StAtins in Frail OldEr Patients with Ischemic Stroke or Transient Ischemic Attack - the Randomized Controlled Trial (SAFEST - RCT)

Two Dutch guidelines (Stroke and Cardiovascular Risk Management) provide conflicting advice on optimal statin treatment in older patients. In the SAFEST - RCT, the investigators will assess the impact of starting versus not starting a statin in frail individuals aged 70 and above with a recent ischemic stroke or transient ischemic attack (TIA) on their health-related quality of life and Major Adverse Cardiovascular Events (MACE) free survival during a two-year follow-up period.

Study Overview

• Status: Not yet recruiting
• Conditions: Ischemic Stroke; Transient Ischemic Attack
• Intervention / Treatment: Drug: Statin (atorvastatin, fluvastatin, pravastatin, rosuvastatin or simvastatin)

Detailed Description

Objective: To assess the impact of starting versus not starting a statin in frail individuals aged 70 and above with a recent ischemic stroke or transient ischemic attack (TIA) on their health-related quality of life and MACE free survival during a two-year follow-up period.

Study population: The patient population consists of frail older (>=70 yrs) patients with a recent acute ischemic stroke or TIA who are admitted to the hospital or visit the outpatient clinic or emergency department for diagnostic evaluation, and who were not receiving statin treatment at the time of the acute event. Frailty is defined by a pre-event Clinical Frailty Scale (CFS) score of 4-7 and/or a post-event score of 6-7.

Description of intervention(s): Participants in the intervention group will start with a statin with target values following the Dutch stroke guideline. The control group will not start with a statin, aligning with the Dutch Cardiovascular Risk Management (CVRM) guideline recommendations.

Outcome measures:

This study has two co-primary endpoints: (1) Health-Related Quality of Life (HrQoL), using the Patient-Reported Outcomes Measurement Information System - Global-10 (PROMIS-10) and (2) Major Adverse Cardiovascular Events (MACE) free survival, after 2 years. We will evaluate these two co-primary outcomes at multiple time points, specifically at 3, 6, 12, 18, and 24 months. For patients enrolled in the beginning of recruitment, an extended follow-up of three years will be conducted to provide additional insights into the two primary endpoints.

• Study Type: Interventional
• Enrollment (Estimated): 612
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Birgit Damoiseaux-Volman, PhD; Phone Number: 0031 20 566 9111; Email: b.a.damoiseaux@amsterdamumc.nl
• Study Contact Backup: Name: Susanna Prins, MSc; Phone Number: 0031 20 566 9111; Email: s.r.prins@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• age = 70 years or older at the time of ischemic stroke or TIA;
• inclusion within 6 weeks after diagnosis of ischemic stroke or TIA;
• not using statin therapy at the time of the index event;
• frailty as defined by a pre-event score of 4-7 and/or post-event score of 6-7 on the validated Clinical Frailty Scfale.[49]

Exclusion Criteria:

• Patients with a stroke or TIA of non-atherosclerotic etiology.
• Previous serious adverse drug reactions (defined as an adverse reaction that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a birth defect40) to statins or other contraindications to statin use.
• Very severe frailty or very limited life expectancy (< 6 months) as defined by a score >= 8 points on the validated Clinical Frailty Scale.
• Inability to communicate in Dutch.
• Inability to respond to questions, either independently or with the assistance of a proxy (a proxy is allowed to assist by writing on behalf of the participant in cases of physical incapacity or by discussing questions with the participant, but the proxy cannot make decisions for the participant).
• Inability or unwillingness to provide written informed consent, either independently or with the assistance of a proxy (a proxy is allowed to assist by writing on behalf of the participant in cases of physical incapacity or by discussing the consent form with the participant, but the proxy cannot make decisions or provide consent on behalf of the participant).
• Extremely high-risk patients, i.e. patients who have had two or more cardiovascular events within a period of one year.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prescribing a statin; Newly prescribing a statin	Drug: Statin (atorvastatin, fluvastatin, pravastatin, rosuvastatin or simvastatin); The intervention group receives statin treatment following the current "Herseninfarct en Hersenbloeding" guideline. The intensity and target value of statin treatment are determined according to this national guideline. Which statin (atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatin) will be selected and what dose will be prescribed is left to the discretion of the treating neurologist. The statins are registered in the Netherlands and use will be according to the licenses of the products. They will be collected at the local pharmacy by the patient (following practice as usual).; Other Names: Lipitor, Lescol XL, Crestor, Zocor
No Intervention: Not prescribing a statin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health-Related Quality of Life (HrQoL)	This will be measured using the PROMIS-10 scale scores (ranging from 0 to 100, with higher scores indicating better health), including global mental health and global physical health subscales. Measurements at 3, 6, 12, 18, 24 (and 36) months.	3, 6, 12, 18, 24 (and 36) months.
Major Adverse Cardiovascular Events (MACE) free survival	Classical 3-point MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and non-cardiovascular death. Measurements at3, 6, 12, 18, 24 (and 36) months.	3, 6, 12, 18, 24 (and 36) months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional Outcome	This will be assessed using the modified Rankin Scale (mRS) 49, with scores ranging from 0 to 6 (lower scores indicating better function).	1 and 2 years
Cognition MoCA	will be measured using the Montreal Cognitive Assessment (MoCA)51 or the Telephone version of the MoCA (T-MOCA)	1 and 2 years
Number of falls	Falls, measured using the falls calender. Participant returns the fall calender every 3 months.	1 and 2 years
Time to first fall	Falls, measured using the falls calender. Participant returns the fall calender every 3 months.	2 years
General quality of life EuroQol Questionnaire (EQ-5D-5L)	General QoL measure by EuroQol Questionnaire (EQ-5D-5L). This will be used to calculate the cost-effectiveness analysis (CAE). Possible scores range from 0-100, the higher, the better.	1 and 2 years
Societal costs	Societal costs measured by The Older Persons and Informal Caregivers Survey - Minimum Data Set (TOPICS-MDS) (questions 23 - 37)	1 and 2 years
Cardiovascular Risk Status	method of assessing is to be decided.	1 and 2 years

Collaborators and Investigators

• Sponsor: Prof. dr. Nathalie van der Velde
• Collaborators: VU University of Amsterdam
• Investigators: Principal Investigator: Nathalie van der Velde, Prof. dr., Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Principal Investigator: Renske van den Berg, Prof. dr., Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2025
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): July 1, 2029

Study Registration Dates

• First Submitted: January 16, 2023
• First Submitted That Met QC Criteria: January 19, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 19, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: quality of life; ischemic stroke; transient ischemic attack; statin
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Brain Infarction; Brain Ischemia; Infarction; Necrosis; Ischemic Stroke; Stroke; Cerebral Infarction; Ischemic Attack, Transient; Ischemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Simvastatin; Pravastatin
• Other Study ID Numbers: 2022-502059-79-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The SAFEST database can be requested by other researchers. These requests will be reviewed according the requirements for sharing SAFEST data.
• IPD Sharing Time Frame: After data-collection/analysis.

IPD Sharing Access Criteria

Requirements for sharing SAFEST data include:

• privacy laws of the Netherlands, policy of NFU and AmsterdamUMC must be followed
• data will anonymously
• data can only be used to study the research question for which participants signed the ICF
• data will not be shared for commercial purposes.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes