Polygenic Risk Driven Pragmatic Statin Trial for Heart Disease Prevention (EE-PRS)

The Pragmatic EE-PRS Trial Assessing Polygenic Risk Driven Statin Therapy for Cardiovascular Disease Prevention

This research investigates the potential advantages of intensive preventive statin treatment for healthy men aged 45-80 and women aged 55-80 who possess a high genetic predisposition to coronary artery disease (CAD). By specifically targeting the top 20% of individuals with elevated CAD polygenic risk scores (PRS), the study seeks to find out whether this tailored approach can notably decrease the occurrence of cardiovascular disease and mortality over a five-year period when compared with usual care. Despite the potential of PRS in pinpointing individuals at heightened risk for cardiovascular disease, there is a lack of focused and prospective investigations in existing research. This study aims to bridge this gap by examining whether preventive statin therapy for individuals with high CAD PRS is not only effective in diminishing cardiovascular events but also economically viable. The comparison between the statin treatment arm and standard care practice is conducted in a pragmatic manner at the primary care level.

Study Overview

• Status: Active, not recruiting
• Conditions: PRS-based Primary Prevention of CVD
• Intervention / Treatment: Drug: Rosuvastatin 20mg

• Study Type: Interventional
• Enrollment (Actual): 2714
• Phase: Phase 4

Contacts and Locations

Study Locations

• Estonia
  • Harju
    • Tallinn, Harju, Estonia
      • North Estonia Medical Centre
  • Tartu
    • Tartu, Tartu, Estonia
      • Tartu University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men aged 45-80 on 1 January 2025
• Women aged 55-80 on 1 January 2025
• CAD PRS top 20% confirmed by the Estonian Biobank (we intend to sample top 15% PRS individuals but we might have to also include 15-20% PRS individuals to fulfil the required sample size)
• The family physician of the study participant has been contracted to participate in the trial
• Written informed consent has been provided to participate in the trial

Exclusion Criteria:

• Diagnosed with ischemic heart disease (I20-I25), stroke or transient ischemia (I60-64, I69, G45), peripheral vascular occlusion (I65-66, I67.2, I70, I73.9), diseases of liver (K70-K77), end stage renal disease (N18.0), mental and behavioural disorders due to psychoactive substance use (F10-F19).

  -- The diagnosis must be present at least 2 times on a health claim or prescription within at least a 6-month period between 1.01.2022-31.12.2024.

• Currently using statin treatment:

  • The individual has at least 1 prescription from ATC groups C10AA or C10BA between 01.01.2022- 31.12.2024.
  • The individual has answered in the recruitment call that he/she is currently using statins or has been prescribed statins in the past 3 years.
• Has familiar hypercholesterolemia (APOB, PCSK9, LDLR genes verified by the Estonian biobank)
• Is currently participating in other clinical trials.
• Has been taking investigative trial medication during the past 30 days prior to study inclusion.
• Co-morbid physical or mental illnesses that prevent the individual from granting consent or participating in the trial (according to the judgement of the investigator).

• Individuals taking:

  • a combination of sofosbuvir/velpatasvir/voxilaprevir (used to treat hepatitis C);
  • ciclosporin
  • fusidic acid orally or by injection.
• Individuals with a substance abuse disorder (alcohol, narcotic substances).
• Individuals with hypersensitivity to the active substance (rosuvastatin or atorvastatin) or its excipients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention arm receiving statin treatment; Intervention arm participants (n=1350) comprise healthy men aged 45- 80 years and women aged 55-80 years with a high (top 20%) coronary artery disease (CAD) polygenic risk score. They are prescribed by their primary care physician the trial medication, rosuvastatin 20mg, 1 tablet per day, for the entire duration of the trial. Intervention arm participants will be measured and regular blood analyses will be taken throughout the trial. They will be having regular primary care visits with their family physician and telemedicine visits with study nurses.	Drug: Rosuvastatin 20mg; Preventive statin treatment with rosuvastatin 20mg, 1 tablet per day, for healthy individuals with top 20% CAD PRS.
No Intervention: Control arm; Control arm participants (n=1350) comprise healthy men aged 45- 80 years and women aged 55-80 years with a high (top 20%) coronary artery disease (CAD) polygenic risk score. Participants in the control arm of the trial will be following regular primary care as their family doctors will not be informed of their patients' participation in the trial. This means that in the control arm real-life primary care activities will take place including potential cholesterol-lowering treatment based on the current treatment and prevention guidelines. At the end of the trial, physicians will be informed about their patients who were in the control arm for scheduling a final study visit and ordering a blood test. During the final trial visit the physicians will inform participants of their CAD PRS, provide counselling and take final measurements.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to the first occurrence of Major Adverse Cardiovascular Events (MACE).	Time to the first occurrence of Major Adverse Cardiovascular Events (MACE), ICD-10 codes: ischaemic heart disease (I20-I25), stroke or transient ischemia (I60-64, I69, G45), peripheral vascular occlusion (I65-66, I67.2, I70, I73.9), revascularization (Z95.1, Z95.5, Z95.8, Z95.9) or cardiovascular death (I00-78) from baseline.	From enrollment to three years after the end of treatment.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence rate of death from any cause among the study participants		From enrollment to three years after the end of treatment.
Treatment adherence in the intervention arm.	Treatment adherence in the intervention arm based on prescriptions and purchases of statins (C10AA, C10BA) and self-reporting using the MARS-5 scale	From enrollment to the end of treatment at 5 years.
Fidelity of intervention implementation.	Intervention fidelity will be calculated as a composite score by combining adherence rates (proportion of prescribed activities completed) and participant feedback (average satisfaction and engagement ratings from online questionnaires).	From enrollment to the end of treatment at 5 years.
Acceptability of the primary prevention program across study participants measured using an online questionnaire assessing satisfaction, perceived relevance, and ease of participation.		From first study visit to the end of treatment at 5 years.
Satisfaction with study processes and results measured using an online questionnaire assessing satisfaction, perceived relevance, and ease of participation.		From study enrollment to the end of treatment at 5 years.
Difference in plasma concentrations of rosuvastatin.	Difference in plasma concentrations of rosuvastatin comparing study participants with and without a mutation in the SLCO1B1, ABCG2, CYP2C9, CYP2C19, UGT-d, SLCO1B3, SLCO2B1, ABCC2, ABCB11 genes.	From enrollment to month 3 of treatment.
Difference in rosuvastatin side effects.	Difference in rosuvastatin side effects between study participants with and without a mutation in the SLCO1B1, ABCG2, CYP2C9, CYP2C19, UGT-d, SLCO1B3, SLCO2B1, ABCC2, ABCB11 genes.	From enrollment to the end of treatment at 5 years.
Utilisation of healthcare resources evaluated through a cost-utilty model	Data on healthcare resource utilization, including non-trial physician and cardiologist visits, hospitalizations, length of stay, informal care, and direct healthcare costs, will be aggregated to develop a cost-utility model.	From enrollment to the end of treatment at 5 years.
Number of participants with adverse events and serious adverse events from statin therapy.		From enrollment to the end of treatment at 5 years.
Number of participants who withdrew or dropped out from the study.		From enrollment to the end of treatment at 5 years.
Utilities from the EQ-5L-5D surveys and productivity costs from the iPCQ survey for calculating quality-adjusted life years (QALY) gained over a lifetime, incremental cost-effectiveness ratio (ICER).		From enrollment to the end of treatment at 5 years.
Difference in CVD risk factors from baseline by the end of the trial in the intervention and control arm;	Difference in CVD risk factors from baseline (LDL-cholesterol, blood pressure, BMI, waist circumference, smoking, alcohol consumption prevalence) by the end of the trial comparing the intervention and control arm;	From enrollment to the end of treatment at 5 years.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between gut microbiome composition and functionality and statin side effect occurrence	Logistic regression models will assess the association between CLR-transformed abundances of microbial species (profiled via MetaPhlAn4) and gene families (profiled via HUMAnN 3.0), Shannon diversity index, observed species count, and UniRef90 gene family count at baseline and after treatment initiation, and the likelihood of experiencing statin side effects. Species and gene families prevalent in >5% of samples will be included; zero-imputation applied before CLR transformation.	From enrollment to three years after the end of treatment.
Change from baseline in gut microbiome composition and functionality in statin vs. control arm	Changes in Shannon diversity index, observed species count, UniRef90 gene family count, and CLR-transformed abundances of microbial species (MetaPhlAn4) and gene families (HUMAnN 3.0) will be analyzed using repeated measures ANOVA adjusted for sex, age at baseline, and baseline BMI. Means and SDs will be reported for both arms at baseline and after treatment initiation.	From enrollment to three years after the end of treatment.
Association between baseline gut microbiome composition and functionality and statin treatment efficacy	Linear models adjusted for sex, age at baseline, and baseline BMI will assess the association between baseline Shannon diversity index, observed species count, UniRef90 gene family count, and CLR-transformed abundances of microbial species (MetaPhlAn4) and gene families (HUMAnN 3.0), and statin treatment efficacy. Species and gene families prevalent in >5% of samples will be included.	From enrollment to three years after the end of treatment.

Collaborators and Investigators

• Sponsor: Mikk JÜRISSON
• Collaborators: Tartu University Hospital; The Estonian Health Insurance Fund; North Estonian Medical Center; Funding: European Union (the sponsor does not fund the study)
• Investigators: Study Director: Mikk Jürisson, PhD, Institute of Family Medicine and Public Health, University of Tartu; Principal Investigator: Aet Elken (Saar), PhD, Heart Clinic, Tartu University Hospital; Principal Investigator: Margus Viigimaa, PhD, North Estonia Medical Centre

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2025
• Primary Completion (Estimated): March 1, 2031
• Study Completion (Estimated): March 1, 2034

Study Registration Dates

• First Submitted: January 22, 2025
• First Submitted That Met QC Criteria: February 5, 2025
• First Posted (Actual): February 11, 2025

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Polygenic Risk Score; Statin Treatment for Primary Prevention; High Polygenic Risk Score for Coronary Artery Disease
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Disease Susceptibility; Genetic Predisposition to Disease; Pathological Conditions, Signs and Symptoms; Genetic Risk Score; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydrocarbons; Amides; Pyrimidines; Hydrocarbons, Halogenated; Sulfonamides; Sulfones; Fluorobenzenes; Hydrocarbons, Fluorinated; Rosuvastatin Calcium
• Other Study ID Numbers: EEPRS12308; 2024-513424-42-01 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No