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.

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, France and the Netherlands. 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.

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 enrollment

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 (does not apply to clearly cardio-embolic causes for stroke e.g. due to atrial fibrillation), OR
   • History of Transient Ischemic Attack, defined as transient neurological deficit without diffusion restriction in MRI, OR
   • History of carotid revascularization (stent, bypass, CEA (carotid thrombendartectomy)), OR
   • History of peripheral arterial disease requiring revascularization (e.g. PTA (percutaneous transluminal angioplasty), stent, femoral TEA (thrombendartectomy), 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)

5. Participation to a clinical trial with potential impact on the STREAM cardiovascular endpoints (based on clinical judgment)

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

Foreseen for one year after publication of the main trial results. Items will be retained indefinitely.

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

The study is open-label, with blinded outcome adjudication. Identification of potential outcome events is performed by blinded study team members.