Statin Treatment for Primary Prevention
Conditions
Keywords
Multimorbidity, Primary prevention, Older adults, Deprescribing, Statin
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. The aim of this randomized controlled trial (RCT) is to provide guidance on the benefits and risks of statin deprescribing in multimorbid older adults.
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, 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.
Interventions
Statin therapy will be stopped. Additional lipid-lowering medication lowering LDL cholesterol will also be stopped.
Sponsors
Insel Gruppe AG, University Hospital Bern
University of Bern
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
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.
Intervention model description
Study subjects are randomly assigned in a 1:1 ratio to either discontinue (intervention arm) or continue (control arm) statin therapy
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite endpoint of all-cause death and major non-fatal CV events (non-fatal myocardial infarction, non-fatal ischemic stroke) | 24 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. The primary analysis timeframe is at 24 months, and data collection is performed up to 48 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite endpoint of all-cause death and major non-fatal CV events (non-fatal myocardial infarction, non-fatal ischemic stroke) | up to 48 months | Composite endpoint of all-cause death and major non-fatal CV events (non-fatal myocardial infarction, non-fatal ischemic stroke). |
| 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 scored from 0-100, with higher scores indicating higher degree of pain. |
| Self-reported falls | 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. |
Countries
France, Netherlands, Switzerland
Contacts
PRINCIPAL_INVESTIGATORNicolas Rodondi, MD, MAS
University of Bern
Outcome results
None listed