Article

Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome: Study Rationale and Design (ASTRO-APS)

Clinical and Applied Thrombosis/Hemostasis 1-9 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029615615960 cat.sagepub.com

Scott C. Woller, MD1,2, Scott M. Stevens, MD1,2, David A. Kaplan, MD2, D. Ware Branch, MD1,3, Valerie T. Aston, BS1, Emily L. Wilson, MS4, Heather M. Gallo, BS1, Eric G. Johnson, MPH1, Matthew T. Rondina, MD2, James F. Lloyd, BS5, R. Scott Evans, PhD5,6, and C. Gregory Elliott, MD1,2

Abstract Background: Antiphospholipid syndrome (APS) is an acquired thrombophilia characterized by thrombosis, pregnancy morbidity, and the presence of characteristic antibodies. Current therapy for patients having APS with a history of thrombosis necessitates anticoagulation with the vitamin K antagonist warfarin, a challenging drug to manage. Apixaban, approved for the treatment and prevention of venous thrombosis with a low rate of bleeding observed, has never been studied among patients with APS. Aims and Methods: We report study rationale and design of Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome (ASTRO-APS), a prospective randomized open-label blinded event pilot study that will randomize patients with a clinical diagnosis of APS receiving therapeutic anticoagulation to either adjusted-dose warfarin or apixaban 2.5 mg twice a day. We aim to report our ability to identify, recruit, randomize, and retain patients with APS randomized to apixaban compared with warfarin. We will report clinically important outcomes of thrombosis and bleeding. All clinical outcomes will be adjudicated by a panel blinded to the treatment arm. A unique aspect of this study is the enrollment of patients with an established clinical diagnosis of APS. Also unique is our use of electronic medical record interrogation techniques to identify patients who would likely meet our inclusion criteria and use of an electronic portal for follow-up visit data capture. Conclusion: ASTRO-APS will be the largest prospective study to date comparing a direct oral anticoagulant with warfarin among patients with APS for the secondary prevention of thrombosis. Our inclusion criteria assure that outcomes obtained will be clinically applicable to the routine management of patients with APS receiving indefinite anticoagulation. Keywords anticoagulants, deep venous thrombosis, lupus inhibitor, venous thromboembolism, pulmonary embolism, stroke

Introduction Antiphospholipid syndrome (APS) is an acquired thrombophilia characterized by thrombosis involving venous and/or arterial circulation, pregnancy morbidity, and the presence of characteristic antibodies.1 Primary APS affects less than about 0.5% of the general population.2 However, APS has a predilection for individuals afflicted by connective tissue disorders (secondary APS), particularly systemic lupus erythematosus. Approximately 50% of patients with systemic lupus erythematosus and antiphospholipid antibodies have a history of either venous or arterial thrombosis.3-5 Patients with APS are at an approximately 16-fold increased risk of venous thromboembolism (VTE).6 A cornerstone of APS therapy among patients with a history of thrombosis is indefinite anticoagulation with the vitamin K antagonist warfarin,7 a challenging drug to manage. Thromboembolism

1

Intermountain Medical Center, Murray, UT, USA Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA 3 Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, UT, USA 4 Division of Statistics, Intermountain Medical Center, Murray, UT, USA 5 Department of Medical Informatics, Intermountain Healthcare, Murray, UT, USA 6 Department of Biomedical Informatics, University of Utah, Salt Lake City, UT, USA 2

Corresponding Author: Scott C. Woller, Intermountain Medical Center, University of Utah School of Medicine, Eccles Outpatient Care Center, 5169S Cottonwood St Suite #307, Murray, UT 84107, USA. Email: [email protected]

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(venous and arterial thrombosis combined) recurred in 1.25% to 1.50% of patients with APS annually receiving doseadjusted warfarin targeting an international normalized ratio (INR) of 2 to 3 in clinical trials.8,9 In a large populationbased observational registry of patients with APS, within 5 years 25% developed thrombosis, despite most receiving anticoagulation.10 Among patients with APS who experienced objectively documented recurrent thrombosis while on therapy, one-half occurred when their INR was below the predetermined target range.9 Concerningly, among patients with APS receiving warfarin with a target INR of 2 to 3, the rate of major bleeding is 1.5% to 2.5% per year.8,9 An oral anticoagulant that requires no monitoring and delivers reliable therapeutic anticoagulation would be of great interest for use among patients with APS. Apixaban, a selective direct factor Xa inhibitor, is believed to terminate the burst of thrombin generation and result in inhibition of thrombus formation with a favorable safety profile. Apixaban has been studied for the treatment and prevention of venous thromboembolic disease,11,12 in addition to stroke prevention among patients with nonvalvular atrial fibrillation,13,14 and additional evidence suggests that among the direct oral anticoagulants (DOACs), the risk of major bleeding with apixaban is low.11-13 Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome (ASTRO-APS) is a phase IV pilot study designed to provide data regarding the aspects of feasibility for enrolling patients with APS and to estimate event rates surrounding efficacy and safety of apixaban compared with usual care for the prevention of recurrent thrombosis among patients with APS (http://clinicaltrials. gov; NCT02295475). ASTRO-APS, along with 2 studies,15,16 represent the first clinical trial use of DOACs among patient with APS.

Study Aims and Hypothesis This pilot study has 2 primary aims. The first aim addresses feasibility of study execution and is to identify patients with a clinical diagnosis of APS and then describe their recruitment, enrollment, screening failure rate, adherence to therapy, clinical characteristics, and APS diagnostic criteria in terms of broadly accepted published standards.1 Essential in this aim is determination of our ability to identify, recruit, randomize, and retain patients with APS receiving a DOAC. We will also report compliance and patient satisfaction, central to durable anticoagulation management. The second aim is to report an estimate of the rates of thrombosis (arterial or venous) and death caused by thrombosis as well as major bleeding plus clinically relevant nonmajor bleeding over 1 year among patients with APS randomized to either warfarin or apixaban.

Study Design Overview ASTRO-APS is a prospective, randomized, open-label blinded event pilot study that will enroll patients from 2 health care

systems (Intermountain Healthcare and University Healthcare, University of Utah) with a clinical diagnosis of APS receiving therapeutic anticoagulation for the prevention of recurrent thrombosis. Our protocol was reviewed by the Intermountain Healthcare institutional review board (IRB) and the University of Utah IRB. The latter granted reciprocity to Intermountain Healthcare allowing for all study-related IRB processes to be managed through one IRB. A data safety monitoring board (DSMB) consisting of physicians expert in thrombosis (a cardiologist, a neurologist, and an academic emergency medicine physician) was empaneled for ASTRO-APS. The DSMB will be aware of events attributable to each treatment arm and compare event rates observed among patients randomized to each group. All outcomes of thrombosis and bleeding will be adjudicated by a committee whose members will be unaware of (blinded to) the treatment assignments. All deaths will be adjudicated as to whether attributable to thrombosis, bleeding, or another cause.

Patient Identification, Recruitment, Eligibility, and Classification We define adult patients with a clinical diagnosis of APS who are actively receiving anticoagulation for the secondary prevention of thrombosis and are at least 6 months removed from thrombosis as eligible. To identify patients who would likely meet inclusion criteria, we used electronic medical record (EMR) interrogation techniques17,18 to probe the Intermountain Healthcare EMR for patient criteria that would likely meet eligibility. Intermountain Healthcare is a not-for-profit, integrated health care system of 22 hospitals and greater than 160 clinics throughout Utah and Southeastern Idaho providing medical care for approximately half of Utah residents. This system has a centralized data repository of all clinical encounters, prescriptions, diagnostic studies, and laboratory tests. Patients with International Classification of Diseases, Ninth Revision (ICD-9) codes representative of APS, or laboratory studies supportive of a diagnosis of APS, in addition to active therapeutic anticoagulation defined as an INR > 1.5 were identified. We then employed a similar EMR interrogation technique to identify likely eligible patients in the University of Utah Healthcare system. Details regarding our EMR interrogation to identify patients who would likely meet inclusion criteria are found in Table 1. We employed a novel approach to patient identification and recruitment. Using the results of our EMR interrogation, we generated a postal mailing list and e-mail mailing list obtained from the respective EMRs. Collaborating with the Intermountain Healthcare Office of Research, we drafted 3 documents. The first was a letter signed by the principal investigator and the Director of the Office of Research introducing ASTROAPS and providing context regarding the communication being based on our institution’s ongoing mission to enhance patient safety, provide quality, and advance medical knowledge through clinical research. The second was a letter providing a layperson summary of the study design, brief inclusion and

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Table 1. Electronic Medical Record Interrogation to Identify Likely Candidates for ASTRO-APS.a Filter

Intermountain Healthcare, n

Lupus anticoagulant present

584

Anticardiolipin IgG/IgM  20 GPL/MPL

213

University of Utah, n

Anti-beta-2-GP-1 IgG/IgM  20 GPL/MPL

29

Diagnostic ICD-9 code supportive of APS

167b

422c

Active anticoagulation

731d

422e

668

422

668

422

Living Total meeting inclusion criteria

Abbreviations: ASTRO-APS, Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome; Ig, immunoglobulin; GPL, IgG Phospholipid Units; MPL, IgM Phospholipid Units; ICD-9, International Classification of Diseases, Ninth Revision; INR, international normalized ratio. a Patients had to meet 1 criteria in the light grey row, or 1 in the lined row plus all criteria in the dark grey rows to be included for contact (bottom row bold). b ICD-9 codes of 289.81 were supportive of APS being present. c 289.81 and 286.53 were supportive of APS being present. d Defined warfarin use as an INR > 1.5. e Defined warfarin use as an active prescription for warfarin.

exclusion criteria, and directions regarding how the patient could obtain more information. Each letter included an e-mail address, telephone number, Web site address, and quick response (QR) code that links directly to the centralized ASTRO-APS Web site (see subsequently). The third document was an amalgamation of the first and second letters for the text of an e-mail. To optimize communication and streamline patient recruitment, we created a Web site and e-mail address that serves as a central information repository and communication portal for patients interested in learning more about ASTRO-APS or being contacted for potential enrollment (https://intermountainhealthcare.org/hospitals/imed/research/ Pages/aps-study-ssl.aspx). To further enhance patient recruitment, we performed an internet search to identify Web sites (eg, Facebook pages with an emphasis on APS) and electronic resources (eg, blogs regarding APS) where individuals who would likely have interest in, and eligibility to participate in our study, might congregate. We created a schedule for posting IRB-approved publicity regarding ASTRO-APS and links to our Web site at routine intervals. Interested patients can link to our Web site behind the Intermountain Healthcare firewall and leave their information in a secure communication requesting a call back regarding ASTRO-APS. Then, the research coordinator uses a standardized inclusion/exclusion checklist to interview and screen patients for participation. All screen failures are captured for cause of failure. Because we anticipate heterogeneity among patients with a clinical diagnosis of APS receiving indefinite anticoagulation and for descriptive purposes, we will define APS as being definite APS, likely APS, or historical APS. Definite APS patients will be defined as patients who report having APS with: (1) occurrence of a qualifying thrombotic event based on a radiology report supportive for thrombosis along with (2) the presence of lupus anticoagulant or anticardiolipin immunoglobulin (Ig) G or IgM or anti-b-2 glycoprotein 1 IgG or IgM >40 IgG phospholipid Units (GPL) or IgM Phospholipid Units (MPL) or

> the 99th percentile, on 2 separate occasions at least 12 weeks apart.1 Likely APS patients will be defined as patients who report having APS with (1) occurrence of a qualifying thrombotic event based on a radiology report supportive for thrombosis along with (2) the presence of lupus anticoagulant or anticardiolipin IgG or IgM or anti-b-2 glycoprotein-1 IgG or IgM > 40 GPL or MPL, or > the 99th percentile at least on 1 occasion. Historical APS patients will be defined as patients who report having APS with (1) active therapeutic anticoagulation for the secondary prevention of thrombosis and report of a qualifying thrombotic event along with (2) a reported history of abnormal laboratory testing, but result not available. While this approach considers eligible a more broad group of patients than those who strictly meet the guideline consensus definition of APS,1 we believe that this approach will increase the generalizability of our findings, as clinicians are often confronted with patients labeled as APS who fit these categories. Also, we will be able to characterize the screened population according to these groups, which would further inform the planning of a future large trial. All patients will have APS studies performed at each visit, and the results (excluding the lupus anticoagulant panel) will also be considered for classification.

Apixaban Dosing Rationale Published phase 3 clinical trials have compared apixaban 5 mg twice a day and 2.5 mg twice a day with placebo for the prevention of recurrent venous thrombosis.11 Apixaban for Extended Treatment of Venous Thromboembolism (AMPLIFY-EXT) was designed to determine whether apixaban 2.5 mg twice a day was as effective and associated with less bleeding than apixaban 5 mg BID and to examine the effect of treatment on arterial thrombotic outcomes. In AMPLIFY-EXT, symptomatic recurrent VTE or death from VTE occurred in 8.8% of patients who received placebo, 1.7% who received apixaban 2.5 mg twice a day, and 1.7% who received apixaban 5 mg

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twice a day. The relative risk of cardiovascular death, stroke, and myocardial infarction (MI) comparing apixaban 2.5 mg twice a day with placebo was 0.36 (95% confidence interval (CI 0.11-1.12). The rates of major bleeding and clinically relevant nonmajor bleeding did not differ between groups. The authors of AMPLIFY-EXT concluded that extended anticoagulation with apixaban at either 5 mg BID or 2.5 mg BID reduced the risk of recurrent VTE without increasing the rate of major bleeding.11 We additionally note that apixaban 2.5 mg BID was used safely among patients with renal insufficiency (serum creatinine of 1.5 mg/dL to 2.5 mg/dL; 133 mmol/L to 221 mmol/L). Because renal insufficiency may occur among patients with APS,19 we perceived this dosing to be favorable. Choosing apixaban 2.5 mg BID allows patients with mild-tomoderate renal insufficiency to be enrolled and thus likely enhances patient enrollment. Patients enrolled in AMPLIFYEXT most closely represent the patient population that we will enroll. Apixaban 2.5 mg BID has been approved by the FDA for the secondary prevention of recurrent VTE among patients who have completed initial therapy for VTE.20

Warfarin Regimen and Rationale Retrospective studies of APS patients managed in the 1980s and 1990s suggested that only high-intensity oral anticoagulation (INR >3) was effective in preventing thrombotic recurrence.21-23 However, high-intensity warfarin anticoagulation is associated with an increased risk of bleeding.24 In prospective trials, investigators observed that high intensity anticoagulation compared with a target INR 2 to 3 was associated with no meaningful reduction in thromboembolic events, yet an increased risk of bleeding.8,9 Thus, recent guidelines25,26 and expert opinion27,28 recommend that patients with APS receiving anticoagulation for the indication of secondary prevention of thrombosis receive dose-adjusted warfarin to a target INR range of 2 to 3 unless special circumstances call for a higher INR. However, some patients are presently managed at a higher INR target based upon clinical circumstances and physician judgment, and the use of warfarin with a target INR 3 to 4 is still considered a valid therapeutic option. We acknowledge equipoise regarding the comparative effectiveness of warfarin (at a physician selected INR target range) and apixaban. It is for this reason that we will consider eligible patients receiving warfarin anticoagulation with an INR target including the INR 2.0. Should such patients be randomized to warfarin, they will continue at their prescribed target INR range which will be recorded, and we will report time in therapeutic range. Should those patients randomized to apixaban, they will receive apixaban 2.5 mg twice a day per study routine. Patients who have a higher target INR range because of event while therapeutic on warfarin at a lower target INR will be excluded.

Primary Outcomes For this pilot study, we will report metrics of our ability to identify, recruit, randomize, and retain patients with APS receiving

a DOAC as well as compliance and patient satisfaction, central to durable anticoagulation management. These outcomes will inform estimates for a larger clinical trial. We have intentionally for the purposes of this pilot study chosen enrollment criteria that include patients who report a clinical history of APS and are receiving therapeutic anticoagulation, however, for whom the diagnosis of APS may have been made years ago and/or for whom laboratory data may not meet diagnostic criteria traditionally adopted in clinical trials. This approach is meaningful, because we will report the rate of patients who present with historical, suspected, and definite APS, information that will inform screening and power analyses for larger prospective randomized clinical trials. Additionally ‘‘real world’’ clinicians need to know what the management choices are for patients they see that are labeled APS given they routinely encounter patients with the label of APS who do not meet the strict criteria. The second aim of this study is to report clinically important events including the primary clinical efficacy outcome, which will be the combined rate of clinically overt thrombosis (VTE, arterial thrombosis, MI, and thrombotic stroke) and vascular death. Venous thromboembolism will be defined as symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) that has been objectively confirmed by a compression ultrasonography, venography, pulmonary-perfusion scan, spiral computed tomography scan, MRA¼ or pulmonary angiogram using defined criteria29-32. Death will be ascribed to thrombosis for cases with a documented diagnosis of (1) MI, pulmonary embolism, or stroke in the absence of any other evident cause, (2) sudden death, and (3) death from heart failure, or (4) death classified clinically as being cardiovascular in nature as previously defined.8 When available autopsy results will be used. Thrombotic stroke will be defined as a clinical diagnosis made on the basis of typical symptoms (abrupt onset of a neurological deficit) lasting at least 24 hours with supportive imaging (mandatory). Acute arterial thrombosis will be diagnosed in the presence of a typical clinical picture (pain and absence of peripheral pulse) with arteriography or surgical findings of thrombosis as previously defined.8 Myocardial infarction will be considered present should at least 2 of the following occur: (1) chest pain of typical intensity and duration, (2) ST segment elevation or depression of 1 mm any limb lead of the electrocardiogram, or 2 mm in any precordial lead, or both, or (3) at least a doubling in cardiac enzymes.8 Ultimately all outcomes will be adjudicated by a committee whose members will be unaware of (blinded to) the treatment assignments. Outcomes are displayed in Table 2.

Primary Safety Outcome The primary safety outcome will be the combined rate of major bleeding and clinically-relevant nonmajor bleeding. Bleeding will be classified as major, clinically relevant non-major, or nuisance bleeding. We define major bleeding in a standardized fashion33 as performed by others,13 as overt bleeding accompanied by one or more of the following: a decrease in the

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Table 2. ASTRO-APS Study Aims. First Aim: Study execution Clinical study performance  Describe ability to reliably identify patients with APS  Describe ability to recruit and randomize patients with APS  Describe ability to retain APS patients in the study for 1 year  Describe screen failure rate  Describe adherence to therapy  Describe patient characteristics Second Aim: Clinical outcomes  Primary clinical efficacy outcome: clinically overt thrombosis  Deep venous thrombosis (all circulations)  Pulmonary embolism  Myocardial infarction  Stroke  Peripheral arterial occlusion  Vascular death Primary safety outcome: clinically overt bleeding  Major bleeding  Clinically relevant non-major bleeding Additional outcomes  Net clinical outcome comparison of apixaban and warfarin  Patient satisfaction using a standardized questionnaire Abbreviation: ASTRO-APS, Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome.

hemoglobin level of 2 g per deciliter or more over a 24-hour period, transfusion of 2 or more units of packed red cells, bleeding at a critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal), or fatal bleeding. Clinically relevant nonmajor bleeding will be defined as overt bleeding that does not satisfy the criteria for major bleeding and that led to hospital admission, physician-guided medical or surgical treatment, or a change in antithrombotic therapy.14 Nuisance bleeding will be defined as any other bleeding reported by the patient who does not meet the aforementioned criteria for major bleeding or clinically relevant nonmajor bleeding, and will be recorded. We will report for the analyses of bleeding events all patients who received at least 1 dose of a study drug and include all events from the time the first dose of a study drug was received until 2 days after the last dose was received as has been performed by others.14

Secondary Outcomes Important secondary outcomes pertain to clinical events in addition to feasibility for a definitive trial. We will report the rate of the net clinical benefit outcome of thrombosis (VTE, arterial thrombosis, MI, and stroke) and bleeding (major bleeding and clinically relevant bleeding) among patients randomized to apixaban or warfarin. The net clinical outcome is a cumulative representation of any benefit and harm attributable to the study intervention compared with usual care. The net clinical outcome will include the clinical outcomes of thrombosis and bleeding from the time the patient received the first dose

of the study drug through 2 days after they received the last dose as has been previously described.14 Regarding study feasibility, we will report the accrual of patients who meet the criteria for definite APS in comparison to all that have a clinical diagnosis of APS as defined above. We will also report rates of consent and compliance with the protocolized administration of study medications. Patient satisfaction will be measured at the time of enrollment and at study encounters using the Anti-Clot Treatment Scale (ACTS). ACTS is a validated patient satisfaction questionnaire that was derived34 and implemented35 comparing a DOAC to warfarin. Outcomes of patient satisfaction will be recorded using a standardized form, and comparisons will be made at baseline and upon follow-up between patients randomized to warfarin and apixaban.

Assessment of Outcomes and Follow-Up A graphic representation of the study timeline and follow-up is found in Figure 1. After enrollment, in-person visits will occur at 6 and 12 months. We will employ electronic data capture for routine follow-ups primarily using e-mail to communicate with enrolled patients through REDCap (Research Electronic Data Capture, Harvard Catalyst, The Harvard Clinical and Translational Science Center, Boston, MA, USA) hosted at Intermountain Medical Center. REDCap is a secure, web-based application designed to support data capture for research studies that provides data entry, audit trails for tracking data and export, data downloads to common statistical packages, and electronic communication portals for patient surveys with assimilation of results.36 A secure link to the patient study data capture site behind the Intermountain Healthcare firewall will be embedded in routinely schedule study visit follow-up emails. REDCap will automatically send surveys directly to the patient’s e-mail and capture data at months 1, 3, 9, and 13. Any patient response that suggests an outcome of interest generates an alert to the study coordinator, and the patient is contacted directly. Patients who do not respond to the e-mail inquiry are contacted by telephone. At the end of the study, a standardized protocol37 to transition those patients randomized to apixaban back to warfarin will be employed. Final patient follow-up for safety and outcomes will occur 1 month after study drug discontinuation. In the case of a bleeding or thrombotic outcome event, subsequent management will occur at the discretion of the treating clinician, and all decision making regarding the application of anticoagulation management will be recorded. Those patients who experience a primary clinical outcome will be thereafter censored and not eligible to contribute to another primary outcome. All patients will be followed until data capture of the last enrolled patient is completed.

Sample Size, Statistical Analysis, and Data Management Previous work by Crowther and Finazzi has reported a rate of VTE among patients with APS anticoagulated with a target

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Figure 1. ASTRO-APS study design. ASTRO-APS indicates Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome.

INR of 2.5 (range 2-3) being 3.4% over 2.7 years9 to 5.5% over 3.6 years.8 These studies suggest a rate of recurrent thrombosis and vascular death among patients with APS receiving warfarin anticoagulation for the secondary prevention of thrombosis (target INR range 2-3) approximating 1.5% per year. We identified upon electronic interrogation a total of 1090 patients who might meet study inclusion criteria. We endeavor to randomize 100 patients into each arm. While the sample size available to us is not amenable to identifying statistically significant differences in thrombosis or mortality rates under a noninferiority, superiority, or equivalence test design, we will report rates of thrombosis and vascular death as well as major and clinically relevant nonmajor bleeding, which then might inform a future randomized clinical trial. We will describe patient demographics (age, sex, weight, body mass index, etc.) with means and proportions (along with their relevant measure of dispersion and 95% confidence intervals). We will calculate the Charlson comorbidity index score at randomization for each patient to adjust for any baseline differences in patient acuity not captured through randomization when conducting post hoc analyses. Event rates will be summarized for qualifying thrombotic events, number of thrombotic events, concomitant antiplatelet use, and other patient specific information relevant to treatment arm events. For discrete measures such as event rates, proportions will be reported and stratified by independent variables to elucidate potential influences on event rates within the study arm.

Given expected low event rates, Fisher exact tests will be used for comparisons where appropriate. For time-based measures such as time to event, Kaplan-Meier curves will be calculated in an effort to compensate for expected right censoring in the data.

Minimization of Bias To minimize the risk of the selective enrollment of patients, consecutive patients who meet eligibility criteria and provide informed consent will be enrolled and randomized using a computer generated randomization tool with built-in random sequence generation and applied with allocation sequence concealment, without exception. Strict diagnostic criteria and subsequent interpretation of studies by an independent adjudication committee blinded to treatment allocation will guard against a differential interpretation of these tests. Incomplete follow-up bias will be avoided by patient registration into a central study cohort to identify patients enrolled. Contact at a minimum of every 3 months will promote retention of patients and avoid attrition bias. Upon the provision of initial patient informed consent, family members and referring physicians may be contacted if there is difficulty contacting patients during follow-up. We acknowledge the possibility of crossovers occurring during the study. We define a crossover as a patient randomized to warfarin who during the study period transitions to apixaban or as a patient randomized to apixaban who

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transitions to warfarin. Crossover will be formally disallowed and will be strongly discouraged and monitored. Yet we acknowledge that in the rare circumstance this may occur. Should crossover occur, the reason will be recorded, and the patient will be followed for primary and secondary study outcomes. Analysis of outcome events will be based upon intention to treat, and on-therapy, as indicated. Should a temporary crossover occur, this will also be documented and any reason will be recorded.

Discussion Patients with APS and a history of thrombosis usually receive indefinite anticoagulation. An alternative to warfarin that is safe, effective, and does not require monitoring would be welcome. A unique aspect of our study design (when compared with prior studies which prospectively enrolled patients at the time of diagnosis of APS8,9) is to consider eligible any patient actively receiving therapeutic anticoagulation for the secondary prevention of thrombosis with a clinical diagnosis of APS. This design facilitates achieving enrollment goals and the provision of outcome data regarding a ‘‘real world’’ population with APS receiving therapeutic anticoagulation. We acknowledged upon study inception that APS is rare, and we identified the need to inform for future study the proportion of patients that present reporting clinical APS, however, do not meet strict Sapporo criteria. In doing so, we will also be able to report the comparative performance of apixaban among patients with a continuum of laboratory data supportive of the diagnosis of APS (yet a history of thrombosis). We will request historical patient laboratory and radiologic data to affirm the diagnosis of APS. We will also obtain relevant APS laboratory studies at the time of enrollment and at each study visit. We prospectively categorize patients with APS(definite, likely, and historical) to permit objective interpretation of patients enrolled. This study design will provide prospective outcome data regarding patients who frequently present to their clinician; those with a diagnosis of APS that variably meet formal APS diagnostic criteria. Describing the proportion of patients that present with ‘‘definitive APS’’ compared with those with a less certain diagnosis will inform anticipated recruitment in a definitive trial among patients diagnosed with APS. Our reporting of patient adherence to the study intervention and follow-up among those randomized to a DOAC will assure feasibility for a definitive study. A second unique aspect of our study is the utilization of EMR interrogation to identify patients who would likely be eligible for participation. We used laboratory criteria supportive of the diagnosis of APS, the presence of supportive ICD-9 codes, and evidence of active therapeutic anticoagulation to identify patients who would likely meet inclusion criteria. However because we acknowledged that the diagnosis of APS among eligible patients for our study may have occurred in the distant past and/or outside of our health care systems, we wished to assure that patients enrolled would be broadly agreed to meet diagnostic criteria for APS by standard definitions. Therefore, we created a standardized approach to request, and

case report forms to document, all patients’ historical data demonstrative of a qualifying clinical event, and laboratory data supportive of the diagnosis of APS from their primary physician. These data will be reported among the demographics of patients enrolled. Additionally, all patients will have standardized testing for APS performed at each study visit. We adopted a multifaceted approach to solicit patient participation using postal mail, e-mail, and the dissemination of study information to clinical settings and Web sites that patients with APS would likely frequent. We also identified and publicized ASTRO-APS on blogs and Facebook pages likely frequented by patients with APS with links through a centralized communication portal that could be accessed via our Web site directly using a QR code or through hyperlinks on any of our online publicity. Enrolling only adult patients who have received anticoagulation for at least 6 months for the indication of thrombosis aligns our protocol with present Food and Drug Administration approved packaging for the use of apixaban 2.5 mg twice a day for the prevention of recurrent thrombosis after 6 months of initial therapy.20 Strengths of our study include a design that facilitates a description of the characteristics of patients who present reporting a clinical diagnosis of APS receiving therapeutic anticoagulation. Another strength is describing enrollment and outcomes ascertainment relevant to clinicians who are confronted with decision-making regarding choice of anticoagulant among patients with APS. Limitations include that our sample size will likely not be adequate to ascertain a significant difference in the rate of thrombosis among patients with APS randomized to warfarin or apixaban for the prevention of recurrent thrombosis or for secondary outcomes. However, we will report and compare rates of outcomes of thrombosis in a descriptive fashion, which will be useful to inform future research. We acknowledge that some might describe our decision to enroll patients with a clinical diagnosis of APS as a limitation, however as described earlier, we believe that for this approach is an advantage for a pilot study in this patient population, as it will provide information on the screened population crucial to inform recruitment in a future large trial. In conclusion, the ASTRO-APS pilot study will be the largest, prospective, randomized, blinded outcome event study to date comparing a DOAC with warfarin for clinically important outcomes of thrombosis and bleeding among patients with APS requiring anticoagulation for the secondary prevention of thrombosis. This study may inform power calculations for a definitive prospective randomized trial and assure feasibly of recruitment and patient follow-up. Finally, should apixaban be found safe and effective for the prevention of recurrent thrombosis among patients with APS, it would represent a potential alternative to indefinite warfarin anticoagulation. Authors’ Note All authors attest to having have contributed to (1) conception and design (2) drafting the article and revising it critically for important

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intellectual content; and (3) final approval of the version to be published. 11.

Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S. Stevens and S. Woller report grant support from Bristol-MeyersSquibb and Iverson Genetics paid to Intermountain Healthcare. C Elliott reports personal fees from Janssen Research & Development. D. Kaplan, E. Wilson, V. Aston, R. Evans, J. Lloyd, H. Gallo, E. Johnson, M. Rondina, and D. Branch report no conflicts to disclose.

12.

13. 14.

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The ASTRO-APS study is supported by an investigator initiated grant paid to the Intermountain Medical Center, Murray UT, by Bristol-MeyersSquibb.

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