BARCELONA, Spain — A single pill that incorporates low doses of three different antihypertensives reduced recurrent stroke by approximately 40% in patients with a history of intracerebral hemorrhage (ICH).
“This is a massive treatment benefit, which shows how dangerous high blood pressure is in ICH patients,” Craig Anderson, MD, The George Institute for Global Health, Sydney, Australia, principal investigator of the TRIDENT trial, told Medscape Medical News.
“Our results show that if we can get blood pressure under really good control, we can prevent patients from having another bleed in the brain.”
The results translate into a number needed to treat of around 36 over 3 years to prevent one recurrent stroke.
“That is approximately one less stroke occurring in every 100 patients treated this way every year, and this is mostly driven by the hemorrhagic stroke reduction,” said the study’s co-investigator, Anthony Rodgers, MD, also from The George Institute for Global Health.“The size of effect can be explained by the strong relationship between blood pressure and stroke risk, especially in ICH patients,” Rodgers added.
The results of the TRIDENT trial were presented on October 22 at the 17th World Stroke Congress (WSC) 2025.
Three Meds, One Pill
Anderson explained that blood pressure control has long been recognized as crucial for secondary stroke prevention, and this is especially true following an ICH.
“But it’s difficult to achieve good blood pressure control in clinical practice. You have to use multiple drugs and up-titrate the dose,” he noted.
Physicians have been cautious, partly because of limited time and fear of overtreatment and because solid evidence was lacking that aggressive blood pressure control helps patients with ICH without causing harm, Anderson added.
The TRIDENT trial evaluated whether tighter blood pressure control below 130 mm Hg could be safely achieved with a single pill combining three low-dose antihypertensives.
The trial used a formulation known as GMRx2, developed by George Medicines, a spin-off social enterprise company from The George Institute for Global Health. The single pill contains low doses of the angiotensin II receptor blocker, telmisartan (20 mg); the calcium blocker, amlodipine (2.5 mg); and the diuretic, indapamide (1.25 mg).
After a 2-week active run-in phase on the triple pill, the TRIDENT trial randomized 1670 patients with a history of ICH and a systolic blood pressure of 130-160 mm Hg either to the triple low-dose pill or to placebo, given once daily in addition to standard of care.
Mean systolic pressure at screening was 143 mm Hg. During follow-up, this value was reduced to 127 mm Hg in the triple combination pill group vs 138 mm Hg in the placebo group, a difference of 9 mm Hg (P < .001).
Minimal Adverse Effects
After an average follow-up of 3 years, the risk for recurrent stroke — the primary outcome — was reduced by 39% (hazard ratio [HR], 0.61; 95% CI, 0.41-0.92; P = .017).
Recurrent ICH rates were reduced by 60% (HR, 0.40; 95% CI, 0.22-0.72; P = .003), and major adverse cardiovascular events — which included death, myocardial infarction, and stroke — were reduced by 33% (HR, 0.67; 95% CI, 0.47-0.94;P = .02).
Anderson said there were minimal adverse effects, with no significant differences in the incidence of falls or syncope between the two groups.
There was an increase in mild-to-moderate signs of impaired renal function with the triple-pill regimen, but Anderson noted that this likely reflects a well-recognized hemodynamic response to intensive blood pressure lowering rather than true kidney injury.
However, he added that monitoring is warranted for managing a decline in the estimated glomerular filtration rate greater than 30%, including assessing fluid balance and considering dose adjustment or temporary treatment cessation.
Anderson noted that renal monitoring is important but easily manageable in routine clinical care. He said the results highlight the need for more aggressive blood pressure control in ICH because current targets are often too conservative to reduce recurrence and improve long-term outcomes.
These findings, he said, mark a potential shift in how clinicians approach blood pressure management in this patient population.
“Our results show that we need to take blood pressure reduction more seriously in ICH patients,” Anderson said.
Need for More Aggressive Blood Pressure Lowering
He noted that routine blood pressure levels are insufficient to prevent recurrent stroke, emphasizing that tighter control is needed to improve long-term survival. The new single-pill strategy, he added, provides clinicians with a practical tool to achieve that goal.
He noted that the study also establishes a new paradigm in stroke care. While previous efforts focused on controlling blood pressure during hospitalization, there is now a growing emphasis on maintaining rigorous blood pressure control after discharge, extending this critical aspect of care into the community.
Rodgers said the findings underscore the growing recognition that achieving effective blood pressure control often requires combining multiple drug classes.
A single-pill combination helps patients reach target pressures faster without relying on the fallible stepwise approach that is still common practice.
The TRIDENT trial was conducted in 12 countries, with the majority of patients recruited in Sri Lanka, with Nigeria and Brazil being the next highest recruiting countries. Other countries enrolling patients included the UK, Australia, and Netherlands.
Both Anderson and Rodgers emphasized that the single triple low-dose combination pill is not limited to low- or middle-income countries. The patients’ clinical characteristics and baseline treatments were comparable to those seen in top centers in North America and Europe.
Anderson noted that options for ICH are limited, so financial differences among patients have little impact on treatment, minimizing confounding.
Rodgers added that numerous trials of low-dose single-pill combinations of three or four antihypertensives have consistently shown superior results than usual care, with benefits evident in both high- and low-income settings.
“This type of combination therapy pretty reliably beats individual drugs and doses, and that’s because everybody gets the benefit straight away, and lots of people don’t get left on suboptimal medications without being up-titrated,” he added.
The Right Thing to Do
Rodgers also addressed concerns about identifying which drug in the combination might be responsible for any adverse effects.
“This doesn’t really bear much scrutiny. Some adverse effects are very characteristic to one type of drug — for example, coughing with an ACE [angiotensin-converting enzyme] inhibitor. Others, like dizziness due to the blood pressure reduction, are caused by all types of drugs. In neither instance do you need separate pills to be able to manage appropriately,” he noted.
The GMRx2 pill is available in three strengths: triple quarter, triple half, and triple standard doses of its three components. TRIDENT tested the triple half-dose version.
Rodgers noted that all intervention group participants received the same dose for simplicity, but this was in addition to usual care. By the end of the trial, control group participants were taking an average of more than two background blood pressure medications each.
Commenting on the TRIDENT trial for Medscape Medical News, Keith Muir, MD, a stroke neurologist at the University of Glasgow, Glasgow, Scotland, said the result confirmed that more aggressive blood pressure reduction in patients with ICH will lead to a significant reduction in recurrent hemorrhage risk and recurrent stroke risk.
“I think there was a very powerful indication from these data to say that this is the right thing to be doing.”
On the use of the single-pill triple combination approach, Muir said this was very much in line with the current move away from using single antihypertensive agents toward a multipronged strategy to lower blood pressure.
“So I think that this is an important result and one that we should be implementing,” he added.
The TRIDENT trial was an investigator-initiated study, led by The George Institute for Global Health and funded by the National Health and Medical Research Council Australia and the Brazilian Ministry of Health, with study medication provided by George Medicines. The George Institute for Global Health has submitted patent applications for low-dose combination products for hypertension, and Rodgers is listed as an inventor. George Medicines Pty Ltd is a subsidiary of George Institute for Global Health, holds a license for these patents, and has received investment to develop these combination therapies. Neither Anderson, Rodgers, nor any other staff at The George Institute for Global Health reported having a financial interest in GMRx2.
