STREAM Trial - Biomarker

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Statin Treatment for Primary Prevention

Intervention / Treatment
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* Other: Statin discontinuation


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Statin discontinuation<br>Discontinuation of statin therapy - statin therapy will be stopped from the next scheduled intake after study inclusion (intervention arm). | Other: Statin discontinuation<br>* Statin therapy will be stopped. Additional lipid-lowering medication lowering LDL cholesterol will also be stopped.<br>* Other names: Intervention arm;|
| No Intervention: Statin continuation<br>Continuation of statin therapy - no change in the prescribed statin therapy (control arm). | |

What is the study measuring?
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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. | Up to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Up to 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular biomarkers, Statins, Primary prevention, Multimorbidity, Older adults