Polypill in Acute Coronary Syndrome

Study Overview
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Brief Summary
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Acute coronary syndromes (ACS) represent a major contributor to mortality, morbidity, and healthcare costs. Effective therapies are widely available; however, adherence is low. This contributes to worse patient outcomes and increased risk of morbidity and mortality. The once-daily polypill leverages a population-based strategy that has previously demonstrated efficacy in improving adherence and access to therapy in low-resource settings, making it an innovative approach for improving post-ACS care. This study aims to investigate the utility of a polypill-based strategy for patients with ACS with drug eluting stent (DES) placement. The polypill will consist of a high-intensity statin (rosuvastatin 40 mg daily), aspirin 81 mg daily, and either clopidogrel 75 mg or prasugrel 10 mg daily.

Detailed Description
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Acute coronary syndromes (ACS) represent a large contributor to patient morbidity and mortality and healthcare costs. Patients with suspected ACS are referred for diagnostic coronary angiography, and if obstructive coronary disease is found, percutaneous coronary intervention (PCI) with a drug-eluding stent (DES) has been proven to reduce mortality and reduce recurrent myocardial infarction. Medical therapy for ACS involves treatment with a statin and dual antiplatelet drug therapy with aspirin and P2Y12 inhibition. Dual antiplatelet therapy (DAPT) is a vital aspect of post-PCI care and ensures stent patency. Aspirin blocks metabolism of arachidonic acid and production of thromboxane A2 through irreversible inhibition of cyclooxygenase 1. Prasugrel and clopidogrel are irreversible inhibitors of the platelet P2Y12 ADP receptors, while ticagrelor is a reversible inhibitor of the platelet P2Y12 ADP receptor. Current guidelines recommend dual antiplatelet therapy for at least 1 month and ideally up to 1 year for patients treated medically, and at least 1 year for patients treated with DES after hospitalization for ACS. Additionally, lipid lowering therapy is a cornerstone of post-ACS care. Multiple studies have demonstrated a direct correlation between low-density lipoprotein cholesterol (LDL-C) levels and ASCVD risk. Statins (3-hydroxy-3-methylgultaryl-coenzyme A reductase inhibitors) are first-line therapies used to achieve LDL-C reductions. High-intensity statins, such as atorvastatin 40 mg or 80 mg or rosuvastatin 20 mg or 40 mg, can lower LDL-C by > 50%, and patients with history of ACS have greater benefit from high-intensity statins versus low-intensity statins. Importantly, administration of a high-intensity statin is a Class 1 recommendation from the AHA/ACC Non-ST-Elevation ACS guidelines and the ST-Elevation ACS guidelines. The combination of prompt diagnosis of ACS, management with coronary angiography with possible DES placement, and medical therapy including DAPT has led to improvements in ACS mortality. However, nonadherence to cardiovascular medications is common. Data from the US Veteran's Affair's hospitals show that nearly 30% of patients did not refill clopidogrel after index hospitalization for ACS. In a study of the PREMIER registry, one in seven patients stopped taking clopidogrel therapy after 1 month, and those who stopped had ninefold elevated risk of death within 1 year. Poor adherence to antiplatelet therapy with either aspirin or P2Y12 inhibitors can lead to in-stent thrombosis, a particularly morbid occurrence characterized by high patient morbidity and mortality. Early stoppage of dual antiplatelet therapy increases risk of stent thrombosis 90-fold. Nonadherence to statins is also well documented. Roughly 1/3 of ischemic heart disease is related to dyslipidemia, and statins are the mainstay of treatment. However, roughly 25-50% of patients discontinue their statin therapy within the first year after treatment initiation. Lipid reduction is a proven strategy to prevent further cardiovascular events, however, medication nonadherence is a significant barrier. The polypill is a potential strategy for increasing utilization of proven ACS therapies. The polypill refers to a fixed-dose combination of once-daily medication with proven benefits. The feasibility of a polypill-based strategy has been demonstrated for the primary prevention of cardiovascular events. Among patients with hypertension at a federally qualified community health center, the polypill led to a reduction in systolic blood pressure (-7 mm Hg, 95% CI: -2 to -12; p=0.003) and low-density lipoprotein cholesterol (-11 mg/dl, 95% CI: -5 to -18; p=0.0003). Multi-drug combinations have additionally been employed in the Indian Polycap Study, HOPE-3 trial, UMPIRE trial and most recently in the PolyIran study, which demonstrated high rates of adherence, and low rates of adverse events.13-16 In PolyIran, the largest of these studies, more than 6500 healthy individuals were enrolled and randomized to treatment with a polypill containing low doses of a thiazide diuretic, aspirin, statin, and ACE/ARB versus no pharmacologic intervention for primary prevention of cardiovascular disease. Among those receiving the polypill, a 34% risk reduction in major cardiovascular events was observed compared to standard treatment. In the smaller UMPIRE trial, moreover, adherence among participants receiving a polypill formulation was more than three-fold higher than in those receiving usual care. Few studies have enrolled disadvantaged U.S populations to date and no study to our knowledge has evaluated a polypill strategy for treatment of heart failure, where pill burden and adherence continue to present obstacles to improving care. No randomized trial has evaluated a polypill strategy for the treatment of ACS. Given the significant pill burden and challenges with adherence, a polypill strategy may have substantial advantages. Thus, we have planned a single-center, open-label, pragmatic pilot study of a polypill-based strategy for the treatment of ACS. The polypill will consist of a high-intensity statin (rosuvastatin 40 mg daily), aspirin 81 mg daily, and clopidogrel 75 mg or prasugrel 10 mg daily. The rationale for the trial is summarized as follows: Acute coronary syndromes represent a major contributor to mortality, morbidity, and healthcare costs Effective therapies are widely available; however, adherence is low. This contributes to worse patient outcomes and increased risk of morbidity and mortality. The once-daily polypill leverages a population-based strategy that has previously demonstrated efficacy in improving adherence and access to therapy in low-resource settings, making it an innovative approach for improving post-ACS care.

Official Title
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Polypill Strategy for Evidence-Based Management of Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention in an Underserved Patient Population

Conditions
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Acute Coronary Syndrome, Lipid Disorder, Coronary Artery Disease

Intervention / Treatment
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* Drug: Polypill
* Drug: Usual Care (individual medications prescribed by primary cardiologist)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Patients admitted with acute coronary syndrome who undergo percutaneous coronary intervention with drug eluting stent placement. Exclusion Criteria: Age < 18 Estimated glomerular filtration rate < 30 mL/min/1.73 m2 as measured by the simplified MDRD formula Current need for inotropes or with cardiac index < 2.2 L/min/m2 History of coronary artery bypass graft surgery Current need for systemic anticoagulation Contraindication to receive any components of the polypill History of allergic reaction or intolerance to aspirin, prasugrel or rosuvastatin, or rosuvastatin Comorbidities that might be expected to limit lifespan within the 1-month study period Inability to provide written informed consent Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Polypill<br>Patients will be randomized to receiving a fixed-dose polypill in addition to other guideline-directed medical therapies prescribed by their physician. Polypill formulations will include rosuvastatin 40 mg, aspirin 81 mg, and prasugrel 10 mg daily or rosuvastatin 40 mg, aspirin 81 mg, and clopidogrel 75 mg. | Drug: Polypill<br>* Polypill formulation consisting of rosuvastatin, aspirin, and prasugrel or consisting of rosuvastatin, aspirin, and clopidogrel.<br>|
| Active Comparator: Usual Care (individual medications prescribed by primary cardiologist)<br>Patients will receive usual post-ACS care and medications prescribed by their provider. All of the individual components will be available at low- or no-cost to participants as individual pill formulations. | Drug: Usual Care (individual medications prescribed by primary cardiologist)<br>* Typical prescriptions for post-acute coronary syndrome care including statin, aspirin, and prasugrel or clopidogrel.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who adhered to antiplatelet drug therapy | The number of participants who adhered to antiplatelet drug therapy is assessed by platelet function aggregometry testing. | 1 month | 
| Number of participants who adhered to statin therapy | The number of participants who adhered to statin therapy is assessed by LDL-C (low density lipoprotein-cholesterol ) levels via lab draw. | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who adhered to medication as assessed by pill count | The number of participants who adhered to medication is assessed by pill count done for each of the participants. | 1 month | 
| Number of participants who adhered to medication as assessed MMAS-8 questionnaire | The number of participants who adhered to medication will be assessed by Morisky Medication Adherence (MMAS-8) questionnaire which is a validated assessment tool used to measure non-adherence. Possible scores range from 0 to 8, with higher scores indicating higher adherence. | 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Statin, Acute coronary syndrome, Antiplatlet therapy, Lipids, Drug eluting stent