Atherosclerotic Cardiovascular Disease (ASCVD), Atherothrombotic Diseases
Conditions
Keywords
Atherothrombotic diseases, Atherosclerotic cardiovascular disease, Polypill, Colchicine
Brief summary
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.
Detailed description
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 with coronary artery disease 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.
Interventions
DRUGCardiovascular Polypill (Valsartan, Atorvastatin, Aspirin)
Cardiovascular Polypill contains Valsartan, Atorvastatin, Aspirin 1. Valsartan 160 mg + Atorvastatin 40 mg + Aspirin 100 mg or 2. Valsartan 160 mg + Atorvastatin 80 mg + Aspirin 100 mg or 3. Valsartan 320 mg + Atorvastatin 40 mg + Aspirin 100 mg or 4. Valsartan 320 mg + Atorvastatin 80 mg + Aspirin100 mg or 5. Valsartan 80 mg + Atorvastatin 40 mg + Aspirin 100 mg or 6. Valsartan 80 mg + Atorvastatin 80 mg + Aspirin 100 mg or 7. Valsartan 80 mg + Atorvastatin 20 mg + Aspirin 100 mg\* or 8. Valsartan 160 mg + Atorvastatin 20 mg + Aspirin 100 mg\* or 9. Valsartan 320 mg + Atorvastatin 20 mg + Aspirin 100 mg\* * The use of these formulations of the cardiovascular polypill will be restricted to cases of Statin-Related Muscle Symptoms (SRMS)
DRUGColchicine 0.5 mg
Colchicine 0.5 mg once daily
DRUGUsual Care Group
Patients allocated to the usual care arm will receive standard of care therapies for secondary prevention according to the guidelines. Drugs and doses will be left at the discretion of the treating physicians.
DRUGColchicine-placebo 0.5 mg
Matching Colchicine-placebo 0.5 mg once daily
Sponsors
Hospital do Coracao
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The polypill factor will be open-label and controlled by standard treatment (usual care). The colchicine factor will be blinded and controlled by placebo.
Intervention model description
They will be randomized, simultaneously, in a 1:1:1:1 ratio to polypill or usual care, and colchicine 0.5 mg once daily versus placebo, in a 2x2 factorial design. Therefore, the study will have four possible groups: Cardiovascular polypill + colchicine 0.5 mg once daily; Cardiovascular polypill + Colchicine placebo once daily; Usual care + Colchicine 0.5 mg once daily; or Usual care + Colchicine placebo once daily.
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
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, high-risk transient 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; * Known history of chronic kidney disease, stage ≥ 4 (estimated glomerular filtration rate ≤ 30 mL/min, if available); * Known history of cirrhosis or severe liver disease (e.g., transaminase levels \> 3 times the upper limit of normal, if available); * Known history of inflammatory muscle disease (e.g., dermatomyositis or polymyositis) or creatine phosphokinase (CPK) levels \> 3 times the upper limit of normal, if available); * Known history of moderate or severe valvular heart disease with anticipated need for valvular intervention within the next 12 months; * Planned arterial revascularization (inclusion is possible 30 days after completion of all planned procedures); * Left ventricular ejection fraction ≤40% (with the exception of patients with documented intolerance to ACE inhibitors and/or sacubitril/valsartan, who remain eligible for study enrollment); * Heart failure with functional class ≥ III according to the New York Heart Association (NYHA), regardless of left ventricular ejection fraction; * Blood pressure \< 120/80 mmHg in the absence of antihypertensive therapy; * 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; * Current or planned use of oral anticoagulant therapy within the next 12 months (except rivaroxaban 2.5 mg twice daily for patients with peripheral artery disease); * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary efficacy endpoint: Major adverse cardiovascular and limb events (MACLE) | Through study completion, an estimated average of 3 years | Time to cardiovascular death, non-fatal type 1 myocardial infarction, non-fatal ischemic stroke, urgent arterial revascularization, and non-traumatic major lower limb amputation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Key secondary endpoint: Major adverse cardiovascular events (MACE) | Through study completion, an estimated average of 3 years | Time to cardiovascular mortality, non-fatal type 1 myocardial infarction, and non-fatal ischemic stroke. |
| Cardiovascular death | Through study completion, an estimated average of 3 years | Time to cardiovascular death |
| Non-fatal type 1 myocardial infarction | Through study completion, an estimated average of 3 years | Time to non-fatal type 1 myocardial infarction |
| Non-fatal ischemic stroke | Through study completion, an estimated average of 3 years | Time to non-fatal ischemic stroke |
Countries
Brazil
Contacts
STUDY_CHAIRPedro Gabriel Melo de Barros e Silva, P.h.D
Hcor Research Institute
PRINCIPAL_INVESTIGATORLucas tramujas, M.D
Hcor Research Institute
PRINCIPAL_INVESTIGATORErlon Oliveira de Abreu-Silva, M.D
Hcor Research Institute
Outcome results
None listed