European Blood Pressure Intensive Control After Stroke (EPICS-Pilot)

European Blood Pressure Intensive Control After Stroke - Pilot Trial

Stroke is the third most common cause of death worldwide and the leading cause of disability. High blood pressure is an important risk factor for stroke. Lowering a person's blood pressure reduces the risk of future stroke or heart attack. However, the optimal target blood pressure after a person suffers a stroke is not known. This is a study designed to establish the feasibility of a larger clinical trial, the aim of which will be to find out if greater blood pressure lowering is safe and effective for patients who suffer a stroke.

Study Overview

• Status: Not yet recruiting
• Conditions: Ischemic Stroke; Transient Ischemic Attack
• Intervention / Treatment: Drug: anti-hypertensive

Detailed Description

Background:

Stroke is the third leading cause of global death, the leading cause of acquired disability and contributes substantially to dementia, cognitive decline, and healthcare costs. Global epidemiological studies such as INTERSTROKE and the Global Burden of Disease study estimated that hypertension is the leading modifiable risk factor for stroke, with a population attributable risk of approximately 50%. Recurrent vascular events (stroke, coronary events, vascular death) cause significant morbidity in ischaemic stroke survivors, affecting approximately 30% at 5 years. Blood-pressure reduction is a proven, inexpensive strategy to prevent stroke with benefits widely-generalizable in developed and developing countries. No randomised trials have demonstrated the efficacy and safety of SBP reduction to prevent secondary vascular events after ischaemic stroke to levels of about 120mmHg compared with 130-139mmHg. Consequently, most guidelines recommend reduction of systolic blood pressure (SBP) less than 140mmHg.

Aim:

The aim is to conduct an initial pilot randomised trial in Ireland and 7 leading European centres involved in the European Stroke Organisation Trials Alliance. This feasibility study will assess key design aspects and establish trial governance, data management, and procedures in preparation for a larger definitive trial.

Methods:

Design: Prospective, open-label, blinded endpoint assessed (PROBE) randomised, parallel-group pilot trial, comparing safety, efficacy, and other feasibility measures of two target SBP goals (intervention 115-125 mmHg, control 130-139 mmHg).

• Study Type: Interventional
• Enrollment (Anticipated): 122
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Katrina Tobin; Phone Number: +353 1 716 4576; Email: katrina.tobin@ucd.ie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥40
2. Ischaemic stroke, proven by imaging (including transient ischaemic attack with imaging evidence of acute brain ischaemia
3. Living at home and independent (walking without the aid of another person, but may have some help for daily activities - equivalent to Rankin score 3 or less)
4. SBP≥130mmHg at entry (average of 2 measures, seated, after resting alone in office for 5 minutes)
5. Qualifying Stroke/TIA between 7 days and 1 year of randomization
6. Glomerular filtration rate (eGFR) greater than or equal to 50 ml/min/m2
7. Medically-stable and capable of participating in a randomised trial, including home BP measures, in the opinion of the study physician
8. Willing to provide informed consent (no surrogate consent will apply)

Exclusion Criteria:

1. Stroke/TIA due to cardio-embolism or other defined causes (eg. dissection, endocarditis, other specified)
2. Severe stenosis of large cranio-cervical artery (>70% stenosis of cervical carotid, vertebral, or Circle of Willis artery)
3. Medical history of primary intracerebral haemorrhage (asymptomatic cerebral microbleeds detected on brain MRI are not excluded)
4. SBP <110mmHg after 3 minutes of standing or other contra-indication to intensive SBP lowering in opinion of treating clinician* (eg. syncope or pre-syncope, recurrent falls)
5. Unlikely to comply with study procedures (home BP measures, follow-up visits) due to severe or fatal co-morbid illness (eg. dementia, active malignancy, severe frailty) or other factor (eg. inability to travel)
6. Women of child-bearing potential

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Target systolic blood pressure 115-125 mmHg; Recommended target SBP 115-125 millimetres of mercury (mmHg).	Drug: anti-hypertensive; The recommended target SBP will be 115-125 mmHg in the intervention arm. A medication algorithm based on the SPRINT trial protocol will be provided. The final choice and dose of antihypertensive treatment(s) will be at the discretion of the treating clinicians. If no contra-indications, indapamide or other thiazide diuretic and/or angiotensin-converting enzyme (ACE) inhibitor (perindopril or other) will be encouraged as initial therapy, with long-acting calcium-channel antagonists (eg.amlodipine) encouraged as third-line therapy. At scheduled face-to-face or remote follow-up, patients will have their home blood pressure monitoring diary reviewed by the study team. If SBP is out of the allocated target range, a prescription to titrate (up or down) antihypertensive medication will be given to the patient.
Active Comparator: Target systolic blood pressure 130-139 mmHg; Target SBP 130-139 mmHg (per American Stroke Association, European Stroke Organisation guidelines).	Drug: anti-hypertensive; The recommended target SBP will be 115-125 mmHg in the intervention arm. A medication algorithm based on the SPRINT trial protocol will be provided. The final choice and dose of antihypertensive treatment(s) will be at the discretion of the treating clinicians. If no contra-indications, indapamide or other thiazide diuretic and/or angiotensin-converting enzyme (ACE) inhibitor (perindopril or other) will be encouraged as initial therapy, with long-acting calcium-channel antagonists (eg.amlodipine) encouraged as third-line therapy. At scheduled face-to-face or remote follow-up, patients will have their home blood pressure monitoring diary reviewed by the study team. If SBP is out of the allocated target range, a prescription to titrate (up or down) antihypertensive medication will be given to the patient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in achieved SBP	The difference in mean SBP in the intensive versus control groups, at 18 months (or end-of-trial visit)	18 months (or end of trial visit)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first composite major vascular event	Defined as recurrent stroke, myocardial infarction, cardiac arrest, and to each component of the composite, stratified as fatal, non-fatal and total.	18 months (or end of trial visit)
Proportions of patients assigned to target goals successfully reaching target		18 months (or end of trial visit)
All-cause death	Time to all-cause death	18 months (or end of trial visit)
Number of dose-titrations required		18 months (or end of trial visit)
Time in target range	Proportion of SBP measures in the assigned target during trial participation	18 months (or end of trial visit)
Loss to follow-up	Number of participants lost to follow-up in both treatment arms	18 months (or end of trial visit)
Time taken to reach target range		18 months (or end of trial visit)
Change in cognition	Change in Montreal cognitive assessment score (range 0-30) at last follow-up compared with baseline score. A lower score indicates greater cognitive impairment.	18 months (or end of trial visit)
Quality of life score	Change in EQ5D-5L score (5 domains assessed with scores of 1-5 ranking the severity of impairment, with higher scores indicating poorer quality of life) at last follow-up compared with baseline	18 months (or end of trial visit)
Difference in mean achieved diastolic blood pressure (DBP) between groups		18 months (or end of trial visit)
Change in SBP and DBP from baseline to end-of-trial		18 months (or end of trial visit)
Time required per follow up visit		18 months (or end of trial visit)
Feasibility of remote BP titration	Qualitative feedback from patients on their views relating to the feasibility of home blood pressure monitoring and remote dose titration will be sought. This design feature will be carefully examined in the pilot, before incorporation into the main trial.	18 months (or end of trial visit)
Disability in intensive-SBP and guideline-based SBP target patients assessed by modified Rankin score (shift analysis and proportion with no, mild, or moderate disability, Rankin score 0-3)	Proportion of participants with disability. The modified Rankin scale is graded from 0-6, with 0 indicating no disability and 6 indicating death.	18 months (or end of trial visit)
Number of adverse events, serious adverse events, and suspected unexpected serious adverse reactions (SUSARs)	Difference in proportion of patients with adverse events, serious adverse events and SUSARS	18 months (or end of trial visit)
Number of pre-specified adverse events		18 months (or end of trial visit)
Qualitative patient feedback obtained via workshops and questionnaires		18 months (or end of trial visit)
Total, direct and indirect (eg. via lost income to study participants or family members) costs associated with face-to-face visits for study participants will be quantified		18 months (or end of trial visit)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients who do not complete the study due to tolerability or other issues	Patients who are not retained in the study will give an insight into anticipated retention in the Phase 3 trial and sample size considerations.	18 months (or end of trial visit)
Ability of sites to rapidly identify eligible patients from clinics and stroke units	The inclusion of prevalent cases already attending stroke clinics or discharged from stroke units within the last year is an important design feature, aimed to rapidly accrue patients into the trial and thus to maximise the duration of follow-up within the terms allowed by funders. This outcome will be judged on the basis of qualitative feedback from participating sites.	18 months (or end of trial visit)
Feasibility of home blood pressure (BP) measures and diary entries	This outcome will be judged on the basis of qualitative feedback from participants and the the proportions of participants adhering to the use of home blood pressure diaries.	18 months (or end of trial visit)
Feasibility of remote (phone/video) visits	The feasibility of remote (phone/video) visits will be assessed by the proportion of patients adhering to participation in remote visit consultations	18 months (or end of trial visit)

Collaborators and Investigators

• Sponsor: University College Dublin
• Collaborators: University of Oslo; Universitaire Ziekenhuizen KU Leuven; St Vincent's University Hospital, Ireland; University of Calgary; National University of Ireland, Galway, Ireland; Newcastle University; University of Limerick; Mater Misericordiae University Hospital; Hospital Universitario La Paz; Cork University Hospital; Attikon Hospital; Tallaght University Hospital; University Hospital Waterford; HRB Stroke Trials Network Ireland

Publications and helpful links

General Publications

• Saiz LC, Gorricho J, Garjon J, Celaya MC, Erviti J, Leache L. Blood pressure targets for the treatment of people with hypertension and cardiovascular disease. Cochrane Database Syst Rev. 2022 Nov 18;11(11):CD010315. doi: 10.1002/14651858.CD010315.pub5.

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2021
• Primary Completion (Anticipated): September 1, 2023
• Study Completion (Anticipated): September 1, 2023

Study Registration Dates

• First Submitted: November 20, 2020
• First Submitted That Met QC Criteria: November 27, 2020
• First Posted (Actual): November 30, 2020

Study Record Updates

• Last Update Posted (Actual): November 30, 2020
• Last Update Submitted That Met QC Criteria: November 27, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: prognosis; hypertension; myocardial infarction; prevention; blood pressure; ischemic stroke; recurrence; randomized control trial; transient ischemic attack; vascular events
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Stroke; Ischemic Stroke; Ischemia; Ischemic Attack, Transient; Antihypertensive Agents
• Other Study ID Numbers: 7580

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: The investigators are open to considering requests for collaborative projects.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No