Triple low-dose antihypertensive pill reduces recurrent stroke risk after intracerebral hemorrhage

In the TRIDENT trial, treatment with three low-dose antihypertensive agents in a single pill, in addition to standard care, reduced the risk of recurrent stroke compared with placebo in patients with a history of intracerebral hemorrhage.

This summary is based on the publication of The Trident Research Group, Anderson CS, Chow CK et al. - Three Low-Dose Antihypertensive Agents in a Single Pill after Intracerebral Hemorrhage. N Engl J Med. 2026 Apr 23;394(16):1571-1582. doi: 10.1056/NEJMoa2515043.

Introduction and methods

Background

Blood-pressure reduction is the only proven strategy to prevent first and recurrent intracerebral hemorrhage [1-2], but long-term blood-pressure control is often inadequate due to poor adherence and therapeutic inertia [3-8].

Aim of the study

The aim of the study was to evaluate the efficacy and safety of a single pill combining three low-dose antihypertensive agents versus placebo, in addition to standard care, in patients with a history of intracerebral hemorrhage.

Methods

The TRIDENT (Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial) trial was a multinational, double-blind, randomized, placebo-controlled trial involving 1670 patients with a history of spontaneous (nontraumatic) intracerebral hemorrhage and SBP 130-160 mm Hg. After a 2-week run-in phase with triple therapy (20 mg telmisartan, 2.5 mg amlodipine, and 1.25 mg indapamide; triple pill), patients were randomized in a 1:1 ratio to continue the triple pill or receive placebo, in addition to standard care. Median follow-up was 2.5 years (IQR: 1.6 to 4.4).

Outcomes

The primary outcome was the first recurrent stroke. Secondary outcomes included blood-pressure control at 6 months, major cardiovascular events (a composite of nonfatal MI, nonfatal stroke or death from cardiovascular causes), death from cardiovascular causes, and safety.

Main results

Efficacy outcomes

• Recurrent stroke occurred in 4.6% of the patients in the triple-pill group and 7.4% of the patients in the placebo group (HR: 0.61; 95%CI: 0.41-0.92; P=0.02).
• Mean SBP during follow-up was 127 mmHg in the triple-pill group versus 138 mmHg in the placebo group (modeled between-group difference: 9 mmHg; 95%CI; 7-10).
• Blood-pressure control (SBP <130 mm Hg) at 6 months was achieved in 49.9% of the patients in the triple-pill group and 26.4% of the patients in the placebo group (OR: 3.15; 95%CI: 2.53-3.92; P<0.001).
• The risk of major cardiovascular events was lower in the triple-pill group compared with the placebo group (6.6% vs. 9.8%; HR: 0.67; 95%CI: 0.47-0.94; P=0.04).
• There was no difference in the risk of death from cardiovascular causes between the two groups (HR: 0.67; 95%CI: 0.36-1.25; P=0.21).

Safety outcomes

• The incidence of serious adverse events was 23.2% in the triple-pill group and 26.0% in the placebo group.
• The incidence of any adverse event leading to treatment discontinuation was higher in the triple-pill group compared with the placebo group (13.6% vs. 6.0%).

Conclusion

In TRIDENT among patients with intracerebral hemorrhage, a fixed-dose combination of three low-dose antihypertensive drugs, in addition to standard care, reduced the risk of recurrent stroke and major cardiovascular events compared with placebo.

Find this article online at N Engl J Med.

References

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