TRIDENT
Three Low-Dose Antihypertensive Agents in a Single Pill after Intracerebral Hemorrhage
Clinical Question
Among patients with prior intracerebral hemorrhage, does a single pill combining three low-dose antihypertensive agents reduce recurrent stroke compared with placebo, when added to standard care?
Study Overview
Objective
To determine whether a single pill combining three low-dose antihypertensive agents, added to standard care, lowers blood pressure and reduces recurrent stroke risk in patients with prior intracerebral hemorrhage.
Study Summary
- Recurrent stroke occurred in 4.6% (triple pill) vs 7.4% (placebo); HR 0.61 (95% CI 0.41–0.92), P=0.02
- Mean systolic BP during follow-up: 127 vs 138 mm Hg (between-group difference 9 mm Hg)
- Major cardiovascular events: 6.6% vs 9.8% (P=0.04)
- Serious adverse events: 23.2% vs 26.0%; early discontinuation due to adverse events: 13.6% vs 6.0% (most commonly ≥20% rise in serum creatinine)
Intervention
Once-daily single pill containing telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg, in addition to standard antihypertensive care.
Patients per Arm
Triple pill: 833; Placebo: 837
Bottom Line
In patients with a history of intracerebral hemorrhage and SBP 130–160 mm Hg, adding a once-daily low-dose triple pill (telmisartan 20 mg + amlodipine 2.5 mg + indapamide 1.25 mg) to standard care lowered SBP by ~9 mm Hg and reduced recurrent stroke by ~39% (HR 0.61) and major cardiovascular events over 2.5 years, with an increase in early treatment discontinuation, most commonly due to a ≥20% rise in serum creatinine.
Major Points
- Triple pill reduced recurrent stroke from 7.4% to 4.6% over a median 2.5-year follow-up (HR 0.61; 95% CI 0.41–0.92; P=0.02).
- Mean follow-up SBP was 127 mm Hg with the triple pill vs 138 mm Hg with placebo (between-group difference 9 mm Hg, 95% CI 7–10).
- Major cardiovascular events (nonfatal MI, nonfatal stroke, or CV death) were lower with the triple pill: 6.6% vs 9.8% (HR 0.67, 95% CI 0.47–0.94; P=0.04).
- Serious adverse events were similar (193 [23.2%] vs 218 [26.0%]; RR 0.90, 95% CI 0.74–1.09), but early discontinuation due to adverse events was more frequent with the triple pill (113 [13.6%] vs 50 [6.0%]), driven mainly by protocol-required discontinuation for a ≥20% rise in serum creatinine (7.1% vs 2.5%; 59 vs 21 patients).
- BP differences attenuated over time as concomitant antihypertensive use increased in the placebo group.
- Trial population was predominantly Asian (72.6%), with two-thirds residing in Sri Lanka.
Design
Study Type: Multinational, double-blind, randomized, placebo-controlled trial
Randomization: 1
Blinding: Double-blind (with single-blind active run-in phase)
Allocation: 1:1 centralized randomization, stratified by country, age, and baseline systolic blood pressure
Enrollment Period: September 28, 2017 to November 30, 2024
Follow-up Duration: Median 2.5 years (IQR 1.6–4.4); planned up to 72 months
Centers: 61
Countries: Australia, Brazil, Georgia, Malaysia, Netherlands, Nigeria, Singapore, Sri Lanka, Switzerland, Taiwan, United Kingdom, Vietnam
Sample Size: 1670
Analyzed: 1670
Analysis: Intention-to-treat; cause-specific Cox proportional-hazards model with stratification factors as fixed covariates; sensitivity analyses with Fine and Gray competing-risks model and restricted mean survival time; Holm–Šídák correction for key secondary outcomes
Power Calculation: Original target 3782 patients (230 events) for HR 0.65; revised in early 2020 to 1500 patients to provide 90% power to detect HR 0.50 with 100 primary events over mean 3-year follow-up, accounting for 5% loss to follow-up and 10% crossover
Registration: ClinicalTrials.gov NCT02699645; ANZCTR ACTRN12616000327482
Inclusion Criteria
- Adults ≥18 years of age
- History of spontaneous (nontraumatic) intracerebral hemorrhage
- Clinically stable condition
- Systolic blood pressure 130–160 mm Hg while seated and at rest (on any background BP-lowering therapy)
- No contraindication to any individual component of the triple pill
- Tolerated triple pill during 2-week active run-in with ≥80% adherence and acceptable side-effect profile
Exclusion Criteria
- Taking an ACE inhibitor that could not be replaced with a suitable alternative
- Unable to complete trial procedures
- Abnormal renal function tests, abnormal liver function tests, or both
- Increase of ≥20% in serum creatinine at end of run-in (or during follow-up) compared with screening
- Withdrawal of consent or investigator decision
- Unacceptable side-effect profile or poor adherence during run-in
Arms
| Field | Triple Pill | Control |
|---|---|---|
| N | 833 | 837 |
| Intervention | Once-daily single pill: telmisartan 20 mg + amlodipine 2.5 mg + indapamide 1.25 mg, in addition to standard care | Matching placebo once daily, in addition to standard care (with options for additional concomitant antihypertensives to achieve SBP <130 or <140 mm Hg target) |
| Duration | Up to 72 months (median follow-up 2.5 years) | Up to 72 months (median follow-up 2.5 years) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| First recurrent stroke (time-to-event analysis) | Primary | 62/837 (7.4%) | 38/833 (4.6%) | 0.61 | 0.02 |
| Mean systolic blood pressure during follow-up | Secondary | 138 mm Hg | 127 mm Hg | Between-group difference 9 mm Hg | |
| Mean diastolic blood pressure during follow-up | Secondary | 86 mm Hg | 82 mm Hg | ~4 mm Hg lower with triple pill | |
| Blood-pressure control (SBP <130 mm Hg) at 6 months | Secondary | 221/837 (26.4%) | 416/833 (49.9%) | OR 3.15 | <0.001 |
| Major cardiovascular events (nonfatal MI, nonfatal stroke, or death from CV causes) | Secondary | 82/837 (9.8%) | 55/833 (6.6%) | HR 0.67; absolute reduction ~3.2 percentage points | 0.04 |
| Death from cardiovascular causes | Secondary | 25/837 (3.0%) | 17/833 (2.0%) | HR 0.67 | 0.21 |
| Any adverse event of special interest by 6 weeks (hypotension, syncope, headache, hyponatremia, hyperkalemia, injurious falls, acute kidney injury) | Safety | 55/837 (6.6%) | 56/833 (6.7%) | ||
| Any serious adverse event | Safety | 218/837 (26.0%) | 193/833 (23.2%) | RR 0.90 | |
| Any adverse event leading to discontinuation of triple pill or placebo | Safety | 50/837 (6.0%) | 113/833 (13.6%) | ||
| Protocol-required discontinuation for ≥20% rise in serum creatinine (subset of discontinuations above) | Safety | 21/837 (2.5%) | 59/833 (7.1%) | ||
| Discontinuation due to hypotension | Safety | 0.6% | 3.0% | ||
| Adverse events of special interest tracked | Adverse | Hypotension, syncope, headache, hyponatremia, hyperkalemia, injurious falls, and acute kidney injury (defined per standard definitions) | |||
| Run-in exclusions due to ≥20% creatinine rise | Adverse | 147/536 (27.4%) of patients excluded during run-in; 68 (12.7%) had ≥30% rise | |||
Subgroup Analysis
Heterogeneity of treatment effect for the primary outcome and BP control was prespecified across 10 subgroups; analysis stratified by race or ethnic group was not possible due to small numbers in some groups.
Criticisms
- Sample size was reduced from 3782 to 1500 in 2020 due to recruitment challenges, limiting power for some analyses.
- Population was predominantly Asian (72.6%), with two-thirds residing in Sri Lanka, which may limit generalizability to other populations.
- Active single-blind run-in phase excluded patients who were intolerant or non-adherent (24.3% did not proceed to randomization), potentially enriching for tolerant patients and underestimating real-world discontinuation rates.
- Higher early discontinuation in the triple-pill group (13.6% vs 6.0%) driven by serum creatinine rises raises concerns about renal safety in broader use.
- Between-group BP differences attenuated over time as concomitant antihypertensives were added in the placebo group, which may have diluted the effect estimate.
- Modest violation of the proportional-hazards assumption noted, though sensitivity analyses were consistent.
- Subgroup analyses by race/ethnicity not feasible due to small numbers.
Funding
National Health and Medical Research Council of Australia and the Brazilian Ministry of Health (Programa de Apoio ao Desenvolvimento Institucional do Sistema Unico de Saúde, Hospital Moinhos de Vento). George Medicines provided the GMRx2 formulation of the triple pill and matching placebo.
Based on: TRIDENT (New England Journal of Medicine, 2026)
Authors: The TRIDENT Research Group (Craig S. Anderson, Lili Song, John Chalmers, ..., et al.)
Citation: N Engl J Med 2026;394:1571-82
Content summarized and formatted by NeuroTrials.ai.