Clinical trial NCT05482399: STREAM Trial - Subclinical Atherosclerosis
Official title: Utility of Coronary Artery Calcification With Statin Therapy in Multimorbid Older Adults - An Ancillary Study Nested Within a Randomized Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Statin Treatment for Primary Prevention
Keywords: Coronary artery calcification
Statins
Primary prevention
Multimorbidity
Older adults
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: University of Bern
First posted: 2022-08-01
Enrollment: 500
Sex: ALL
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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. To better target adults who may benefit from statins in primary prevention, coronary artery calcium (CAC) measurement is rapidly increasing in clinical use and is recommended for risk re-classification in some guidelines. Older patients with a high burden of subclinical atherosclerosis 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 CAC to determine if the risk of a composite outcome of CV events and all-cause mortality after statin discontinuation differs among those with evidence of subclinical atherosclerosis at baseline as measured by CAC.

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). To better target adults who may benefit from statins in primary prevention, coronary artery calcium (CAC) measurement is rapidly increasing in clinical use and is recommended for risk re-classification in some guidelines. Older patients with a high burden of subclinical atherosclerosis 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 CAC to determine if the risk of a composite outcome of CV events and all-cause mortality after statin discontinuation differs among those with evidence of subclinical atherosclerosis at baseline as measured by CAC.

Specific aim:

To determine if the risk of a composite outcome of CV events and all-cause mortality after statin discontinuation differs among those with evidence of subclinical atherosclerosis at baseline as measured by CAC.

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. The investigators will use baseline native cardiac computed tomography scan to measure CAC to identify participants with subclinical atherosclerosis.

Eligibility criteria: 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:

1. 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)
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-c, 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 an online tool: https://cancersurvivalrates.com)
5. Body measures exceeding the CT scanner limits (morbid obesity exceeding weight and diameter limits)
6. Cardiac implants with metallic interference, such as pacemaker and mechanical heart valves
7. Orthopedic hardware in the mid or lower thoracic spine
8. Inability to hold breath for 10 seconds

Primary 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
Secondary outcomes:
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: Up to 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: Bern
country: Switzerland
facility: University Hospital of Bern, University of Bern
Study officials:
affiliation: University Hospital of Bern, University of Bern, Switzerland; Institute of Primary Health Care, University of Bern, Switzerland
name: Manuel R Blum, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: