STREAM-Bio: STREAM Trial - Biomarker

Sponsor

University Hospital Inselspital, Berne (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05482386

Collaborator

University of Bern (Other)

500

Enrollment

Location

Arms

Anticipated Duration (Months)

9.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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. Older patients with elevated biomarkers associated with cardiovascular (CV) risk might benefit from continuing statins to prevent CV outcomes, but this hypothesis has not been rigorously tested in randomized clinical trials (RCTs). To address these questions, the investigators conduct a RCT in 500 multimorbid adults ≥70 years old taking statins for primary prevention who will be randomized to statin continuation vs. statin discontinuation, and measure baseline biomarkers to determine if the risk of a composite outcome of CV events and all-cause mortality after statin discontinuation differs among those with baseline levels of previously validated blood biomarkers associated with increased risk of CV outcomes.

Condition or Disease	Intervention/Treatment	Phase
Statin Treatment for Primary Prevention	Other: Statin discontinuation	N/A

Detailed Description

Background & rationale: The benefit of statin use for primary prevention is uncertain in older adults with multimorbidity, while harms such as side effects may be more common in this population. Therefore, the 2018 AHA/ACC cholesterol guidelines mention that it may be reasonable to discontinue statins in multimorbid older adults without cardiovascular disease (CVD). Older patients with elevated biomarkers associated with cardiovascular (CV) risk might benefit from continuing statins to prevent CV outcomes, but this hypothesis has not been rigorously tested in randomized clinical trials (RCTs). To address this question, the investigators conduct a RCT in 500 multimorbid adults ≥70 years old taking statins for primary prevention who will be randomized to statin continuation vs. statin discontinuation, and measure baseline biomarkers to determine if the risk of a composite outcome of CV events and all-cause mortality after statin discontinuation differs among those with baseline levels of previously validated blood biomarkers associated with increased risk of CV outcomes.

Specific aim:

To determine if the risk of a composite outcome of CV events and all-cause mortality after statin discontinuation differs according to the baseline levels of previously validated blood biomarkers associated with increased risk of CV outcomes (lipoprotein(a), inflammatory markers [high-sensitivity C-reactive Protein], myocardial damage/wall strain [NT-proBNP, troponin]).

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. We will measure previously validated biomarkers at baseline.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Masking Description:

The study is open-label, with blinded outcome adjudication. Identification of potential outcome events is performed by blinded study team members. Participants, care providers, investigators and outcomes assessors are blinded to the baseline biomarker levels.

Primary Purpose:

Treatment

Official Title:

Utility of Biomarkers With Statin Therapy in Multimorbid Older Adults - An Ancillary Study Nested Within a Randomized Trial

Anticipated Study Start Date :

Aug 1, 2022

Anticipated Primary Completion Date :

Nov 1, 2026

Anticipated Study Completion Date :

Nov 1, 2026

Arms and Interventions

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).

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).

Outcome Measures

Primary Outcome Measures

Composite endpoint of all-cause death and major non-fatal CV events (non-fatal myocardial infarction, non-fatal ischemic stroke) [Up to 48 months]
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.

Secondary Outcome Measures

All-cause death [Up to 48 months]
All deaths (for any reason)
Non-CV death [Up to 48 months]
All deaths except of deaths due to major CV events
Major CV events [Up to 48 months]
CV death, non-fatal myocardial infarction and non-fatal ischemic stroke
Total CV events [Up to 48 months]
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)
Total composite events [Up to 48 months]
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)
EQ-5D questionnaire [3, 12 (primary analysis), 24, 36, 48 months]
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.
Verbal numeric pain rating score (VNPRS) [3 months]
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.
Self-reported falls [Up to 12 months]
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).
Strength, assistance with walking, rising from a chair, climbing stairs, and falls (SARC-F questionnaire) [12 (primary analysis), 24, 36, 48 months]
5-item questionnaire, the score ranges from 0 to 10 with higher scores indicating higher degree of sarcopenia.
Girerd medication adherence scale [12 (primary analysis), 24, 36, 48 months]
6-item questionnaire, the score ranges from 0 to 6, higher scores indicating worse medication adherence.

Eligibility Criteria

Criteria

Ages Eligible for Study:

70 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

≥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
Taking a statin for ≥80% of the time during the year before baseline

Exclusion criteria:

Secondary prevention based on previous large statin trials, defined as:

History of myocardial infarction type 12 (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 ischemic 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)

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
Diagnosis of familial hypercholesterolemia based on Dutch lipid score ≥6 based on available documents (LDL-c, Family History, Personal History)
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 an online tool: https://cancersurvivalrates.com)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital of Bern, University of Bern	Bern		Switzerland	3010

Sponsors and Collaborators

University Hospital Inselspital, Berne
University of Bern

Investigators

Principal Investigator: Manuel R Blum, MD, MSc, University Hospital of Bern, University of Bern, Switzerland; Institute of Primary Health Care, University of Bern, Switzerland