Clinical trial NCT05178420: STREAM Trial - Statins in Multimorbid Older Adults Without Cardiovascular Disease
Official title: Discontinuing Statins in Multimorbid Older Adults Without Cardiovascular Disease (STREAM) - a Randomized Non-inferiority Clinical Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Statin Treatment for Primary Prevention
Keywords: Multimorbidity
Primary prevention
Older adults
Deprescribing
Statin
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: University of Bern
First posted: 2022-01-05
Enrollment: 1881
Sex: ALL
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Study subjects are randomly assigned in a 1:1 ratio to either discontinue (intervention arm) or continue (control arm) statin therapy
Primary purpose: TREATMENT

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Composite endpoint of all-cause death and major non-fatal CV events (non-fatal myocardial infarction, non-fatal ischemic stroke)
timeFrame: 24 months
Secondary outcomes:
measure: Composite endpoint of all-cause death and major non-fatal CV events (non-fatal myocardial infarction, non-fatal ischemic stroke)
timeFrame: up to 48 months
measure: All-cause death
timeFrame: up to 48 months
measure: Non-CV death
timeFrame: up to 48 months
measure: Major CV events
timeFrame: up to 48 months
measure: Total CV events
timeFrame: up to 48 months
measure: Total composite events
timeFrame: up to 48 months
measure: EQ-5D questionnaire
timeFrame: 3, 12 (primary analysis), 24, 36, 48 months
measure: Verbal numeric pain rating score (VNPRS)
timeFrame: 3 months
measure: Self-reported falls
timeFrame: 12 months
measure: Strength, assistance with walking, rising from a chair, climbing stairs, and falls (SARC-F questionnaire)
timeFrame: 12 (primary analysis), 24, 36, 48 months
measure: Girerd medication adherence scale
timeFrame: 12 (primary analysis), 24, 36, 48 months
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: UNIVERSITY HOSPITAL CENTER of Bordeaux
state: Nouvelle Acquitaine
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
state: South Holland
city: Barmelweid
country: Switzerland
facility: Klinik Barmelweid AG
state: Aargau
city: Bienne
country: Switzerland
facility: Centre hospitalier Bienne
state: Bern
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden
state: Graubünden
city: Crans-Montana
country: Switzerland
facility: Luzerner Höhenklinik Montana AG
state: Valais
city: Schlieren
country: Switzerland
facility: Spital Limmattal
state: Zürich
city: Aarau
country: Switzerland
facility: Kantonsspital Aarau
city: Baden
country: Switzerland
facility: Kantonsspital Baden
city: Basel
country: Switzerland
facility: Universitätsspital Basel
city: Bellinzona
country: Switzerland
facility: Ospedale Regionale di Bellinzona e Valli
city: Bern
country: Switzerland
facility: Clinic for General Internal Medicine, Bern University Hospital Bern
city: Burgdorf
country: Switzerland
facility: Hospital Burgdorf
city: Fribourg
country: Switzerland
facility: HFR Fribourg
city: Geneva
country: Switzerland
facility: Hôpital La Tour
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires de Genève (Geriatrics)
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires de Genève (Internal Medicine)
city: Langnau im Emmental
country: Switzerland
facility: Hospital Langnau
city: Lausanne
country: Switzerland
facility: CHUV Lausanne
city: Neuchâtel
country: Switzerland
facility: Hôpital Neuchâtelois
city: Saint Gallen
country: Switzerland
facility: Hospital St. Gallen (Geriatrics)
city: Schaffhausen
country: Switzerland
facility: Kantonsspital Schaffhausen
city: Zuerich
country: Switzerland
facility: Stadspital Waid
city: Zuerich
country: Switzerland
facility: Stadtspital Triemli
Study officials:
affiliation: University of Bern
name: Nicolas Rodondi, MD, MAS
role: PRINCIPAL_INVESTIGATOR
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