Evaluation of a POlypill and Colchicine for Risk Reduction in Patients With Established Atherosclerotic Cardiovascular Disease

The EPOCA study (Evaluation of a POlypill and Colchicine for risk reduction in patients with established Atherosclerotic cardiovascular disease) will be a randomized, superiority, parallel, 2x2 factorial, multicenter clinical trial which will include at least 7713 and up to a maximum of 10797 participants with established atherosclerotic cardiovascular disease.

Cardiovascular disease is the leading cause of morbidity and mortality worldwide and in Brazil. Additionally, cardiovascular risk factors are highly prevalent conditions which are, frequently, present in association. Despite the last therapeutic advances, rates of adequate control of these conditions are still low. One proposed strategy to increase such control and decrease cardiovascular risk is the use of fixed-dose combinations of different pharmacological classes, to be taken on single daily dose - a polypill. This strategy has already been studied in other parts of the world, especially in patients with established or at risk for coronary heart disease (CHD).

Furthermore, there has been a need to explore other therapeutic targets beyond traditional risk factors that could impact the process of atherosclerosis. Among the various options evaluated, colchicine has emerged as a viable alternative, given its clinical use experience, mechanism of action, and the results showing a reduction in inflammatory biomarkers as well as clinical outcomes in individuals with different manifestations of coronary artery disease. However, it is important to highlight some key points regarding the available studies evaluating both the treatment strategy based on a polypill and the use of colchicine in the context of atherosclerotic cardiovascular disease (ASCVD).

The studies supporting both approaches were primarily conducted with participants from centers in Europe, the U.S., Iran, Oceania, and India, and there is a lack of robust evidence regarding these therapeutic strategies in other countries with a diverse population like Brazil, as well as in individuals with other manifestations of ASCVD (including peripheral arterial disease and cerebrovascular disease).

Given high prevalence of atherosclerotic cardiovascular disease and its traditional risk factors, low control rates, high levels of poor adherence and therapeutic inertia, and the specific realities of the population and healthcare system, evaluating the efficacy of a polypill strategy (fixed-dose an antihypertensive, aspirin, and high-potency statin) with a single daily dose, along with colchicine, in preventing cardiovascular events could contribute to improving cardiovascular care.

Eligibility Criteria:
Inclusion Criteria:

Individuals aged ≥ 45 years AND

● Signature of the Informed Consent Form (ICF) AND at least one of the following criteria:

Previous atherothrombotic cardiovascular event (acute coronary syndrome, ischemic stroke, acute limb ischemia/arterial occlusion, or non-traumatic limb amputation) AND/OR

Previous arterial revascularization (percutaneous, surgical, and/or hybrid) OR

● Diagnosis of significant atherosclerotic disease with ≥ 50% obstruction in any arterial territory (coronary, cerebrovascular, or peripheral), in the absence of a prior cardiovascular event or arterial revascularization.

Exclusion Criteria:

* Pregnant or lactating women;
* Women of childbearing age who do not use any form of contraception;
* Chronic kidney disease, stage ≥ 4 (eGFR ≤ 30 ml/min);
* History of cirrhosis or severe liver disease (transaminase levels exceeding three times the upper limit of normal) in the past 12 months;
* History of inflammatory muscle disease (e.g., dermatomyositis and polymyositis) or creatine phosphokinase (CPK) levels exceeding three times the upper limit of normal in the past 12 months;
* History of moderate to severe valvular heart disease with planned valve intervention within the next 12 months;
* Planned arterial revascularization (inclusion is possible 30 days after completion of all planned procedures);
* Heart failure with functional class ≥ III according to the New York Heart Association (NYHA);
* Life expectancy ≤ 12 months;
* Acute arterial event (acute coronary syndrome, non-cardioembolic ischemic stroke, acute limb ischemia) in the past 30 days;
* Substance abuse/alcoholism;
* Psychiatric and/or neurodegenerative disorder limiting self-care capacity;
* Concurrent participation in another randomized clinical trial;
* Contraindication to any component of the polypill;
* Use of oral anticoagulants (at the time of randomization or under evaluation/planned use in the next 12 months);
* High risk of bleeding (e.g., but not limited to: blood dyscrasias, hemophilia, previous gastrointestinal or central nervous system bleeding);
* Contraindication to colchicine;
* Current use of colchicine.