Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial: Rationale, design and progress

Abstract

Background: Patients who suffer intracerebral hemorrhage (ICH) are at very high risk of recurrent ICH and other serious cardiovascular events. A single-pill combination (SPC) of blood pressure (BP) lowering drugs offers a potentially powerful but simple strategy to optimize secondary prevention. Objectives: The Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial (TRIDENT) aims to determine the effects of a novel SPC “Triple Pill,” three generic antihypertensive drugs with demonstrated efficacy and complementary mechanisms of action at half standard dose (telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg), with placebo for the prevention of recurrent stroke, cardiovascular events, and cognitive impairment after ICH. Design: An international, double-blind, placebo-controlled, randomized trial in adults with ICH and mild-moderate hypertension (systolic BP: 130–160 mmHg), who are not taking any Triple Pill component drug at greater than half-dose. A total of 1500 randomized patients provide 90% power to detect a hazard ratio of 0.5, over an average follow-up of 3 years, according to a total primary event rate (any stroke) of 12% in the control arm and other assumptions. Secondary outcomes include recurrent ICH, cardiovascular events, and safety. Results: Recruitment started 28 September 2017. Up to 31 October 2021, 821 patients were randomized at 54 active sites in 10 countries. Triple Pill adherence after 30 months is 86%. The required sample size should be achieved by 2024. Conclusion: Low-dose Triple Pill BP lowering could improve long-term outcome from ICH.

Rationale for a New Low-Dose Triple Single Pill Combination for the Treatment of Hypertension

“…Following regulatory approval of GMRx2, additional studies and implementation research will be required to further delineate the role and cost-effectiveness of GMRx2 compared to current usual care modalities in different patient populations and geographies. Further indications will also be explored such as the prevention of stroke in people with intracerebral hemorrhage [46] and the prevention of dementia [52]. A key issue will be reimbursement in HIC markets, availability and affordability.…”

“…TRIDENT is an investigator initiated and conducted, multicenter, international, double-blinded, placebo-controlled, parallel-group, randomized trial designed to determine the efficacy of more intensive BP control with a low-dose SPC (GMRx2 dose 2) strategy in addition to standard of care, on stroke recurrence in patients with a history of acute stroke due to intracerebral hemorrhage [46]. Eligible participants are adults with a history primary intracerebral hemorrhage, SBP of 130-160 mmHg, and no contraindication to the randomization of GMRx2-dose version 2 or placebo in addition to any existing BP lowering regimen.…”

Review of Long-Term Blood Pressure Control After Intracerebral Hemorrhage: Challenges and Opportunities

“…82–85 TRIDENT (The Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial; https://www.clinicaltrials.gov; Unique identifier: NCT02699645) is a multicenter, international RCT evaluating the effectiveness of a novel triple single-pill combination containing telmisartan, amlodipine, and indapamide (versus placebo) on the risk of recurrent stroke in 1500 ICH patients, with results expected in 2024. 86…”

“…[82][83][84][85] TRIDENT (The Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial; https://www.clinicaltrials.gov; Unique identifier: NCT02699645) is a multicenter, international RCT evaluating the effectiveness of a novel triple single-pill combination containing telmisartan, amlodipine, and indapamide (versus placebo) on the risk of recurrent stroke in 1500 ICH patients, with results expected in 2024. 86 Another approach to the management of hypertension is self-monitoring of BP (SMBP), which can improve the awareness of hypertension, identify masked hypertension, and differentiate white coat from true hypertension. 87,88 SMBP is commonly recommended by primary care providers, and is already used by 40% to 50% of hypertensive patients.…”