Triple Pill Gets Intracerebral Hemorrhage Survivors Closer to BP Goals

Additional antihypertensive treatment with a three-drug polypill benefitted patients after intracerebral hemorrhage (ICH), the placebo-controlled TRIDENT trial found.

Among ICH survivors already on good background therapy randomized to additional treatment with the GMRx2 polypill — containing telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg — the risk of recurrent stroke was significantly reduced over a median 2.5 years (4.6% vs 7.4% with placebo, HR 0.61, 95% CI 0.41-0.92), according to Craig Anderson, MBBS, PhD, of the George Institute for Global Health, University of New South Wales in Sydney, and colleagues.

The clinical benefit may be attributed to the overall lower average systolic blood pressure (BP) maintained over the course of the study (127 vs 138 mmHg) and better BP control at 6 months in the polypill group (49.9% vs 26.4% achieving systolic BP <130 mmHg, OR 3.15, 95% CI 2.53-3.92), the researchers reported in the New England Journal of Medicine. Results were previously presented at last year’s World Stroke Congress.

The TRIDENT investigators reported that the number of patients who would need to be treated to prevent one stroke was just 35. Of note, recurrent ICH strokes in particular were strongly reduced by polypill therapy (1.8% vs 4.4%, HR 0.40, 95% CI 0.22-0.73).

“TRIDENT is a major advance in showing the enormous benefits of effective BP control after an intracerebral hemorrhage, and a simple and effective strategy in which this can be achieved, with relevance to patients all over the world,” commented the president of the World Stroke Organization, Jeyaraj Pandian, MBBS, of Christian Medical College, Ludhiana, India, in a statement.

“We hope GMRx2 is approved for this indication by regulatory authorities throughout the world, and if so that it is widely used as an effective approach with the potential to improve the outcome for patients affected by intracerebral hemorrhage, and also ischemic stroke, across the globe,” Anderson said in a press release.

Anderson and colleagues noted that BP lowering is the only proven treatment to prevent first and recurrent ICH strokes. They cited prior work showing that each 10-mmHg drop in systolic BP was associated with a reduction of approximately 40% in ICH risk.

“However, the benefits of intensive BP lowering and the preferred approach to treatment are uncertain,” they said. “Although most survivors of stroke are discharged from the hospital with a prescription for medications to lower BP, long-term BP control is generally inadequate owing to poor adherence to treatment, uncertainty surrounding the degree of benefit, varying guideline recommendations, insufficient intensification of treatment when BP remains elevated, and therapeutic inertia.”

BP is thus just as poorly controlled in survivors of ICH as it is in the wider U.S. population — with approximately 50% meeting the target of <140/90 mmHg and under 21% a stricter target of <130/80 mmHg -- according to Ayush Batra, MD, and Farzaneh Sorond, MD, PhD, both of Northwestern University Feinberg School of Medicine in Chicago.

In an accompanying editorial, they suggested that the 50% BP control seen with the polypill in TRIDENT, while an improvement over controls, is still not enough and “leaves us incompletely satisfied with its effect.”

“If a streamlined strategy still leaves half of patients unprotected, we must ask: can we do more to drive up the level of BP control among survivors of ICH? Absolutely — and the path forward is clear. Meaningful BP control after ICH 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,” Batra and Sorond wrote.

“Therapeutic inertia remains our most modifiable (and neglected) barrier. Beyond the primary care office, every healthcare professional, from neurologist to pharmacist, must treat strict BP targets as a nonnegotiable priority for secondary prevention,” the duo urged.

The double-blind TRIDENT trial was conducted from 2017 to 2024 in 12 countries on several continents.

Study candidates had a history of spontaneous ICH and baseline systolic BP 130-160 mmHg who were in clinically stable condition. Patients had to show that they were able to adhere to an initial 2 weeks of the triple pill without adverse effects, only after which they were randomly assigned to continue receiving the triple pill or to receive matching placebo.

This run-in phase had a substantial number of people drop out because of an increase in serum creatinine, local investigator decision, poor adherence, among other reasons, the researchers reported.

Ultimately, investigators randomized 1,670 people (mean age 58 years and 33.7% women). Randomization occurred at a median of 54 days after the index ICH. Two-thirds of the cohort came from Sri Lanka.

A secondary endpoint, major cardiovascular events — a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular causes — also came out lower with the triple pill than with placebo (6.6% vs 9.8%, HR 0.67, 95% CI 0.47-0.94), though the individual components did not show a significant difference between groups.

Serious adverse events occurred in 23.2% and 26.0% of polypill and placebo groups, respectively. Early discontinuation of the trial regimen due to an adverse event occurred in 13.6% and 6.0%, respectively, and this event was most commonly an increase of 20% or more in serum creatinine.

Study findings may only be applicable to people who could tolerate the run-in period with the GMRx2 pill, the authors stressed.

“The prominent influence of dietary and lifestyle choices on BP, as well as genetic predisposition to medication responsiveness, also cannot be ignored,” added Batra and Sorond. “The predominance of high-salt-diet-associated hypertension in Sri Lanka, where the majority of the trial population resided, limits the broader generalizability of these findings.”