A single pill combining three low-dose blood pressure medications reduced the risk of recurrent stroke by 39% in patients with intracerebral hemorrhage (ICH) published results of the TRIDENT trial show. 

At a median follow-up of 2.5 years, the combination pill was associated with fewer recurrent strokes — 4.6% vs 7.4% with usual care (hazard ratio (HR), 0.61; P = .02) along with substantially better blood pressure control.

“These study results have the potential to mark a real shift in how we manage blood pressure following a stroke. This single-pill triple combination helped patients reach target blood pressure levels,” lead investigator, Craig Anderson, MD, The George Institute for Global Health, Sydney, said in a press release. 

The study which was published April 23 in The New England Journal of Medicine, was first reported at the World Stroke Congress last fall. 

Key Findings 

Currently the only proven treatment to prevent recurrent ICH is effective blood pressure reduction. However, long-term blood-pressure control is generally inadequate.

The TRIDENT study evaluated whether a single pill combining three low-dose antihypertensive agents — telmisartan (20 mg), amlodipine (2.5 mg), and indapamide (1.25 mg) — added to standard care could improve blood pressure control and reduce recurrent stroke risk following ICH.

The trial included 1670 clinically stable patients (mean age, 58 years) with a history of ICH and baseline systolic blood pressure of 130-160 mm Hg. After a 2-week run-in phase during which all patients received the once-daily triple pill, participants were randomized to continue the regimen or switch to matching placebo.

At a median follow-up of 2.5 years, the primary outcome of recurrent stroke occurred in 4.6% of patients in the triple-pill group and 7.4% in the placebo group (HR, 0.61; 95% CI, 0.41-0.92; P = .02). 

Mean systolic blood pressure during follow-up was 127 mm Hg in the triple-pill group and 138 mm Hg in the placebo group. This difference was achieved despite the use of background antihypertensive therapy in a high proportion of patients in both groups. 

The incidence of major cardiovascular events was lower with the triple pill than with placebo (6.6% vs 9.8%; P = .04). Serious adverse events occurred in 23.2% of those in the triple-pill group and 26.0% of those in the placebo group. 

Early discontinuation of the trial regimen due to an adverse event occurred in 13.6% and 6.0%, respectively. The most common adverse event leading to discontinuation was an increase of 20% or more in the serum creatinine level.

The researchers report that the number of patients who would need to be treated to prevent one stroke was 35, which is consistent with previous evidence suggestive of benefits from intensive blood pressure lowering in those with ICH.

The authors noted that most patients were from Sri Lanka, which may limit generalizability. However, blood pressure reductions with the triple pill were consistent across participating countries and demographic groups, and the age, sex, and disease profile of the study population were similar to those of patients with ICH worldwide.

In addition, the mean systolic blood pressure of approximately 140 mm Hg in the placebo group was similar to that seen in ICH patients in the US.

Is It Enough? 

In an accompanying editorial, Ayush Batra, MD, and Farzaneh Sorond, MD, both from Northwestern University, Feinberg School of Medicine, Chicago, note that effective blood pressure control is the cornerstone of post-ICH management, yet remains suboptimal, with fewer than 50% of patients reaching targets below 140/90 mm Hg and only 20.7% achieving levels below 130/80 mm Hg.

While they characterize the triple combination pill approach in TRIDENT as “clearly beneficial,” they note that target blood pressure control of less than 130 mm Hg systolic was still only achieved in 50% of patients in the triple-pill group (vs 26% in the placebo group) at 6 months, which “leaves one wondering whether the triple-pill approach is enough.”

“The clinical message is clear: maintaining a systolic blood pressure of less than 130 mm Hg reduced the risk of recurrent deep intracerebral hemorrhage over the median of 2.5 years in this trial. 

“However, the triple pill failed to shatter the glass ceiling of blood-pressure control (achievement of control in >50% of the treatment group), which leaves us incompletely satisfied with its effect.”

They add that although American Heart Association guidelines support single-pill combinations for hypertension because of improved adherence, faster blood pressure control, and long-term cost-effectiveness, the priority in ICH survivors should be achieving blood pressure control by any means, rather than the use of fixed-dose combinations.

“Meaningful blood-pressure control after intracerebral hemorrhage requires a coordinated, systemwide commitment that integrates team-based care, expanded access to medication, and real-time monitoring to bridge the gap between clinic visits and daily management,” they wrote

Batra and Sorond conclude that “therapeutic inertia remains one of the most modifiable yet overlooked barriers to care.” All clinicians involved in stroke management — from neurologists to pharmacists — should treat strict blood pressure targets as a priority for secondary prevention. With fewer than half of survivors achieving adequate control, they argue this gap “is not a ceiling but an opportunity we cannot afford to waste,” they conclude. 

The TRIDENT trial was funded by the National Health and Medical Research Council of Australia and the Brazilian Ministry of Health.