STREAM Trial - Statins in Multimorbid Older Adults Without Cardiovascular Disease (STREAM)

Discontinuing Statins in Multimorbid Older Adults Without Cardiovascular Disease (STREAM) - a Randomized Non-inferiority Clinical Trial

Statins are among the most widely used drugs. While they were found to be effective for primary and secondary prevention of cardiovascular disease (CVD) in middle-aged subjects, their benefits for primary prevention in older adults (aged ≥70 years) without CVD are uncertain, particularly for those with multimorbidity. The aim of this randomized controlled trial (RCT) is to provide guidance on the benefits and risks of statin deprescribing in multimorbid older adults.

Study Overview

• Status: Recruiting
• Conditions: Statin Treatment for Primary Prevention
• Intervention / Treatment: Other: Statin discontinuation

Detailed Description

Background:

Until now, no RCT examining the benefits of statins in primary prevention has exclusively recruited multimorbid participants aged 70 years and older (70+), and 70+ participants are under-represented in most RCTs, including those examining statin benefits for primary prevention. However, statin side effects and drug interactions are common in populations of multimorbid older adults and might negatively impact quality of life. The proportion of patients developing myalgia on statins has been shown to be as high as 5-20% in observational studies; older age and polypharmacy are known risk factors for developing muscle problems under statins. Furthermore, multimorbid older adults with polypharmacy are more likely to experience side effects with statins (e.g. elevated liver enzymes, diabetes, myopathy, rhabdomyolysis) and drug-drug interactions (e.g. antibiotics, antifungals), with the potential consequences of drug toxicity, reduced physical activity, sarcopenia and falls. In practice, statins are often discontinued in multimorbid older adults without CVD after side effects. The net clinical benefit of statins for primary prevention in multimorbid 70+ older adults remains unclear, and the effect of multimorbidity might shift the evidence towards favoring no statin treatment, but no large RCT examined this issue.

Design:

The study is a multicenter, randomized, non-inferiority trial conducted in multiple centers in Switzerland. Study subjects are randomly assigned in a 1:1 ratio to either discontinue (intervention arm) or continue (control arm) statin therapy. The study is open-label, with blinded outcome adjudication. After inclusion the study participants will be followed with phone calls, first after 3 months and then yearly for a mean of 24 months (min. follow-up period 12 months, max. follow-up period 48 months). Outcomes are assessed at each study follow-up.

• Study Type: Interventional
• Enrollment (Anticipated): 1800
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Manuel R. Blum, MD, MSc; Phone Number: 8008 +41 31 632 21 11; Email: manuel.blum@biham.unibe.ch
• Study Contact Backup: Name: Nicolas Rodondi, MD, MAS; Phone Number: +41 31 632 00 69; Email: nicolas.rodondi@insel.ch

Study Locations

• Switzerland
  • Aarau, Switzerland
    • Recruiting
    • Kantonsspital Aarau
    • Contact: Philipp Schütz, Prof.
    • Principal Investigator: Philipp Schütz, Prof.
  • Baden, Switzerland
    • Recruiting
    • Kantonsspital Baden
    • Contact: Maria Wertli, Prof.
    • Principal Investigator: Maria Wertli, Prof.
  • Basel, Switzerland
    • Recruiting
    • Universitatsspital Basel
    • Contact: Mirjam Christ-Crain, Prof.
    • Principal Investigator: Mirjam Christ-Crain, Prof.
  • Bellinzona, Switzerland
    • Recruiting
    • Ospedale Regionale di Bellinzona e Valli
    • Contact: Luca Gabutti, Prof.
    • Principal Investigator: Luca Gabutti, Prof.
  • Bern, Switzerland, 3010
    • Recruiting
    • Clinic for General Internal Medicine, Bern University Hospital Bern
    • Principal Investigator: Nicolas Rodondi, MD MAS
    • Contact: Nicolas Rodondi, MD, MAS; Phone Number: +41 31 632 00 69; Email: nicolas.rodondi@insel.ch
  • Burgdorf, Switzerland
    • Recruiting
    • Hospital Burgdorf
    • Contact: Robert Escher, PD Dr.
    • Principal Investigator: Robert Escher, PD Dr.
  • Fribourg, Switzerland, 1752
    • Recruiting
    • HFR Fribourg
    • Contact: Marco Mancinetti, Dr.
    • Principal Investigator: Marco Mancinetti, Dr.
  • Geneva, Switzerland
    • Recruiting
    • Hôpital La Tour
    • Contact: Omar Kherad, Prof.
    • Principal Investigator: Omar Kherad, Prof.
  • Geneva, Switzerland
    • Recruiting
    • Hôpitaux Universitaires de Genève (Geriatrics)
    • Contact: Dina Zekry, Prof.
    • Principal Investigator: Dina Zekry, Prof.
  • Geneva, Switzerland
    • Recruiting
    • Hôpitaux Universitaires de Genève (Internal Medicine)
    • Contact: Sebastian Carballo, PD Dr.
    • Principal Investigator: Sebastian Carballo, PD Dr.
  • Langnau im Emmental, Switzerland
    • Recruiting
    • Hospital Langnau
    • Contact: Martin Egger, Dr.
    • Principal Investigator: Martin Egger, Dr.
  • Lausanne, Switzerland
    • Recruiting
    • CHUV Lausanne
    • Contact: Marie Méan, Dr.
    • Principal Investigator: Marie Méan, Dr.
  • Neuchâtel, Switzerland
    • Recruiting
    • Hôpital neuchâtelois
    • Contact: Jacques Donzé, Prof.
    • Principal Investigator: Jacques Donzé, Prof.
  • Saint Gallen, Switzerland
    • Recruiting
    • Hospital St. Gallen (Geriatrics)
    • Contact: Thomas Münzer, PD Dr.
    • Principal Investigator: Thomas Münzer, PD Dr.
  • Sion, Switzerland
    • Not yet recruiting
    • Hospitals Valais (Martigny, Sion)
    • Contact: Pierre-Auguste Petignat, Prof.
    • Principal Investigator: Pierre-Auguste Petignat, Prof.
  • Zuerich, Switzerland
    • Recruiting
    • Stadtspital Triemli
    • Contact: Lars Huber, Prof.
    • Principal Investigator: Lars Huber, Prof.
  • Zuerich, Switzerland
    • Recruiting
    • Universitätsspital Zürich & Stadspital Waid
    • Contact: Heike Bischoff-Ferrari, Prof.
    • Principal Investigator: Heike Bischoff-Ferrari, Prof.
  • Zürich
    • Schlieren, Zürich, Switzerland, 8952
      • Recruiting
      • Spital Limmattal
      • Contact: Alain Rudiger, Prof.
      • Principal Investigator: Alain Rudiger

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent
• ≥70 years of age
• Multimorbid with ≥2 coexistent chronic conditions (defined by ICD-10 codes) with an estimated duration of 6 months or more based on clinical decision, besides dyslipidemia treated by statins
• Intake of a statin for ≥80% of the time during the year before enrolment
• Participation to a clinical trial with potential impact on the STREAM cardiovascular endpoints

Exclusion Criteria:

1. Cardiovascular secondary prevention setting based on previous large statin trials, defined as:

   • History of myocardial infarction type 1 (NSTEMI/STEMI), OR
   • History of unstable angina, defined as ACS symptomatic at rest, crescendo or new- onset angina (CCS 2 or 3) without ECG or cardiac biomarker changes (based on available documents), OR
   • Stable angina pectoris with a documented ischemia on a stress test or with a significant coronary disease defined as a coronary stenosis >50%, OR
   • History of percutaneous coronary intervention (balloon or stent) or coronary artery bypass graft, OR
   • History of Stroke, OR
   • History of Transient Ischemic Attack, defined as transient neurological deficit without diffusion restriction in MRI, OR
   • History of carotid revascularization (stent or bypass), OR
   • History of peripheral arterial disease requiring revascularization (stent or bypass; Fontaine IV)
2. Aortic disease that required a vascular repair or aortic aneurysm with a maximum diameter >5.5 cm (men) or >5.2 cm (women) based on available documents
3. Diagnosis of familial hypercholesterolemia based on Dutch lipid score ≥6 based on available documents (LDL cholesterol, family history, personal history)

4. Elevated risk of death within 3 months after baseline, defined as:

   • Hospitalized patients planned for palliative care within 24h of admission OR
   • Hospitalized patients with a Palliative Performance Scale (PPS) level <30% (based on situation at least 1 month before hospitalization), this corresponds to an estimated survival of 43% after 3 months; OR
   • Patients with an advanced metastatic cancer prognosis of ≤20% survival rate within 1 year after baseline (based on: https://cancersurvivalrates.com)

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: Statin discontinuation; Discontinuation of statin therapy - statin therapy will be stopped from the next scheduled intake after study inclusion (intervention arm).	Other: Statin discontinuation; Statin therapy will be stopped. Additional lipid-lowering medication lowering LDL cholesterol will also be stopped.; Other Names: Intervention arm
No Intervention: Statin continuation; Continuation of statin therapy - no change in the prescribed statin therapy (control arm).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite endpoint of all-cause death and major non-fatal CV events (non-fatal myocardial infarction, non-fatal ischemic stroke)	The primary endpoint is a composite endpoint of all-cause death and major non-fatal CV events (non-fatal myocardial infarction, non-fatal ischemic stroke). All-cause death (and not CV death only) is chosen to account for a possible shift from CV to other causes of death. The composite endpoint was selected to assess the net clinical benefit in this population with expected high mortality. The clinical event committee which classifies suspected events for the primary and secondary clinical outcomes is blinded. The primary analysis timeframe is at 24 months, and data collection is performed up to 48 months.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite endpoint of all-cause death and major non-fatal CV events (non-fatal myocardial infarction, non-fatal ischemic stroke)	Composite endpoint of all-cause death and major non-fatal CV events (non-fatal myocardial infarction, non-fatal ischemic stroke).	up to 48 months
All-cause death	All deaths (for any reason)	up to 48 months
Non-CV death	All deaths except of deaths due to major CV events	up to 48 months
Major CV events	CV death, non-fatal myocardial infarction and non-fatal ischemic stroke	up to 48 months
Total CV events	CV death, non-fatal myocardial infarction, hospitalization for unstable angina, non-fatal ischemic stroke (including TIA) and arterial revascularization (coronary and peripheral urgent and non-urgent revascularization)	up to 48 months
Total composite events	All-cause death, non-fatal myocardial infarction, hospitalization for unstable angina, non-fatal ischemic stroke (including TIA) and arterial revascularization (coronary and peripheral urgent and non-urgent revascularization)	up to 48 months
EQ-5D questionnaire	EQ-5D is the name of the instrument and not an acronym. General quality of life assessment. The possible range of scores goes from 0 to 1.0, with higher scores indicating better quality of life.	3, 12 (primary analysis), 24, 36, 48 months
Verbal numeric pain rating score (VNPRS)	To assess statin associated muscle symptoms. The VNPRS is an 11-point scale scored from 0-10, with higher scores indicating higher degree of pain.	3 months
Self-reported falls	Self-reported falls, each participant will collect and list all falls during the first 12 months after randomization. Circumstances and medical consequences of each fall will be collected. Aggregated as rate of falls (falls per person per year).	12 months
Strength, assistance with walking, rising from a chair, climbing stairs, and falls (SARC-F questionnaire)	5-item questionnaire, the score ranges from 0 to 10 with higher scores indicating higher degree of sarcopenia.	12 (primary analysis), 24, 36, 48 months
Girerd medication adherence scale	6-item questionnaire, the score ranges from 0 to 6, higher scores indicating worse medication adherence.	12 (primary analysis), 24, 36, 48 months

Collaborators and Investigators

• Sponsor: University Hospital Inselspital, Berne
• Collaborators: University of Bern
• Investigators: Principal Investigator: Nicolas Rodondi, MD, MAS, University of Bern

Publications and helpful links

General Publications

• Han BH, Sutin D, Williamson JD, Davis BR, Piller LB, Pervin H, Pressel SL, Blaum CS; ALLHAT Collaborative Research Group. Effect of Statin Treatment vs Usual Care on Primary Cardiovascular Prevention Among Older Adults: The ALLHAT-LLT Randomized Clinical Trial. JAMA Intern Med. 2017 Jul 1;177(7):955-965. doi: 10.1001/jamainternmed.2017.1442.
• Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019 Feb 2;393(10170):407-415. doi: 10.1016/S0140-6736(18)31942-1.
• van der Ploeg MA, Streit S, Achterberg WP, Beers E, Bohnen AM, Burman RA, Collins C, Franco FG, Gerasimovska-Kitanovska B, Gintere S, Gomez Bravo R, Hoffmann K, Iftode C, Pestic SK, Koskela TH, Kurpas D, Maisonneuve H, Mallen CD, Merlo C, Mueller Y, Muth C, Petrazzuoli F, Rodondi N, Rosemann T, Sattler M, Schermer T, Ster MP, Svadlenkova Z, Tatsioni A, Thulesius H, Tkachenko V, Torzsa P, Tsopra R, Tuz C, Vaes B, Viegas RPA, Vinker S, Wallis KA, Zeller A, Gussekloo J, Poortvliet RKE. Patient Characteristics and General Practitioners' Advice to Stop Statins in Oldest-Old Patients: a Survey Study Across 30 Countries. J Gen Intern Med. 2019 Sep;34(9):1751-1757. doi: 10.1007/s11606-018-4795-x. Epub 2019 Jan 16.
• Kutner JS, Blatchford PJ, Taylor DH Jr, Ritchie CS, Bull JH, Fairclough DL, Hanson LC, LeBlanc TW, Samsa GP, Wolf S, Aziz NM, Currow DC, Ferrell B, Wagner-Johnston N, Zafar SY, Cleary JF, Dev S, Goode PS, Kamal AH, Kassner C, Kvale EA, McCallum JG, Ogunseitan AB, Pantilat SZ, Portenoy RK, Prince-Paul M, Sloan JA, Swetz KM, Von Gunten CF, Abernethy AP. Safety and benefit of discontinuing statin therapy in the setting of advanced, life-limiting illness: a randomized clinical trial. JAMA Intern Med. 2015 May;175(5):691-700. doi: 10.1001/jamainternmed.2015.0289. Erratum In: JAMA Intern Med. 2015 May;175(5):869. JAMA Intern Med. 2019 Jan 1;179(1):126-127.
• Byrne P, Cullinan J, Smith SM. Statins for primary prevention of cardiovascular disease. BMJ. 2019 Oct 16;367:l5674. doi: 10.1136/bmj.l5674. No abstract available.
• Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002 Nov 23;360(9346):1623-30. doi: 10.1016/s0140-6736(02)11600-x.
• Ruscica M, Macchi C, Pavanello C, Corsini A, Sahebkar A, Sirtori CR. Appropriateness of statin prescription in the elderly. Eur J Intern Med. 2018 Apr;50:33-40. doi: 10.1016/j.ejim.2017.12.011. Epub 2018 Jan 5.

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2021
• Primary Completion (Anticipated): November 15, 2026
• Study Completion (Anticipated): November 15, 2026

Study Registration Dates

• First Submitted: November 15, 2021
• First Submitted That Met QC Criteria: December 16, 2021
• First Posted (Actual): January 5, 2022

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Older adults; Primary prevention; Statin; Deprescribing; Multimorbidity
• Additional Relevant MeSH Terms: Cardiovascular Diseases
• Other Study ID Numbers: STREAM

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data will be deposited in the BORIS Research Data, the research data repository of the University of Bern. BORIS Research Data allows searching and is indexed by search engines. All items are stored with a unique Digital Object Identifier (DOI) that can be referenced in respective publication. It should be noted that the investigators plan to register and deposit data that relates to individual, primary publications and not the whole study database as such, as the investigators will use them for secondary analysis. This enables other researchers to replicate published analyses and results as well as to re-use the data for additional analyses such as metaanalysis.

It is planned to disseminate the results of the trial to key target groups using the Lavis' framework for research knowledge transfer

• IPD Sharing Time Frame: Foreseen for one year after publication of the main trial results. Items will be retained indefinitely.

IPD Sharing Access Criteria

All efforts will be made to protect privacy and to de-identify the data. However, datasets contain sensitive data. Therefore, data will be shared on request under the following conditions:

• A meaningful study question by the requester
• Outline of the planned analyses
• Valid methodology Signed data sharing agreement that contains a confidentiality agreement and other obligations to ensure privacy of trial participants

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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