Treatment with a combination of three low-dose antihypertensive agents in a single pill in addition to standard care was associated with a lower incidence of recurrent stroke and major cardiovascular events, and improvements in blood pressure (BP), compared with placebo, among patients with a history of an intracerebral hemorrhage, according to results of the TRIDENT trial published April 23 in the NEJM.

In the double-blind trial, the Trident Research Group randomized 1,670 clinically stable patients (mean age, 58 years; 34% women; 73% Asian) with a history of spontaneous intracerebral hemorrhage to either a once-daily pill containing three antihypertensive agents at low doses (telmisartan 20 mg, amlodipine 2.5 mg and indapamide 1.25 mg) (n=833) or matching placebo (n=837) following a two-week active run-in phase. Randomization took place a median of 54 days after the index intracerebral hemorrhage. While patients were enrolled across 57 sites in 10 countries, 67% of participants resided in Sri Lanka.

Results showed that at a median follow-up of 2.5 years, the primary endpoint of recurrent stroke occurred in 38 patients (4.6%) in the treatment arm vs. 62 (7.4%) in the placebo arm (hazard ratio [HR], 0.61; p=0.02), largely driven by prevention of recurrent intracerebral hemorrhage (1.8% vs. 4.4%; HR, 0.40).

Incidence of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke or death from cardiovascular causes, was also lower in the treatment group (6.6% vs. 9.8%; HR, 0.67; p=0.04).

The goal of a systolic BP <130 mm Hg at six months was achieved by 50% of patients in the treatment arm vs. 26% in the placebo arm (HR, 3.15; p<0.001) and their mean systolic BP during the entire follow-up was 127 mm Hg and 138 mm Hg, respectively. BP reductions were consistent across subgroups and demographics.

Serious adverse events occurred in 23% vs. 26% of patients in the treatment and placebo arms (HR, 0.90), and discontinuation due to an adverse event occurred in 14% vs. 6%, respectively. The most common event leading to discontinuation was an increase of ≥20% in serum creatine level, occurring in 7% of the treatment arm and 2.5% of the placebo arm; the authors note this could be the result of a hemodynamic response and not long-term progression of kidney disease.

Despite its importance, long-term BP control following intracerebral hemorrhage, "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," write the study's authors. "Combination antihypertensive therapy delivered in a single pill holds considerable promise as a strategy to improve [it]."

Noting the results, "achievement of blood-pressure control in 50% of the patients in the triple-pill group as compared with 26% in the placebo group, while clearly beneficial, leaves one wondering whether the triple-pill approach is enough," write Ayush Batra, MD, and Farzaneh Sorond, MD, PhD, in an accompanying editorial comment. "If a streamlined strategy still leaves half of patients unprotected, we must ask: can we do more to drive up the level of blood-pressure control among survivors of intracerebral hemorrhage?"