg. At six months, systolic blood pressure <130 mm Hg was achieved in 49.9% versus 26.4% (odds ratio 3.15; 95% CI 2.53–3.92; P<0.001). Major cardiovascular events occurred in 6.6% versus 9.8% (hazard ratio 0.67; 95% CI 0.47–0.94; P=0.04). The reduction in recurrent stroke appeared to be driven largely by fewer recurrent intracerebral haemorrhages (1.8% vs 4.4%; hazard ratio 0.40; 95% CI 0.22–0.73).
Serious adverse events were reported in 23.2% of the triple-pill group and 26.0% of the placebo group. Early discontinuation due to an adverse event was more frequent with the triple pill (13.6% vs 6.0%), most commonly related to a ≥20% rise in serum creatinine. In the discussion, the authors report a number needed to treat of 35 to prevent one stroke.
