Patient case: 54-year-old male with malignant hyperthermia; genetic feature: RYR1

Clinical trial: Triple Antithrombotic Therapy in Cardiac Patients Requiring Revascularization

Summary: 1.2. Aim(s)/Objective(s)
  -  To evaluate the safety and efficacy of triple antithrombotic therapy in patients taking DAPT of aspirin and a P2Y12 inhibitor in addition to either a NOAC or warfarin for the prevention of thromboembolic or acute coronary syndrome (ACS) events in patients with non-valvular atrial fibrillation (AF), history of coronary artery disease (CAD)/stent placement or recurrent ACS event.
  -  To determine the Methodist Health System (MHS) prescribing practices and patterns in cardiac patients with a history of AF who are admitted for CAD or an ACS event requiring PCI.
  1.4. Hypothesis 1.4.1. Primary Hypothesis Cardiac patients with a history of AF and an indication for long-term NOAC who are also prescribed DAPT following an ASC event or revascularization with stenting will demonstrate a significant difference in cardiovascular outcomes and major bleeding events when compared with warfarin-based triple therapy.

Detailed description: Atrial fibrillation (AF) is the most common arrythmia in clinical practice that often requires stroke prevention with an anticoagulant. Oral anticoagulation (OAC) with either warfarin or non-vitamin K oral anticoagulants (NOACs) significantly decreases the incidence of ischemic stroke and peripheral embolism in patients with AF.1 Approximately 10% of patients receiving percutaneous coronary intervention (PCI) are found to have a history of AF. 1-3 In cardiac patients requiring PCI with stent placement, dual antiplatelet therapy (DAPT) has been associated with a decreased risk of recurrent myocardial infarction (MI) and stent thrombosis when compared with aspirin alone or the combination of a vitamin K antagonist (VKA) plus aspirin.2 Triple therapy is defined as the concurrent use of OAC, such as warfarin or NOACs, and DAPT with aspirin and a P2Y12 inhibitor such as clopidogrel, prasugrel and ticagrelor.1-4 The most common clinical indication for triple therapy is stroke prevention with OAC in patients with non-valvular AF in the setting of an acute coronary syndrome (ACS) event or PCI with stent placement.5
  Common practice reflects an increase in use of triple therapy for the potential reduction in ischemic events associated with stent placement and AF. Yet, there is limited evidence and guidance on prescribing triple therapy in high risk patients. In American and European guidelines, triple therapy of DAPT with aspirin plus a P2Y12 inhibitor is the standard regimen for the prevention of stent thrombosis, MI, death, and stroke among stented PCI patients.6-8 Specifically, the 2016 European Society of Cardiology (ESC) Guidelines for the management of AF recommends the use of triple therapy with warfarin, clopidogrel and aspirin in AF patients undergoing coronary stenting.9 The 2016 American College of Cardiology (ACC)/ American Heart Association (AHA) focused update on duration of DAPT recommend the initiation of DAPT following an ACS event or stent placement and suggest triple therapy be kept as short as possible citing clopidogrel as the preferred P2Y12 inhibitor.10 Prolonged triple therapy, from 1 month up to 6 months, has been recommended among AF patients at elevated ischemic risk or following an ACS. However, the 2017 ESC focused update on DAPT in patients with coronary artery disease (CAD) recommend for one-month duration of triple therapy or dual therapy using clopidogrel and OAC in patients with bare metal stent (BMS) placement or those with a high risk of bleeding. 11
  Managing OAC in patients on triple therapy is most challenging due to safety concerns with increased risk for major bleeds and clinically relevant non-major bleeds (CRNMB). Triple therapy carries a higher risk of bleeding than DAPT or dual therapy with OAC plus aspirin or a P2Y12 inhibitor. The risk increases as duration increases.5-8 Data from retrospective studies has demonstrated a 3- to 5-fold increase in bleeding rates associated with triple therapy compared with alternative antithrombotic regimens of dual therapy.2-3 Additional strategies hypothesized to decrease bleeding risk was shortening the duration of DAPT for AF patients prescribed triple therapy. The ISAR-TRIPLE trial evaluated the net clinical outcome of reduction in thrombosis and bleeding events in 614 patients requiring OAC undergoing drug-eluting stent (DES) placement after coronary intervention plus DAPT with clopidogrel for 6-weeks versus 6-months.12 The study demonstrated an absolute reduction in Bleeding Academic Research Consortium (BARC) bleeding events among patients with a shorter 6-week duration of triple therapy when compared to a 6-month duration of triple therapy. Nonetheless, the study showed no reduction of net clinical benefit in death, MI, stent thrombosis, stroke, and major bleeding.
  Historically, increased bleeding complications among patients with AF who require PCI was associated with VKA-based triple therapy and prompted the investigation of alternative antithrombotic regimens to minimize bleeding risk.2-4 For AF patients following stent placement, NOACs were shown to be a safe and effective alternative to VKA-based therapy in the secondary prevention of thromboembolic events based on the results of the PIONEER AF-PCI and RE DUAL PCI trials.13-14 In the PIONEER AF-PCI trial, 2124 AF patients who had recently undergone stent placement were randomized to either receive rivaroxaban 15mg once daily plus a P2Y12 inhibitor, low dose rivaroxaban 2.5mg twice daily plus DAPT (P2Y12 inhibitor plus low-dose aspirin), or triple therapy with VKA plus DAPT (P2Y12 inhibitor plus low-dose aspirin).13 Patients on triple therapy were stratified to groups based on the duration of DAPT (1, 3, 6, or 12 months). While the rivaroxaban-based triple therapy regimens were associated with a significant reduction in clinically significant bleeding compared with VKA-based regimens, the rates of CV death, MI, or stroke were comparable among all 3 treatment arms.
  The RE-DUAL PCI trial randomized 2725 AF patients who had undergoing PCI to receive either dual therapy with low dose dabigatran 110 mg plus a P2Y12 inhibitor, dual therapy with full dose dabigatran 150 mg plus a P2Y12 inhibitor, or triple therapy with VKA plus DAPT (P2Y12 inhibitor plus low-dose aspirin).14 The dual therapy treatment arms with both full and low dose dabigatran demonstrated a lower rate of major or clinically relevant non-major bleeding when compared with VKA-based triple therapy. Again, the study showed no difference between groups for rates of the composite endpoint of all-cause death, MI, stroke or systemic embolism, or unplanned revascularization.
  The WOEST trial investigated 573 patients who had undergone PCI to either triple therapy (any OAC plus P2Y12 inhibitor plus aspirin) or dual therapy (OAC plus P2Y12 inhibitor without aspirin).15 The study demonstrated that dual therapy was associated with a significant reduction in both endpoints of bleeding complications and all-cause mortality. The study also showed no reduction in CV mortality and no increase in the rate of thrombotic events.15 It is worth noting that it is unknown whether the results of this study can be extrapolated to NOACs as the majority of patients were on warfarin for OAC.
  Although the various combinations of antithrombotic regimens are not well studied in regards to safety and efficacy, it is suspected that current prescribing patterns for triple therapy are not evidence based. According to the 2016 ACC/AHA guideline focused update on duration of DAPT, ticagrelor is preferred over clopidogrel for maintenance P2Y12 inhibitor therapy in patients with ACS treated with DAPT after coronary stent implantation. This update further complicates the antithrombotic triad that will be prescribed in clinical practice. As demonstrated in a single-center retrospective analysis of antithrombotic prescribing in AF following PCI, less than half of patients received non-evidence-based triple therapy which is suggestive of vast variability in prescribing patterns for triple therapy among cardiologists.16 The purpose of this study is to evaluate the safety and efficacy of triple antithrombotic therapy (Aspirin + OAC + P2Y12 Inhibitor) in patients with non-valvular AF following an ACS event or PCI requiring stent placement and to evaluate prescribing patterns of such therapy.
  1.3. Rationale for the study The rationale for this study is to evaluate the efficacy and 1-, 3-, 6- and 12-month safety outcomes of patients treated with NOAC-based triple therapy following PCI with stenting compared with warfarin-based triple therapy. In order to assess prescribing patterns and practices at MHS, baseline demographics, the PCI procedural characteristics, and bleeding risks will be carefully defined.
  1.5. Potential Risks and Benefits of the study 1.5.1. Potential Risks Due to the retrospective nature of this chart review, clinical intervention will be unaffected by the investigator of this study. The risks include non-permitted disclosure of protected health information and private medical information.
  1.5.2. Potential Benefits Possible benefits include optimization of antithrombotic strategies and regimens in high risk AF patients requiring DAPT and long-term OAC to minimize adverse events related to major bleeds and negative cardiovascular outcomes.
  2. OBJECTIVES AND STUDY OUTCOME MEASURES 2.1. Study Objectives 2.1.1. Primary Objectives:
  -  To evaluate the incidence of thrombosis and readmission rates for major adverse cardiovascular events (MACE) in warfarin-based triple therapy treatment arm compared with NOAC-based triple therapy treatment arm.
  -  To identify the incidence of major bleeding events (defined as all bleeding events that led to hospitalization or presentation to an acute care facility) in patients discharged with warfarin-based triple therapy compared with NOAC-based triple therapy.
  2.1.2. Secondary Objectives:
  -  To identify differences in prescribing patterns and practices among prescribers who initiate DAPT in AF patients on OAC following PCI with stenting.
  -  To assess characteristics, management and outcomes in patients with AF who experience a major bleeding event while taking aspirin, an anticoagulant (NOAC or warfarin) and a P2Y12 inhibitor.
  -  To individually assess the incidence of thrombosis and readmission rates for MACE in the subgroups for each antithrombotic agent: P2Y12 inhibitors (clopidogrel vs. prasugrel vs. ticagrelor) and NOACs (edoxaban vs. dabigatran vs. rivaroxaban vs. apixaban).
  -  To individually assess the incidence of major bleeding events in the subgroups for each antithrombotic agent: P2Y12 inhibitors (clopidogrel vs. prasugrel vs. ticagrelor) and NOACs (edoxaban vs. dabigatran vs. rivaroxaban vs. apixaban).
  2.2. Study Outcome Measures 2.2.1. Primary Outcome
  -  To compare the incidence of MACE, stroke (ischemic and hemorrhage), MI (STEMI and NSTEMI), stent thrombosis, systemic embolism (VTE), death (all-cause, cardiac and non-cardiac) and CAD-associated hospitalizations/ED visits) in patients who received warfarin-based triple therapy versus NOAC-based triple therapy.
  2.2.2. Secondary Outcome(s)
  -  To compare incidence of major bleeding defined by a modified International Society on Thrombosis and Haemostasis (ISTH) criteria17 including documented bleeding events in medical record/progress note, fatal bleeding, symptomatic bleeding into a critical organ, bleeding into a surgical site requiring reoperation, and bleeding that led to hospitalization or an acute care facility in patients who received warfarin-based triple therapy versus NOAC-based triple therapy at 30 days, 90 days, 6 months and 1 year.
  3. STUDY DESIGN
  -  Multi-center, retrospective cohort chart review study design
  -  Data will be collected on all triple therapy recipients who were discharged from a Methodist Health System (MHS) facility with prescriptions for a combination of aspirin, P2Y12 Inhibitor and an OAC of either a NOAC or warfarin between April 1, 2017 - April 1, 2018
  -  Patient list will be generated in EPIC
  -  All data will be obtained from EPIC
  -  All data will be collected retrospectively after the patient is discharged from the hospital
  -  Data collection (planned completion date): May 2019
  4. STUDY ENROLLMENT AND WITHDRAWAL 4.1. Study Inclusion Criteria:
  -  18 years or older
  -  AF diagnosis
  -  ICD10 for ACS, STEMI or NSTEMI
  -  Discharged with triple therapy agents of aspirin, P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor), and OAC (warfarin, edoxaban, dabigatran, rivaroxaban, or apixaban) status post-stent
  4.2. Study Exclusion Criteria:
  -  Patients less than 18 years of age
  -  Prior intracranial bleeding prior to study start date
  -  GI hemorrhage within 1 month prior to study start date
  -  Major bleeding event with 1 month prior to study start date
  -  Hemorrhage disorder
  -  Stroke within 1 month prior to study start date
  -  Cardiogenic shock during admission at start date
  -  Contraindication to use of the study medications
  -  Peptic ulcer in the prior 6 months prior to study start date
  -  Thrombocytopenia (platelet concentration lower than 50×109/L)
  -  Thrombolysis In Myocardial Infarction (TIMI) major bleeding in the prior 12 months of study start date
  -  Pregnancy
  -  History of DVT or PE currently on OAC
  4.3. Premature Termination or suspension of study Due to the retrospective nature of this chart review, determination of premature termination or suspension of study is arbitrary. This study may be suspended or prematurely terminated if there is sufficient reasonable cause. Written notification documenting the reason for study suspension or termination will be provided by the suspending or terminating party. If the study is prematurely terminated or suspended, the principal investigator will promptly inform the IRB and will provide the reason(s) for suspension or termination.
  Circumstances that may warrant termination include, but are not limited to:
  -  Determination of unexpected, significant, or unacceptable risk to subjects
  -  Insufficient adherence to protocol requirements
  -  Data that are not sufficiently complete and/or evaluable
  -  Determination of futility
  5. STATISTICAL CONSIDERATIONS 5.1. Sample Size Considerations This is a retrospective observational study limited to only patients meeting inclusion criteria. Any correlation between the above-mentioned factors and safety or efficacy outcomes will be strengthened by larger cohort of patients. As this is a retrospective study with limited patients available for the cohort, all patients meeting inclusion criteria from April 1, 2017 - April 1, 2018 will be included to obtain the largest sample size possible. This study will include two group comparisons and will also generate a summary and overall evaluation of prescribing patterns of DAPT initiation in patients on OAC or vice versa.
  5.2. Statistical Analysis Plan Descriptive analysis will be performed for all continuous variables. Mean ± standard deviation will be presented for normally distributed variables and median ± interquartile range will be presented for non-normal variables. Count and proportions will be presented for all categorical variables. Normally distributed continuous outcomes will be analyzed with Student's t-test and non-normally distributed continuous outcomes will be analyzed with nonparametric Wilcoxon-Mann-Whitney test. Categorical outcomes will be analyzed using chi-square test or Fisher's exact test for smaller samples.
  6. ETHICS/PROTECTION OF HUMAN SUBJECTS 6.1. Ethical Standard The investigators will ensure that this study is conducted in full conformity with the principles set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, as drafted by the US National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6.
  6.2. Institutional Review Board The protocol and all participant materials will be submitted to the IRB for review and approval. Approval of the protocol will be obtained before any participant information is collected. All document changes will be resubmitted for review by IRB. Only approved documents will be utilized for patients.
  6.3. Informed Consent Waiver
  The investigators ask the IRB to waive consent for this retrospective chart review:
  • This research is not regulated by the FDA
  • The research involves no more than minimal risk to the subjects
  -  The waiver or alteration will not adversely affect the rights or welfare of the subjects
  -  The research could not practicably be carried out without the waiver
  -  It is not feasible to provide subjects with pertinent information after participation
  6.4. Participant Confidentiality Information will be accessed by the principal investigator (PI) or sub-investigators only. Data collected will be stored during the data collection period and while it is being analyzed on computers at Methodist Dallas Medical Center (MDMC) using password protection for the computer and files. Personal identifying information will be deleted from the computer at the end of the described time and any physical copies of information will be placed into confidential shredding boxes located at MDMC.
  7. DATA MANAGEMENT PLAN 7.1. Physical Controls The principal investigator (PI) will maintain adequate and accurate records to enable the conduct of the study to be fully documented and the study data to be subsequently verified. All clinical study documents will be stored in a secure, limited access location. The Investigators will take measures to ensure that these essential documents are not accidentally damaged or destroyed. All clinical study documents will be retained by the PI until at least 3 years after study completion or according to local laws, whichever is longer.
  7.2. Technical Controls All data collected will be de-identified. This is a retrospective study with no intervention, for which a patient incurs no health risk. Informed consent will be waived. All data collected will be entered on a database with access limited to research investigators and will be stored on computers at Methodist Dallas Medical Center (MDMC).
  7.3. Source Document Management Data collected during this study will be recorded on the appropriate source documents. The source data will be collected with the assistance of the electronic medical/health record software. The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB review, and regulatory inspection(s), providing direct access to source data documents.
  7.4. Data Capture Methods Data will be entered regarding drug cost, patient outcomes and technical notes into a database on Methodist Hospital System computer system. Data collected will include patient demographics, primary care provider (PCP), OAC prescriber, DAPT prescriber, date of DAPT initiation, date of OAC initiation, serum creatinine on admission, creatinine clearance on admission, INR on admission, comorbidities (obesity using body mass index (BMI), diabetes, chronic kidney disease, end stage renal disease (ESRD), smoker, and other cardiac-related comorbidities), indication for PCI, artery location of stenosis, type of stent (BMS or DES), PCI vessel location, severity of coronary lesion, percentage of stenosis, fractional flow reserve (FFR) measurement, medications on admission (proton pump inhibitor (PPI), NSAIDs, beta-blocker (BB), ACE inhibitor, statin, diuretic, or calcium channel blocker (CCB)), CHADS2VASc score, HAS-BLED score, total number of bleeding events, location of worst bleeding event, Left Ventricular Ejection Fraction (LVEF), and medications that significantly interact with warfarin (i.e., CYP3A4 inhibitors that increase bleeding risk). All data collected will be entered into an excel sheet and recorded. All data collection methodologies will be maintained under strict surveillance with an encrypted and protected password. All data capture and storage methods will be Health Insurance Portability and Accountability Act (HIPAA) compliant as per Methodist Health System (MHS) policy. All patient identifiers will be deleted from such database collection. Patients will be assigned a random numerical identifier (i.e., patient number) instead. Data reports shall be generated annually or as required in frequency by the IRB and MDMC.
  7.5. Data Use and Sharing The principal investigator (PI) is committed to disseminate research results in a timely fashion. Sharing of data generated by this project will be carried out through presentation at national scientific meetings and/or publication in Open Access Journals. The PI will also make the data and associated documentation available to users only under a data-sharing agreement that provides for: (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the data after analyses are completed.
  8. RECORD RETENTION/ARCHIVING The principal investigator (PI) will maintain, at the investigative site, in original format all essential study documents and source documentation that support the data collected on the study patients in compliance with ICH/GCP guidelines. Study records will be maintained up to 3 years after study closure at the study site location. Records will be destroyed via shredding or medical paper waste management company with proper protocols after the 3-year period. The PI will take measures to ensure that these essential documents are not accidentally damaged or destroyed. If for any reason the PI withdraws responsibility for maintaining these essential documents, custody of the documents will be transferred to an individual who will assume responsibility and CRI and IRB will receive written notification of this custodial change. Records will also be accessible to Methodist Health System (MHS) staff upon request unless constituting a violation of patient confidentiality.
  9. PUBLICATION PLAN All information will be blinded in compliance with GCP. The principal investigator (PI) will make all possible efforts to ensure compliance with all policies regarding sharing of protected health information (PHI) or research information. Only de-identified PHI will be shared in relevant research mediums. These mediums may range from national, regional, local and/or international sites. In addition, study data and findings may be submitted for presentation at the Texas Society of Health-System Pharmacists (TSHP) Alcalde Southwest Leadership Conference and manuscript submitted for publication in American Journal of Cardiology, JAMA Cardiology, European Heart Journal, Journal of American College of Cardiology, JACC: Cardiovascular Interventions, American heart Journal, Journal of the American Heart Association, Heart, CHEST, Clinical Research in Cardiology, Heart Rhythm, European Journal of Preventive Cardiology, or Annals of Pharmacotherapy (AOP).
  10. BUDGET 10.1. Services Cost Total Cost(with 30% indirect cost) IRB Fees Initial Study Review Fee (Includes 1 informed consent) $1,265 $1,644.50 Continuing Review for Main Study File $880 $1,144.00 Study Close Out - Study Level $275 $357.50 Review of Subject Materials (ads, retention, protocol clarification, etc.) (per document) $240 $312.00 Protocol Amendment (no Revised Informed Consent) Per Site $345 $448.50 Protocol Amendment (with Revised Informed Consent) Per Site $420 $546.00 Acknowledgement of Submissions (Safety Reports, etc.) $50 $65.00 Administrative Fees $5,000 $6,500.00 Data Collection (20 hours, $80/h) $1600 $2080.00 Data Analysis (10 hours, $80/h) $800 $1040.00 Education and Training $500 $650.00 Subject Stipend(s) $0 $0.00 Study Coordination and Administration (3 hours, $80/h) $240 $312.00
  Archiving $600 $780.00 Total $11,017.50
  REFERENCES/CITATIONS
  1. Hansen ML, Sorensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010;170:1433-41.
  2. Schomig A, Sarafoff N, Seyfarth M. Triple antithrombotic management after stent implantation: when and how? Heart 2009;95:1280-5.
  3. Nguyen MC, Lim YL, Walton A, et al. Combining warfarin and antiplatelet therapy after coronary stenting in the Global Registry of Acute Coronary Events: is it safe and effective to use just one antiplatelet agent? Eur Heart J 2007;28:1717-22.
  4. Holmes DR Jr., Kereiakes DJ, Kleiman NS, Moliterno DJ, Patti G, Grines CL. Combining antiplatelet and anticoagulant therapies. J Am Coll Cardiol 2009;54:95-109.
  5. Karjalainen PP, Porela P, Ylitalo A, et al. Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting. Eur Heart J 2007;28:726-32.
  6. Mega J, Carreras ET. Antithrombotic therapy: triple therapy or triple threat? Hematology Am Soc Hematol Educ Program. 2012;2012:547-552 https://doi.org/10.1182/asheducation-2012.1.547.
  7. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med. 1998;339(23):1665-1671. https://doi.org/10.1056/NEJM199812033392303.
  8. Nikolsky E, Mehran R, Dangas GD, et al. Outcomes of patients treated with triple antithrombotic therapy after primary percutaneous coronary intervention for ST-elevation myocardial infarction (from the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trial). Am J Cardiol. 2012;109(6):831-838 https://doi.org/10.1016/j.amjcard.2011.10.046.
  9. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38): 2893-2962 https://doi.org/10.1093/eurheartj/ehw210.
  10. Levine GN, Bates ER, Bittl JA, et al. 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;134(10):e123-e155 https://doi.org/10.1161/CIR.0000000000000404.
  11. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. Eur Heart J 2018;39:213-60.
  12. Fiedler KA, Maeng M, Mehilli J, et al. Duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation: the ISAR-TRIPLE trial. J Am Coll Cardiol. 2015;65(16):1619-1629 https://doi.org/10.1016/j.jacc.2015.02.050.
  13. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375(25):2423-2434 https://doi.org/10.1056/NEJMoa1611594.
  14. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377(16):1513-1524 https://doi.org/10.1056/NEJMoa1708454.
  15. Dewilde WJM, Oirbans T, Verheugt FWA, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107-1115 https://doi.org/10.1016/S0140-6736(12)62177-1.
  16. Wang TY, Robinson LA, Ou F-S, et al. Discharge antithrombotic strategies among patients with acute coronary syndrome previously on warfarin anticoagulation: physician practice in the CRUSADE registry. Am Heart J. 2008;155(2):361-368 https://doi.org/ 10.1016/j.ahj.2007.09.003.
  17. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017;377:1319-30.
  18. Zhao HJ, Zheng ZT, Wang ZH, et al. "Triple therapy" rather than "triple threat": a meta-analysis of the two antithrombotic regimens after stent implantation in patients receiving long-term oral anticoagulant treatment. Chest 2011;139:260-70.
  19. Pérez-Gómez F, Alegría E, Berjón J, et al. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol. 2004;44(8):1557-1566 https://doi.org/10.1016/j.jacc.2004.05.084.
  20. Sørensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet. 2009;374(9706):1967-1974 https://doi.org/10.1016/S0140-6736(09)61751-7.
  21. Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9-19https://doi.org/10.1056/ NEJMoa1112277.
  APPENDICES
  1. Appendix A: Data Collection Manual of Operations and Dictionary (see attached)
  2. Appendix B: Data Collection Excel Spreadsheet (see attached)

Eligibility: Inclusion Criteria:
  -  • 18 years or older
  -  AF diagnosis
  -  ICD10 for ACS, STEMI or NSTEMI
  -  Discharged with triple therapy agents of aspirin, P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor), and OAC (warfarin, edoxaban, dabigatran, rivaroxaban, or apixaban) status post-stent
  Exclusion Criteria:
  -  • Patients less than 18 years of age
  -  Prior intracranial bleeding prior to study start date
  -  GI hemorrhage within 1 month prior to study start date
  -  Major bleeding event with 1 month prior to study start date
  -  Hemorrhage disorder
  -  Stroke within 1 month prior to study start date
  -  Cardiogenic shock during admission at start date
  -  Contraindication to use of the study medications
  -  Peptic ulcer in the prior 6 months prior to study start date
  -  Thrombocytopenia (platelet concentration lower than 50×109/L)
  -  Thrombolysis In Myocardial Infarction (TIMI) major bleeding in the prior 12 months of study start date
  -  Pregnancy
  -  History of DVT or PE currently on OAC

Relevance to patient case: not relevant