Polypill in Acute Coronary Syndrome (POLY-ACS)

• ClinicalTrials.gov Identifier: NCT05514938
• Recruitment Status: Recruiting
• First Posted: August 25, 2022
• Last Update Posted: December 20, 2022
• Sponsor: University of Texas Southwestern Medical Center
• Information provided by (Responsible Party): Ambarish Pandey, University of Texas Southwestern Medical Center

Study Description

Brief Summary:

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 prasugrel 10 mg daily.

Condition or disease	Intervention/treatment	Phase
Acute Coronary Syndrome; Lipid Disorder; Coronary Artery Disease	Drug: Polypill; Drug: Control treatment	Phase 2

Detailed Description:

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 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Polypill Strategy for Evidence-Based Management of Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention in an Underserved Patient Population
• Actual Study Start Date: November 30, 2022
• Estimated Primary Completion Date: April 2023
• Estimated Study Completion Date: April 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Polypill; 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.	Drug: Polypill; Polypill formulation consisting of rosuvastatin, aspirin, and prasugrel.
Active Comparator: Control; 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: Control treatment; Typical prescriptions for post-acute coronary syndrome care including statin, aspirin, and prasugrel.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Number of participants who adhered to medication as assessed by pill count [ Time Frame: 1 month ]
   The number of participants who adhered to medication is assessed by pill count done for each of the participants.
2. Number of participants who adhered to medication as assessed MMAS-8 questionnaire [ Time Frame: 1 month ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Patients admitted with acute coronary syndrome who undergo percutaneous coronary intervention with drug eluting stent placement.

Exclusion Criteria:

1. Age < 18
2. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 as measured by the simplified MDRD formula
3. Current need for inotropes or with cardiac index < 2.2 L/min/m2
4. History of coronary artery bypass graft surgery
5. Current need for systemic anticoagulation
6. Contraindication to receive any components of the polypill
7. History of allergic reaction or intolerance to aspirin, prasugrel, or rosuvastatin
8. Comorbidities that might be expected to limit lifespan within the 1-month study period
9. Inability to provide written informed consent
10. Pregnancy

Contacts and Locations

Contacts

Contact: Ambarish Pandey, MD, MSCS; 214-645-9762; ambarish.pandey@utsouthwestern.edu

Locations

United States, Texas

UT Southwestern Medical Center; Recruiting

Dallas, Texas, United States, 75235

Contact: Ambarish Pandey, MD 214-645-9762 ambarish.pandey@utsouthwestern.edu

Sub-Investigator: Neil Keshvani, MD

Sponsors and Collaborators

University of Texas Southwestern Medical Center

Investigators

• Principal Investigator: Ambarish Pandey, MD, MSCS; UT Southwestern Medical Center

More Information

Publications:

Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Dec 23;64(24):e139-e228. doi: 10.1016/j.jacc.2014.09.017. Epub 2014 Sep 23. No abstract available. Erratum In: J Am Coll Cardiol. 2014 Dec 23;64(24):2713-4. Dosage error in article text.

Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L, Mehran R, Mukherjee D, Newby LK, O'Gara PT, Sabatine MS, Smith PK, Smith SC Jr. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation. 2016 Sep 6;134(10):e123-55. doi: 10.1161/CIR.0000000000000404. Epub 2016 Mar 29. No abstract available. Erratum In: Circulation. 2016 Sep 6;134(10):e192-4.

Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov. 2003 Jan;2(1):15-28. doi: 10.1038/nrd985.

Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005 Oct 8;366(9493):1267-78. doi: 10.1016/S0140-6736(05)67394-1. Epub 2005 Sep 27. Erratum In: Lancet. 2005 Oct 15-21;366(9494):1358. Lancet. 2008 Jun 21;371(9630):2084.

Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004 Apr 8;350(15):1495-504. doi: 10.1056/NEJMoa040583. Epub 2004 Mar 8. Erratum In: N Engl J Med. 2006 Feb 16;354(7):778.

Ho PM, Peterson ED, Wang L, Magid DJ, Fihn SD, Larsen GC, Jesse RA, Rumsfeld JS. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA. 2008 Feb 6;299(5):532-9. doi: 10.1001/jama.299.5.532. Erratum In: JAMA. 2008 May 28;299(20):2390.

Spertus JA, Kettelkamp R, Vance C, Decker C, Jones PG, Rumsfeld JS, Messenger JC, Khanal S, Peterson ED, Bach RG, Krumholz HM, Cohen DJ. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement: results from the PREMIER registry. Circulation. 2006 Jun 20;113(24):2803-9. doi: 10.1161/CIRCULATIONAHA.106.618066. Epub 2006 Jun 12.

Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, Airoldi F, Chieffo A, Montorfano M, Carlino M, Michev I, Corvaja N, Briguori C, Gerckens U, Grube E, Colombo A. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005 May 4;293(17):2126-30. doi: 10.1001/jama.293.17.2126.

Lemstra M, Blackburn D. Nonadherence to statin therapy: discontinuation after a single fill. Can J Cardiol. 2012 Sep-Oct;28(5):567-73. doi: 10.1016/j.cjca.2012.03.018. Epub 2012 May 31.

Roshandel G, Khoshnia M, Poustchi H, Hemming K, Kamangar F, Gharavi A, Ostovaneh MR, Nateghi A, Majed M, Navabakhsh B, Merat S, Pourshams A, Nalini M, Malekzadeh F, Sadeghi M, Mohammadifard N, Sarrafzadegan N, Naemi-Tabiei M, Fazel A, Brennan P, Etemadi A, Boffetta P, Thomas N, Marshall T, Cheng KK, Malekzadeh R. Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial. Lancet. 2019 Aug 24;394(10199):672-683. doi: 10.1016/S0140-6736(19)31791-X.

Munoz D, Uzoije P, Reynolds C, Miller R, Walkley D, Pappalardo S, Tousey P, Munro H, Gonzales H, Song W, White C, Blot WJ, Wang TJ. Polypill for Cardiovascular Disease Prevention in an Underserved Population. N Engl J Med. 2019 Sep 19;381(12):1114-1123. doi: 10.1056/NEJMoa1815359.

Indian Polycap Study (TIPS); Yusuf S, Pais P, Afzal R, Xavier D, Teo K, Eikelboom J, Sigamani A, Mohan V, Gupta R, Thomas N. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. 2009 Apr 18;373(9672):1341-51. doi: 10.1016/S0140-6736(09)60611-5. Epub 2009 Mar 30.

Thom S, Poulter N, Field J, Patel A, Prabhakaran D, Stanton A, Grobbee DE, Bots ML, Reddy KS, Cidambi R, Bompoint S, Billot L, Rodgers A; UMPIRE Collaborative Group. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA. 2013 Sep 4;310(9):918-29. doi: 10.1001/jama.2013.277064. Erratum In: JAMA. 2013 Oct 9;310(14):1507. Naik, Nitish [added]; Reddy, Srinivas [added]; Balaji, Sham [corrected to Achuthan, Shyambalaji]; Damodra Rao, Modem [corrected to Damodra Rao, Kodem].

Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, Pais P, Lopez-Jaramillo P, Leiter LA, Dans A, Avezum A, Piegas LS, Parkhomenko A, Keltai K, Keltai M, Sliwa K, Peters RJ, Held C, Chazova I, Yusoff K, Lewis BS, Jansky P, Khunti K, Toff WD, Reid CM, Varigos J, Sanchez-Vallejo G, McKelvie R, Pogue J, Jung H, Gao P, Diaz R, Lonn E; HOPE-3 Investigators. Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016 May 26;374(21):2021-31. doi: 10.1056/NEJMoa1600176. Epub 2016 Apr 2.

• Responsible Party: Ambarish Pandey, ASSISTANT PROFESSOR, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT05514938
• Other Study ID Numbers: STU2022-0604
• First Posted: August 25, 2022
• Last Update Posted: December 20, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Ambarish Pandey, University of Texas Southwestern Medical Center:

Acute coronary syndrome; Antiplatlet therapy; Statin; Lipids; Drug eluting stent

Additional relevant MeSH terms:

Coronary Artery Disease; Acute Coronary Syndrome; Lipid Metabolism Disorders; Syndrome; Disease; Pathologic Processes; Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Metabolic Diseases