Until final results come in you'll have to demand your doctor provide a protocol that prevents that next stroke. This also assumes that your doctor is up-to-date on research and can create interventions from research.
Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial: Rationale, design and progress
Craig S Andersonhttps://orcid.org/0000-0002-7248-48631,2,3,4, Anthony Rodgers1, H Asita de Silva5,6, Sheila Ouriques Martins7,8, Catharina JM Klijn9, Bimsara Senanayake10, Ruth Freed1, Laurent Billothttps://orcid.org/0000-0002-4975-97931,11,12, Hisatomi Arima13, Nguyen Huy Thang14, Wan Asyraf Wan Zaidi15, Tinatin Kherkheulidze16, Kolawole Wahab17, Urs Fisherhttps://orcid.org/0000-0003-0521-405118,19, Tsong-Hai Lee20,21, Christopher Chen22, Octavio Pontes-Netohttps://orcid.org/0000-0003-0317-843X23, Thompson Robinson24, Jiguang Wang25, Sharon Naismith26, Lili Songhttps://orcid.org/0000-0002-6105-17201,2, Floris H Schreuderhttps://orcid.org/0000-0002-7815-02079, Richard I Lindleyhttps://orcid.org/0000-0002-0104-56791,27, Mark Woodward1,11, Stephen MacMahon1,11, Rustam Al-Shahi Salmanhttps://orcid.org/0000-0002-2108-922228, Clara K Chow1,27, and John Chalmershttps://orcid.org/0000-0002-9931-05801,* TRIDENT Research Group
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.
Keywords
Hypertension, blood pressure lowering, intracerebral hemorrhage, clinical trial, outcomes
1The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
2The George Institute China at Peking University Health Sciences Center, Beijing, China
3Heart Health Research Center, Beijing, China
4Neurology Department, Royal Prince Alfred Hospital, Sydney, NSW, Australia
5Clinical Trials Unit, Department of Pharmacology, Faculty of Medicine, University of Kelaniya, Colombo, Sri Lanka
6Institute of Neurology, National Hospital of Sri Lanka, Colombo, Sri Lanka
7Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
8Neurology Service, Hospital Moinhos de Vento, Porto Alegre, Brazil
9Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
10Neurology Department, National Hospital of Sri Lanka, Colombo, Sri Lanka
11The George Institute for Global Health, School of Public Health, Imperial College London, London, UK
12University of Bordeaux, Bordeaux, France
13Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
14Stroke Unit, 115 Hospital, Ho Chi Minh City, Vietnam
15Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
16Department of Neurology, Tbilisi State Medical University, Tbilisi, GA, USA
17Department of Medicine, University of Ilorin, Ilorin, Nigeria
18Department of Neurology, University Hospital Bern and University of Bern, Bern, Switzerland
19Department of Neurology, University Hospital Basel, Basel, Switzerland
20Stroke Center and Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan, UK
21College of Medicine, Chang Gung University, Taoyuan, UK
22Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
23Department of Neurosciences and Behavioural Sciences, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil
24College of Life Sciences and NIHR Biomedical Research Centre, University of Leicester, Leicester, UK
25Centre for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
26Faculty of Science, Charles Perkins Centre and Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia
27Westmead Applied Research Centre, Faculty of Medicine and Health, University of Sydney, Westmead Hospital, Westmead, NSW, Australia
28Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
Corresponding author(s):
Craig S Anderson, The George Institute for Global Health, University of New South Wales, Sydney, NSW 2050, Australia. Email: canderson@georgeinstitute.org.au
*
Full list of members of the TRIDENT Research Group outlined in Supplemental Appendix
Background and rationale
Intracerebral hemorrhage (ICH) affects several million people worldwide each year,1 but accounts for greater disability-adjusted life years than ischemic stroke due to its poorer prognosis, fewer proven treatments, and very high risk of recurrent ICH, other cardiovascular events, and cognitive impairment/dementia.2 Randomized controlled trials (RCTs) have shown stronger proportional benefits from BP lowering therapy in preventing recurrent ICH than ischemic stroke,3 and for more intensive BP lowering.4 However, clinicians consider intensive BP lowering may cause falls and increase the risk of dementia in older people, concerns reinforced by J-shaped relationships between BP and cardiovascular events seen in some epidemiological studies and post hoc secondary analysis of RCTs.5 Some hypertension management guideline committees have taken a conservative view in recommending higher systolic BP (SBP) targets in the elderly, and for monotherapy being the preferred approach in them; if combination therapy is considered, it should be initiated at low doses and titrated slowly with careful monitoring to avoid adverse events.6 Clinicians may also have misgivings over BP lowering therapy in patients where hypertension is not considered an important cause, such as in “lobar” ICH, where about half of the cases are presumed to be caused by cerebral amyloid angiopathy.7 Yet, studies have shown that hypertension is associated with both “deep” and “superficial” ICH,8 and of similar benefits of BP lowering by location of ICH.9
Single-pill combination (SPC) BP lowering can simplify therapy to improve adherence and tolerability, reduce pill burden, lower medical costs and resource consumption, reduce physician inertia, and achieve better BP control compared to conventional multiple-pill therapy for hypertension.10–12 Since risk reductions are proportional to magnitude of BP lowering, a more intensive SPC approach may be appropriate for the very “high-risk,” ICH patient group.
The Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial (TRIDENT) aims to determine the effectiveness of a novel “Triple Pill” SPC of generic antihypertensive agents at half-dose (telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg) on recurrent stroke and other outcomes. The components of the Triple Pill were chosen on the basis of demonstrated tolerability, efficacy in reducing BP, major cardiovascular outcomes and mortality, and in being the most common combination regimes recommended in hypertension management guidelines.6,10–12 We outline the study protocol, its modifications, and progress to date.
Keywords
Hypertension, blood pressure lowering, intracerebral hemorrhage, clinical trial, outcomes
1The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
2The George Institute China at Peking University Health Sciences Center, Beijing, China
3Heart Health Research Center, Beijing, China
4Neurology Department, Royal Prince Alfred Hospital, Sydney, NSW, Australia
5Clinical Trials Unit, Department of Pharmacology, Faculty of Medicine, University of Kelaniya, Colombo, Sri Lanka
6Institute of Neurology, National Hospital of Sri Lanka, Colombo, Sri Lanka
7Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil
8Neurology Service, Hospital Moinhos de Vento, Porto Alegre, Brazil
9Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
10Neurology Department, National Hospital of Sri Lanka, Colombo, Sri Lanka
11The George Institute for Global Health, School of Public Health, Imperial College London, London, UK
12University of Bordeaux, Bordeaux, France
13Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
14Stroke Unit, 115 Hospital, Ho Chi Minh City, Vietnam
15Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
16Department of Neurology, Tbilisi State Medical University, Tbilisi, GA, USA
17Department of Medicine, University of Ilorin, Ilorin, Nigeria
18Department of Neurology, University Hospital Bern and University of Bern, Bern, Switzerland
19Department of Neurology, University Hospital Basel, Basel, Switzerland
20Stroke Center and Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan, UK
21College of Medicine, Chang Gung University, Taoyuan, UK
22Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
23Department of Neurosciences and Behavioural Sciences, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil
24College of Life Sciences and NIHR Biomedical Research Centre, University of Leicester, Leicester, UK
25Centre for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
26Faculty of Science, Charles Perkins Centre and Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia
27Westmead Applied Research Centre, Faculty of Medicine and Health, University of Sydney, Westmead Hospital, Westmead, NSW, Australia
28Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
Corresponding author(s):
Craig S Anderson, The George Institute for Global Health, University of New South Wales, Sydney, NSW 2050, Australia. Email: canderson@georgeinstitute.org.au
*
Full list of members of the TRIDENT Research Group outlined in Supplemental Appendix
Background and rationale
Intracerebral hemorrhage (ICH) affects several million people worldwide each year,1 but accounts for greater disability-adjusted life years than ischemic stroke due to its poorer prognosis, fewer proven treatments, and very high risk of recurrent ICH, other cardiovascular events, and cognitive impairment/dementia.2 Randomized controlled trials (RCTs) have shown stronger proportional benefits from BP lowering therapy in preventing recurrent ICH than ischemic stroke,3 and for more intensive BP lowering.4 However, clinicians consider intensive BP lowering may cause falls and increase the risk of dementia in older people, concerns reinforced by J-shaped relationships between BP and cardiovascular events seen in some epidemiological studies and post hoc secondary analysis of RCTs.5 Some hypertension management guideline committees have taken a conservative view in recommending higher systolic BP (SBP) targets in the elderly, and for monotherapy being the preferred approach in them; if combination therapy is considered, it should be initiated at low doses and titrated slowly with careful monitoring to avoid adverse events.6 Clinicians may also have misgivings over BP lowering therapy in patients where hypertension is not considered an important cause, such as in “lobar” ICH, where about half of the cases are presumed to be caused by cerebral amyloid angiopathy.7 Yet, studies have shown that hypertension is associated with both “deep” and “superficial” ICH,8 and of similar benefits of BP lowering by location of ICH.9
Single-pill combination (SPC) BP lowering can simplify therapy to improve adherence and tolerability, reduce pill burden, lower medical costs and resource consumption, reduce physician inertia, and achieve better BP control compared to conventional multiple-pill therapy for hypertension.10–12 Since risk reductions are proportional to magnitude of BP lowering, a more intensive SPC approach may be appropriate for the very “high-risk,” ICH patient group.
The Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial (TRIDENT) aims to determine the effectiveness of a novel “Triple Pill” SPC of generic antihypertensive agents at half-dose (telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg) on recurrent stroke and other outcomes. The components of the Triple Pill were chosen on the basis of demonstrated tolerability, efficacy in reducing BP, major cardiovascular outcomes and mortality, and in being the most common combination regimes recommended in hypertension management guidelines.6,10–12 We outline the study protocol, its modifications, and progress to date.
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