The Adherence eValuation After Ischemic Stroke Longitudinal (AVAIL) Registry: Design, rationale, and baseline patient characteristics

The Adherence eValuation After Ischemic Stroke Longitudinal (AVAIL) Registry: Design, rationale, and baseline patient characteristics Cheryl Bushnell, MD, MHS, a Louise Zimmer, MA, MPH, b Lee Schwamm, MD, c Larry B. Goldstein, MD, b Nancy Clapp-Channing, MPH, b Tina Harding, RN, BSN, b Laura Drew, RN, BSN, b Xin Zhao, MS, b and Eric Peterson, MD, MPH b Winston-Salem and Durham, NC; and Boston, MA

Background Approximately one third of the 780,000 people in the United States who have a stroke each year have recurrent events. Although efficacious secondary prevention measures are available, levels of adherence to these strategies in patients who have had stroke are largely unknown. Understanding medication-taking behavior in this population is an important step to optimizing the appropriate use of proven secondary preventive therapies and reducing the risk of recurrent stroke. Methods

The Adherence eValuation After Ischemic Stroke Longitudinal (AVAIL) registry is a prospective study of adherence to stroke prevention medications from hospital discharge to 1 year in patients admitted with stroke or transient ischemic attack. The primary outcomes are medication usage as determined by patient interviews after 3 and 12 months. Potential patient-, provider-, and system-level barriers to persistence of medication use are also collected. Secondary outcomes include the rates of recurrent stroke or transient ischemic attack, vascular events, and rehospitalization and functional status as measured by the modified Rankin score.

Results The AVAIL enrolled about 2,900 subjects from 106 hospitals from July 2006 through July 2008. The 12-month follow-up will be completed in August 2009. Conclusions

The AVAIL registry will document the current state of adherence and persistence to stroke prevention medications among a nationwide sample of patients. These data will be used to design interventions to improve the quality of care post acute hospitalization and reduce the risks of future stroke and cardiovascular events. (Am Heart J 2009;157:428-435.e2.)

Background Each year, an estimated 780,000 people in the United States have a stroke or transient ischemic attack (TIA).1 Within 3 months, 17% of patients who had a TIA and 18% who had a nondisabling stroke will have a recurrent stroke.2 After 5 years, the number of patients who have had stroke with a recurrent event rises to nearly one third.3 Mortality after a second stroke is greater than after a first stroke (24-month survival rates are 48% vs 57%, respectively).4 Among stroke survivors, as many as 90% have some functional deficit—totaling approximately

From the aWake Forest University Health Sciences, Winston-Salem, NC, bDuke University Medical Center, Durham, NC, and cMassachusetts General Hospital, Boston, MA. Dr. Mauricio G. Cohen served as guest editor for this manuscript. Submitted August 25, 2008; accepted November 2, 2008. Reprint requests: Cheryl Bushnell, MD, MHS, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157. E-mail: [email protected] 0002-8703/$ - see front matter © 2009, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2008.11.002

5 million people in the United States living with the sequelae of stroke.1,5 Appropriate patient risk stratification, triage, and initiation of secondary prevention strategies during the initial hospitalization for acute ischemic stroke are the first steps to decreasing recurrence and improving patient outcomes.6 Interventions and therapies demonstrated to reduce the risk of recurrent stroke among specific patient subgroups include use of blood pressure–lowering medications, antiplatelet therapy, anticoagulation with warfarin for patients with atrial fibrillation, carotid endarterectomy in patients with high-grade symptomatic stenosis, and smoking cessation programs.7-11 The implementation and adherence to secondary risk reduction strategies are critical for reducing the risk of recurrent stroke. Based on short- and long-term outcomes studies, these secondary prevention strategies should be started early, adherence monitored frequently and maintained over the long term.12,13 The “Get With the Guidelines-Stroke” (GWTG) intervention provides data on the use of effective therapies for acute ischemic stroke or TIA as well as initiation of

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secondary prevention education and therapies at hospital discharge. To date, this program has demonstrated significant improvements 1 year post baseline in acute care as well as in secondary prevention.14 Most of the data on adherence to stroke secondary prevention treatments come from randomized controlled trials or observational studies on specific risk factor interventions, such as treatment of hypertension or hypercholesterolemia and the use of antithrombotic therapy. Although adherence to treatment varies dramatically, it is generally suboptimal. For example, in an inner city population, patient adherence rates were about 75% for antiplatelet therapy, 41% for anticoagulant therapy, and 70% for antihypertensive therapy at 90 days poststroke.15 Another study found that patients managed in a stroke prevention clinic had no improvement in diabetes control or in smoking cessation at 1 year followup, although lipid and hypertension control did improve.16 The Preventing Recurrence of Thromboembolic Events through Coordinated Treatment (PROTECT) study focused on implementing treatment goals and behavioral modification strategies during the hospital stay.13 At 3 months post hospitalization, patients reported high adherence (80%-100%) to regimens prescribed at discharge and had fewer vascular events (8.4% vs 22%) than similar patients at a control hospital.13,17 Successful continuation of secondary prevention strategies over the long term depends on patient-level, system-level (ie, hospital policies, insurance types), and provider-level (prescribing practices, effective communication, and education) factors. Patient-related factors that affect use and persistence of medications include ability to pay for prescriptions, cognitive and emotional well-being, caregiver support, and patients' beliefs about medications. The Adherence eValuation After Ischemic Stroke Longitudinal Registry (AVAIL) was designed to better understand medication-taking behavior of patients discharged after an ischemic stroke or TIA. Its methodology is unique in that it expands upon a successful, ongoing, hospital-based quality improvement program (GWTGStroke) administered by the American Heart Association/ American Stroke Association (AHA/ASA both in Dallas, TX). Using this existing resource, AVAIL collected both inhospital and longitudinal medication use from a diverse group of academic and nonacademic, rural, suburban, and urban hospitals from all parts of the country. The AVAIL emphasized the collection and measurement of the multiple patient-level factors (eg, stroke-related disability, total number of medications and frequency of dosing, depression, quality of life) associated with and predictive of adherence to treatment and persistence of therapy. Although AVAIL identified whether or not patients were on medications 3 and 12 months after stroke, the study was focused on learning the reasons behind use (or nonuse) of secondary

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prevention interventions. Ultimately, AVAIL was designed as the first stage in an effort to improve both inpatient and outpatient quality of care of patients who have had stroke. By characterizing barriers to achieving long-term secondary prevention, AVAIL was intended to provide information on ways to improve medication persistence through targeted quality improvement initiatives.

Overview of AVAIL registry The primary objectives of AVAIL are to describe the adherence to medications and behavioral recommendations in the year after hospital discharge of patients with TIA and patients who have had stroke and to identify specific patient, provider, and system factors associated with adherence. Secondary objectives include measuring longitudinal trends in clinical and functional outcomes at 3 and 12 months after hospital discharge and their relationship to adherence.

Study design The study was conceived and designed by the AVAIL team, a group of researchers at the Duke Clinical Research Institute (DCRI, Durham, NC), along with the project Executive Committee and an AHA representative. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents, with approval by the Executive Committee. Bristol Myers Squibb (Kenilworth, NJ)/Sanofi Pharmaceuticals (Paris, France) Partnership staff are provided an opportunity to review drafts of all papers and abstracts and receive a copy of aggregated data from baseline and each follow-up time point. The sponsor does not have direct access to the database, which is housed at the data coordinating center at DCRI. Site selection The AVAIL was implemented in collaboration with the AHA/ASA GWTG-Stroke Program. The AHA GWTG-Stroke team made initial contacts with 676 hospitals participating in the program and invited them to participate in AVAIL. Of this total, 109 hospitals initially agreed, and 106 ultimately enrolled patients. All sites were required to obtain local institutional review board approval of the protocol before study initiation. For a complete list of AVAIL members and sites, see Appendices A and B, available online. Patient population To be eligible for enrollment into AVAIL, a patient had to meet the following criteria: • Age 18 or older • Hospitalization for a primary diagnosis of acute ischemic stroke or TIA based on GWTG-Stroke International Classification of Diseases, Ninth Edition codes.

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• Direct admission based on physician evaluation or arrival through the emergency department (ED), including patient transfers from 1 ED to the recruiting site ED • Ability of patient or legally authorized representative to provide informed consent. • Record submission to the GWTG-Stroke Program Subjects with a diagnosis of subarachnoid or intracerebral hemorrhage or who were expected to survive 6 months or less were excluded.

Screening and baseline data collection At hospitalization, study personnel screened patients for AVAIL eligibility according to the screening procedures for GWTG-Stroke14 and then obtained informed consent. The GWTG-Stroke data collection form served as the primary source of baseline data. Following GWTG methodology, these data are abstracted from inpatient medical records by trained site personnel. In-hospital variables included demographics; medical history; National Institutes of Health Stroke Scale on admission; presentation information; stroke symptoms, evaluation, and diagnoses; acute therapies, including thrombolytics and deep vein thrombosis prophylaxis; discharge medications/interventions for recurrent stroke risk reduction; treating physician specialty; and discharge status and destination. In addition, AVAIL required sites to collect sociodemographic information, as well as detailed drugand dose-specific information at both the admission and discharge time points. Subjects provided contact information at enrollment for themselves and 2 alternate contacts, as well as for that of their primary physician. Sites received nominal reimbursement for enrollment in AVAIL. Reimbursement was contingent upon receipt of completed baseline data collection forms and a copy of a signed informed consent. Follow-up data collection Patients are contacted at 3 months and 12 months postdischarge by telephone by trained research personnel at the DCRI who used standard scripts to collect study data. The enrollee is the targeted respondent for the questionnaire, although proxy interviews are conducted when it was impossible to speak to the patient or when the information provided by the patient is deemed unreliable by the interviewer. The baseline hospitalization is used as the reference anchor for assessment of 3-month adherence and outcomes. The reference changes to the 3-month follow-up interview for the 12-month questionnaire. If a 3-month interview is not completed, the reference reverts to the baseline hospitalization. Follow-up questionnaire content Whenever possible, the follow-up questionnaire includes validated scales to assess medication adherence, functional status, and clinical outcomes. Medication use

Table I. Study procedures and assessments Screening/ 3 12 Enrollment Baseline mo mo Informed consent Confirmation of inclusion/ exclusion criteria via medial record review Hospital survey (one time only for each recruitment site) Follow-up contact form GWTG-Stroke data collection form DCRI discharge medications collection form Patient telephone interview questionnaire

X X

X X X X X

X

at follow-up is collected through a series of questions targeting current prescriptions compared to prior medication lists. A modified version of the Morisky scale is used to assess patient adherence to current medications,18 a medication-taking behavior scale that has been widely used to assess medication adherence among patients with cardiovascular disease.19 If a medication had been discontinued, the reason is documented categorically according to whether the health care provider stopped the medication or the patient stopped because of cost, side effects, perception of medication ineffectiveness, or another reason. Other domains related to medication use include patient-provider communication,20 patient knowledge of medication purpose, and medication costs. To assess health status, we administer the modified Rankin Score, a structured interview that measures functional outcomes after stroke, along with the EQ5D, a non–disease-specific instrument that allows patients to describe and value their health status.21,22 Because depression is prevalent in patients who have had stroke and may impact medication adherence, we use the Patient Health Questionnaire-8 (PHQ-9 with the suicidality assessment excluded) to measure depression.23 The PHQ9 has been validated and performs well as a brief screening tool for poststroke depression.24 The PHQ-8 and PHQ-9 tools use the same scores to assign depression severity.25 Clinical outcomes include residual stroke symptoms, clinical events, and medical care, including rehospitalization rates, procedures, and poststroke therapy. Once formulated, the questionnaire was refined through 2 phases of pilot testing, which included versions administered to either patients or their caregiver proxies. Through this process, we eliminated redundancies, improved clarity of the questions, and streamlined the system of questions used to administer the modified Rankin Scale. Further, we developed a proxy questionnaire for caregivers of study patients. The 3- and 12-month questionnaires are identical in content (Table I).

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Data management Outcome Sciences, Inc, of Cambridge, MA, serves as the Web-based data entry vendor and data coordination center for GWTG-Stroke. Web-based data entry access is password restricted to formally trained personnel at each site. All data queries are resolved by the site coordinator at the point of entry. Outcome Sciences transfers data quarterly to the DCRI Coordinating Center, at which time additional data validations are executed and the data set finalized for analysis. The additional AVAIL baseline data collection forms are mailed or faxed to the DCRI Coordinating Center. These additional baseline forms and all follow-up interview data are entered into a local, password-protected Microsoft Access database. Random data validations, routine quality control queries, and discrepancy resolution are performed throughout data collection. This research project was supported by unrestricted funds from Bristol-Myers Squibb (Kenilworth, NJ)/ Sanofi Pharmaceuticals (Paris, France) Partnership and conducted through collaboration with the American Heart Association and the “Get With the GuidelinesStroke” program.

Outcome definitions Adherence and persistence Adherence (also referred to as compliance) and persistence represent 2 different aspects of medicationtaking behaviors. Adherence is defined as how well a patient's medication-taking behavior corresponds with recommendations from a health care provider.26 It assumes that there is a partnership between the patient and provider and that the patient is not simply a passive participant. Adherence typically is reported as the proportion of prescribed doses taken.27 Persistence broadly represents the accumulation of time from initiation to discontinuation of therapy and is measured in terms of duration.27 Patients' compliance with treatment recommendations implies that the patient agrees with the prescribed therapy and understands how to take medications correctly.28 Patients, however, may not understand or misinterpret instructions for taking medications, may be unable to afford their medication, or believe that medications prescribed are unnecessary or ineffective.28-30 It has been estimated that up to 75% of medication nonadherence is an intentional response to perceived side effects, inadequate therapeutic response, and high medication costs.29 Therefore, AVAIL included questions about these factors to identify barriers to adherence and persistence in patients who have had stroke. The primary outcome in AVAIL is self-reported use of stroke secondary prevention medications, including both adherence and persistence. Data are obtained using telephone questionnaires. Excellent agreement between telephone self-reported adherence and analysis of phar-

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Figure 1

Persistence diagram. Persistence represents the duration of time from initiation to discontinuation of therapy. Patients on a medication at 1 study time point who report taking the medication at a further study time point are considered to be persistent through that period (dark green arrows). Patients for whom the timing of medication initiation is unknown, that is, begun after a study time point, are considered initiators (indicated by dotted green line). Unknown end date for medication use is indicated by a dotted red line.

maceutical claims data has been previously reported.31 Therefore, AVAIL uses telephone self-reported persistence and adherence as a reasonable estimate of actual use. Nonpersistence is defined as medication discontinuation between the last contact and the follow-up assessment (between discharge and 3 months, between 3 and 12 months, and between discharge and 12 months). Reasons for discontinuation are further characterized as medication stopped by the provider or by the patient (due to cost, side effects, perceived ineffectiveness, or other) at each time point. The level of persistence is assessed by individual medication and by class, specifically the use of antiplatelet medications, warfarin, antihypertensives (ie, β-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium-channel blockers, diuretics), lipid-lowering agents (ie, statins, nonstatin), and hyperglycemic agents (ie, insulin and oral diabetic agents). Overall persistence is derived based on aggregated persistence across all prescribed classes at each follow-up time point. Persistence at 12-month follow-up is defined as subjects on medication at 3 months and at 12 months as compared to discharge (Figure 1). In addition to the 3 month nonpersistence categories, nonpersistence at 12 months was defined as medicine stopped by subject or provider between 3 months and 12 months. Subjects who were not on a therapy at discharge but initiated therapy at some time point between discharge and 3 months or between 3 and 12 months will initially be excluded from the analysis of nonpersistent versus persistent. Additional analyses will be conducted with these “initiators” to determine if they have any characteristics that distinguish them from persistent subjects. The initiators will be included in the medication utilization rates at the prespecified time points.

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Clinical outcomes Clinical outcomes that are assessed by patient selfreport or proxy at 3 and 12 months include the following: death from a vascular cause (stroke, myocardial infarction [MI], or other cardiac causes, peripheral arterial disease) or any cause, recurrent stroke or TIA, acute coronary syndromes, carotid artery procedure, peripheral arterial disease diagnosis or procedure, or bleeding complication. Rehospitalization for N 24 hours will be documented, including the dates and the reason for rehospitalization. Functional outcomes are assessed at the same time points and include the following: status of stroke recovery, ability to perform daily activities, depression, and overall quality of life.

Analysis and statistical considerations Estimating adherence and persistence with secondary prevention medications Dichotomous variables will be created for persistence of each of the following secondary risk reduction therapies: antiplatelet agents, warfarin, antihypertensive, lipid-lowering, and hyperglycemic therapy. These categories will also be combined to create a composite persistence variable. Subjects will also be grouped by class of medication to determine persistence by class (ie, β-blockers, statins, and so forth). Adherence for each individual medication will be measured according to the Likert scale of the frequency of missing medications (never, rarely, sometimes, and often) and will be analyzed as an ordinal variable. Additional dichotomous variables will be created to indicate in-hospital use (yes/no) of each therapy at discharge and self-reported utilization (yes/no) at 3 and 12 months after discharge. Descriptive analyses for each therapy will include: (i) the proportion of patients who receive the therapy before discharge, (ii) the proportion of eligible patients who report utilization at 3 months after discharge but not at discharge (initiators), (iii) the proportion of patients reporting utilization at 3 months among those patients who were prescribed the therapy before discharge (ie, discharge to 3-month persistence), (iv) the proportion of eligible patients who report utilization at 12 months after discharge (including initiators between 3 months or last contact and 12 months), (v) the proportion of patients reporting utilization at 12 months among those patients who were prescribed the therapy before discharge (ie, 12-month persistence), (vi) the proportion of patients reporting utilization at 12 months among those patients who reported utilization at 3 months (ie, 3- to 12-month persistence; see Figure 1). Patients who die or are lost to follow-up before the 3- or 12-month assessments will initially be excluded from the relevant persistence rate calculations. Because this approach will potentially overestimate the true utilization

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rate (if the probability of mortality and loss to follow-up is greater among patients who do not persistently take therapy compared to those who do persistently take therapy), the calculations will be repeated by assuming that patients who died or were lost to follow-up did not utilize the therapy. All of these calculations will be reported as a simple percentage. Descriptive analyses with baseline characteristics, patient-related factors, provider-related factors, and hospital- or systems-related factors will be compared in the persistence versus nonpersistence groups at 3 and 12 months. Prespecified patient-level explanatory variables include age, gender, race, level of education, marital status, discharge status, socioeconomic status, working status, perceived financial burden of medication cost, and help with medication taking. Provider-level characteristics include provider type (primary care, neurologist, cardiologist) and patient satisfaction with provider communication. Hospital characteristics to be explored include academic versus community hospital, state or national certification as a primary stroke center, bed size, stroke volume, and regional differences. The factors associated with persistence or nonpersistence in univariable analysis at each time point will be added to a multivariable logistic regression model, which will then be used to assess the importance of each predictor variable while simultaneously adjusting for all other potential predictor variables. Candidate explanatory variables will be identified a priori or will be selected based on results from univariate analyses (described above). All logistic regression models will either be fit using generalized estimating equations or will contain random effects to adjust for clustering of observations within hospitals.

Estimating rates and identifying predictors of clinical outcomes The second goal of this study is to describe the frequency of selected clinical end points for 2 periods: (i) time from hospitalization to 3 months postdischarge and (ii) from 3 to 12 months postdischarge. Binary end points of interest are (i) recurrent stroke or TIA, (ii) death from vascular disease, and (iii) MI, acute coronary syndromes, or revascularization. If there are a sufficient number of deaths to permit analysis, a time-to-event analysis of mortality through 12 months of follow-up will be performed. Ordinal end points include (i) disability (modified Rankin score), (ii) quality of life (defined as median EQ5D score), and (iii) depression (as defined by median PHQ-8). The estimated probability of each binary outcome will be reported as a simple percentage. Ordinal variables will be reported as medians and interquartile ranges. Predictors of clinical outcomes and changes in functional status that occur during the follow-up period

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Table II. Hospital characteristics Hospital characteristics Location

Type No. of beds No. of ischemic stroke discharges/year (based on GWTG data)

Table III. Baseline patient characteristics

n = 93

n

%

Northeast South Midwest West Academic Non-academic Mean (SD) 301+ 101-300 0-100 Missing

25 24 27 17 27 66 426.2 (±208) 41 35 7 10

26.9 25.8 29.0 18.3 29.0 71.0 44.1 37.6 7.5 10.8

Patient characteristics Stroke type

Age Sex Race

Education level

Marital status

for patients who have had stroke are still poorly understood. For AVAIL, the main explanatory variable of interest is persistence with secondary risk reduction therapies, as summarized by a composite persistence variable. Additional candidate explanatory variables include age, gender, race, stroke severity, discharge status, hospital type, certification as a primary stroke center, hospital size, and the numbers of patients who have had stroke admitted annually. The frequency of binary end points will be compared across subgroups of interest using a χ2 test for independent proportions (or, alternatively, an analogous test statistic that adjusts for clustering of outcomes within hospitals). The Wilcoxon rank sum test will be used for continuous variables. The Mantel-Haenszel χ2 test will be used for testing across category differences for binary and ordinal variables. Logistic regression will be used to explore the association between explanatory variables of interest and each binary end point while adjusting for covariates. Ordinal outcomes such as modified Rankin score will be analyzed using a proportional odds logistic regression model. Generalized estimating equations or hierarchical modeling will be used to adjust for clustering of outcomes among patients within the same hospital. Cox's proportional hazards will be used to model timeto-event data. Missing data. Patients who are not eligible at baseline will be excluded from the analysis (ie, patients who were not prescribed the medication class of interest). Patients who died or withdrew from the study between hospital discharge and follow-up will also be excluded, as well as those who did not complete the questionnaire. No missing outcomes are expected in the analysis population. Missing rates for the covariates are expected to be low. If necessary, medical history will be imputed as absent, the body mass index will be imputed to the gender-specific mean, and others will be imputed to the most common category. The AVAIL registry progress. The target enrollment is 3,000 subjects, with an enrollment period of 27 months. The original design was to recruit 75 hospitals, and for each hospital to enroll 40 subjects.

Living situation

Medical history

n = 1761

n

%

Ischemic stroke TIA Stroke NOS or other Median % male White African American/Black Other/Unknown High school or greater Less than high school Unknown Married or living as married Widowed Divorced Separated Never married Missing With spouse/significant other and/or children With relatives or friends Alone Nursing home/Hospice Rehab institution Missing Prosthetic heart valve Previous stroke/TIA Prior MI/CAD Carotid stenosis Diabetes Peripheral vascular disease Hypertension Smoker Dyslipidemia None of the above

1361 387 13 66.0 942 1433 199 129 1396 316 49 1045 342 207 41 114 12 1168

77.3 22.0 1.0

177 382 16 4 14 22 399 434 78 466 55 1292 430 749 158

10.0 21.7 0.9 0.2 0.8 1.3 22.7 24.7 4.4 26.5 3.1 73.4 24.4 42.5 9.0

53.5 81.4 11.3 7.3 79.3 18.0 3.0 59.3 19.4 11.8 2.3 6.5 0.7 66.3

NOS, Not otherwise specified; CAD, coronary artery disease.

Additional sites were recruited because many sites were unable to enroll the minimum number of subjects, and 3 sites were closed as a result of the lack of coordinator support for enrollment. Among enrolling sites, 30% described themselves as academic hospitals and 70% as community based; N80% are certified primary stroke centers. The regional distribution of sites is listed in Table II. The hospitals' average number of inpatient beds is 426. More than 44% of enrolled hospitals had N300 ischemic stroke patient discharges per year. Baseline characteristics of these patients are presented in Table III. The demographics and risk factors of AVAIL subjects are similar to other cohorts of patients who have had stroke.32,33 Although 3- and 12-month interviews are still ongoing, the current follow-up rate is 95%.

Discussion Many of the prior studies of stroke prevention adherence have been limited to 1 site or a small region of the United States. The AVAIL program has successfully identified a geographically diverse group of investigators

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and does not overrepresent academic centers as compared with US hospitals. About 2,900 subjects have been enrolled over the first 27 months of recruitment. The characteristics of patients enrolled include a representative spectrum of the stroke population (50% women and 20% with less than a high school education; Table III). However, minority enrollment was slightly lower than that seen in the GWTG-Stroke program. The percentage enrolled at any 1 center tends to represent only a fraction of those hospitalized with stroke. This is in part indicative of the difficulty in reaching patients to obtain informed consent as has been reported in other studies.34 Follow-up rates are N90%, exceeding our expectations because of the great difficulty in successfully reaching patients who might be in nursing homes or rehabilitation centers and/or who have a significant stroke-related disability. In AVAIL, we plan to perform analyses based on both provider- and patient-initiated nonpersistence. We also plan to analyze persistence based on individual medications, classes of medications (ie, change from 1 β-blocker to different β-blocker), or categories of medications (ie, changes among any class of antihypertensive medications). These analyses will provide important data related to medication utilization and prescribing practices for multiple types of secondary prevention therapies. The AVAIL data will also be a logical extension of GWTGStroke inpatient quality improvement program because it will not only provide information about the utilization of evidence-based therapies after hospitalization but will also address why a patient is not still taking a medication. Analyses of persistence will include descriptive factors related specifically to baseline characteristics, financial burden, provider type, hospital and regional characteristics, and new vascular events. In addition to the impact these variables have on persistence, we will be able to assess the impact of persistence on the risk of recurrent stroke, TIA, other cardiovascular events, rehospitalization, and death. These data will address the effectiveness of stroke prevention therapies for reducing stroke and cardiovascular events in a high-risk population outside of the setting of a randomized controlled trial. The AVAIL has several potential limitations. Like any volunteer registry requiring informed consent, selection bias can occur. Subjects also need to have a telephone to be contacted. Cognitive or memory problems, as well as speech/language difficulties and depression, are common among patients who have had stroke and may limit responses to questionnaires. To address this potential limitation, we sought out proxy caregiver respondents when the patient was not able to participate in the telephone surveys. We do not know if processes used to improve adherence were initiated during the study period. Our measure of medication adherence was selfreported. Such data are likely to be at least as accurate as those gained from office chart review (as the source of

office records is also the patient and may be biased by patient's subjective responses to the ordering physician). Alternatives for confirming medication use (such as blood levels, pill bottle openings, or pharmacy renewals) were not deemed possible given the size of the registry. Similarly, all outcomes are self-reported, including hospitalizations and clinical events, which may lead to underreporting. Thus, we believe that our study may provide conservative estimates of both medication use and outcomes. Lastly, although the study included a large number of institutions that were selected to be diverse based on size, case mix, and geography, they all were selected from centers participating in the AHA/ASA GWTG-Stroke program and thus may not be representative of all US hospitals.

Conclusions The AVAIL expands on the quality improvement program of GWTG-Stroke from the hospital to the outpatient setting. The data we have collected may be a critical component in improving the longitudinal care of patients who have had stroke and increasing the use of evidence-based treatments for secondary prevention. In addition, the results of AVAIL could lead to the development of interventions to improve medication-taking behavior in patients who have had stroke by addressing the multidimensional issues related to comorbidities, disability, and caregiver support. The AVAIL could be a valuable step in improving the care of patients who have had stroke and preventing future stroke and cardiovascular events.

Acknowledgements We wish to thank the study coordinators and investigators at participating sites for their assistance in conducting the study (see Appendix A and B, available online). Special thanks to Mark Peters, PharmD, for his unwavering support and commitment to this project.

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5. Alberts M, Ovbiagele B. Current strategies for ischemic stroke prevention: role of multimodal combination therapies. J Neurol 2007; 254:1414-26. 6. Moroney JT, Bagiella E, Paik MC, et al. Risk factors for early recurrence after ischemic stroke. The role of stroke syndrome and subtype. Stroke 1998;29:2118-24. 7. Hart RG, Halperin JL, Pearce LA, et al. Lessons from the Stroke Prevention in Atrial Fibrillation Trials. Ann Intern Med 2003;138: 831-8. 8. Tran H, Anand SS. Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA 2004;292:1867-74. 9. Donnan G, Fisher M, Macleod M, et al. Stroke. Lancet 2008;371: 1612-23. 10. Hankey J, Warlow C. Treatment and secondary prevention of stroke: Evidence, costs and effects on individuals and populations. Lancet 1999;354:1457-63. 11. O'Rourke F, Dean N, Akhtar N, et al. Current and future concepts in stroke prevention. CMAJ 2004;170:1123-33. 12. Hardie K, Hankey GJ, Jamrozik K, et al. Ten-year risk of first recurrent stroke and disability after first-ever stroke in the Perth Community Stroke Study. Stroke 2004;35:731-5. 13. Ovbiagele B, Saver JL, Fredieu A, et al. In-hospital initiation of secondary stroke prevention therapies yields high rates of adherence at follow-up. Stroke 2004;35:2879-83. 14. LaBresh K, Reeves M, Frankel M, et al. Hospital treatment of patients with ischemic stroke or transient ischemic attack using the “Get With the Guidelines” program. Arch Intern Med 2008;168: 411-7. 15. Hillen T, Dundas R, Lawrence E, et al. Antithrombotic and antihypertensive management 3 months after ischemic stroke. A prospective study in an inner city population. Stroke 2000;31: 469-75. 16. Mouradian MS, Majumdar SR, Senthilselvan A, et al. How well are hypertension, hyperlipidemia, diabetes, and smoking managed after a stroke or transient ischemic attack? Stroke 2002;33: 1656-9. 17. Rahiman A, Saver J, Porter V, et al. In-hospital initiation of secondary prevention is associated with improved vascular outcomes at 3 months. J Stroke Cerebrovasc Dis 2008;17:5-8. 18. Morisky D, Green L, Levine D. Concurrent and predictive validity of a self-reported measure of medication adherence. Med Care 1986;24: 67-74.

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Appendix A. AVAIL Executive Committee members (in alphabetical order) Mark Alberts, MD, Northwestern University; Bruce Coull, MD, University of Arizona; Cheryl Bushnell, MD, MHS, Wake Forest University Health Sciences; Pamela Duncan, PhD, Duke University; Susan Fagan, PharmD, University of Georgia; Michael Frankel, MD, Grady Memorial Hospital; Larry Goldstein, MD, Duke University Medical Center; Philip Gorelick, MD, MPH, University of Illinois at Chicago; S. Claiborne Johnston, MD, PhD, MPH, UCSF Medical Center; Chelsea Kidwell, MD, NINDS; Ken LaBresh, MD, GWTG Representative; Pamela Mitchell, RN, PhD, University of Washington; Frederick Munschauer, MD, Buffalo General Hospital; Eric D. Peterson, MD, MPH, Duke University Medical Center; Ralph Sacco, MD, MS, Neurological Institute, Columbia University; Lee Schwamm, MD, Massachusetts General Hospital; Linda Williams, MD, Indiana University School of Medicine Roudebush VAMC; Richard Zorowitz, MD, Johns Hopkins Bayview Medical Center.

Appendix B. AVAIL participating sites, PIs, and coordinators in alphabetical order by site: Abington Memorial Hospital, B. Franklin Diamond, Vanessa Thomas; Albany Medical Center, Gary Bernardini, Deborah Johnson; Alexian Brothers Medical Center, Wende Fedder, Mona Olges; Alta Bates Summit Medical Center, Terri Nielsen; Aultman Hospital, John Andrefsky, Judy Werstler; Ball Memorial Hospital, John Wulff, Sherry Simmonds; Baptist Hospital, David Bear, Tammie Stefanko; Baptist Medical Center, Doreen Donohue, Michelle Silver; Bayfront Medical Center, John Gannon, Andrea Hrin; Benefis Healthcare, Ann Lamere; Berkshire Medical Center, Alec Kloman, Deborah Ewell; Beverly Hospital, Ann Pianka, Ann Pianka; Billings Clinic, Dan Rodriguez, Bobbie Nolan; Bluffton Regional Medical Center, Vicki Hanselman, Jon Grandstaff-Dunphy; Borgess alth, Rashmi Kothari, Sue Fales; Bryan LGH Medical Center, James Bobenhouse, Kathy Ware; Centra Health, Donna Falwell; Central Dupage Hospital, Henry Echiverri, Susan Strickland; Central Florida Regional Hospital, Elias Gizaw, Wanda Shaver; Charleston Area Medical Center, Harry Reahl, Deborah Rectenwald; Columbia-St. Mary's, Carter, Karen McCuaig; Community Hospital Indianapolis, Debbie Ferguson, Debbie Ferguson; Conemaugh Memorial Medical Center, Alfred Bowles, Monica Updyke; Decatur General, Gina Briscoe, Amy Foster; Doctors Hospital, Cindy Wagner, Cindy Wagner; Doylestown Hospital, Wendy Wickward, Wendy Wickard; Ellis Hospital, Tang Kejan, Rose Watroba; Enloe Medical Center, Michael O'Brien, Sherry Wirt; Firelands Regional Medical Center,

American Heart Journal March Year

Kathy Sciarappa, Kathy Sciarappa; Flagler Hospital, Pamela Petry, Betty Brown; Forsyth Medical Center-Stroke & Vascular Center, Chere Chase, Gwen Ainsworth; Hamot Medical Center, James DeMatteis, Patty Henry Harris Methodist Fort Worth Hospital, Debbie Estes, Sheri Muska; Huntsville Hospital, Scott Hitchcock, Mary Brethour; Indiana Neuroscience Institute, Jeffrey Hilburn, Jaci Drexler; Jersey Shore University Medical Center, Stephen J. Martino, Alison Trembly; John T Mather Hospital, Christopher Sinclair, Lori Blom; JPS Health Network, Kent Taub, Allison Rico; Lahey Clinic Medical Center, Eileen Allosso, Claudia Fitzgerald; Lancaster General Hospital, Judy Erb, Joan Vance; Legacy Emanuel Hospital, Paul Ash, Jean Carlton; Legacy-Meridian Park Hospital, Paul Ash, Jean Carlton; Long Beach Memorial Medical Center, Randolph Shey, Angie West; Loyola University Medical Center, Michael Schneck, Linda Chadwick; Lutheran Hospital of Indiana, Lisa Guyll; Maryland Stroke & Brain Attack Team: University of Maryland Medical System, Karen Yarbrough; Massachusetts General Hospital, Lee Schwamm, Shihab Masrur; Maury Regional Hospital, Brenda Hogan, Sandra Studebaker; Mease Dunedin, Patricia Farrell, Victoria Lindemann; Medical Center of Plano, Nicki Roderman; Medical College of Wisconsin/Froedtert Memorial Lutheran Hospital, Michel Torbey, Erin Brandenburg; Medical University of Ohio, Gretchen Tietjen, Andrea Korsnack; Mercy Medical Center, Jennifer Pary, Deb Motz; Mercy Medical Center, Jennifer Pary, Diane Handler; Mercy Medical Center, Mark Young, Deb Motz; Mercy Medical Center, Mark Young, Diane Handler; Metro Health Medical Center, Joseph Hanna, Dana Cook; Morton Plant Hospital, Ajay Arora, Teresa Jones; Munroe Regional Medical Center, Janice Ulmer, Janice Ulmer; Northeast Georgia Medical Center, Tricia Westbrook, Amanda Grindle; Northeast Health-Albany Memorial, David Hart, Christine Ball; Northeast Health-Samaritan Hospital, David Hart, Christine Ball; Northern Michigan Hospital, Roger Gietzen, Elaine Siwiec; Ocean Medical Center, Stephen Martino, Jane Kaiser; Parkview Hospital, Fen-Lei Chang, Lynn Wilton; Penn State Hershey Medical Center, Raymond Reichwein, Judy Dillon; Pitt County Memorial Hospital, Marie Welch; Presbyterian Hospital, Aris Chaconas, Amy Holland; Providence Everett Medical Center, Julie McDonald, Julie McDonald; Reading Hospital, Walter Bohnenblust, Ruth Bailey; Renown Regional Medical Center, Paul Katz, Nicholas Green; Riverview Medical Center, Noah Gilson, Rebecca Graboso; Rochester General Hospital, W. Burgin, Cheryl Weber; Rush University Medical Center, Shyam Prabhakaran, Susan Dvojack; Saint Anthony's Central Hospital, Richard Smith, Christine Potzer; Saint Mary's Regional Medical Center, Teri Kozik, Judith Brady; Saint Thomas Hospital, Michael Kaminski, Deb Pitts; Sanford USD Medical Center, Michelle VanDemark, Michelle Van Demark; Sinai Hospital of Baltimore, Adrian Goldszmidt,

American Heart Journal Volume 157, Number 3

Kathleen Birnbaum; Sparks Regional Medical Center, Margaret Tremwel, Cheryl Hyde; St. Alexius Medical Center, Wende Fedder, Mona Olges; St. Joseph Mercy Hospital, Susan Hickenbottom, Kimberly Gray; St. Mary's Medical Center, Carl McComas, Jennifer Edwards; St. Mary's Duluth Clinic Health System, Steve Erlemeier, Jennifer Gottschald; St. Peter's Hospital, Lee Vanderburgh, Nancy J. Newkirk; St. Vincent's Medical Center, Srinath Kadimi, Jennifer Nascimento; Summa Health System, Robert Lada, Jan Weinhardt; Sunrise Hospital and Medical Center, Kyle Malone; Swedish Medical Center, William Likosky, Jeannie Bush; The Nebraska Medical Center, Pierre Fayad, Mary Phillips; The Queen's Medical Center, Deborah Green, Lyle

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Oshita; The Queen's Medical Center, Deborah Green, Tracy Stern; UCLA Medical Center, Bruce Ovbiagele, Sandra Pineda; United Regional Healthcare System, Mehari Gebreyohanns, Cindy Hoff; University of Louisville Hospital, Kerri Remmel, Elizabeth Wise; UPMC Stroke Institute, Larry Wechsler, Sharon DeCesare; Virginia Mason, Michael Elliot, Melinda Carter; Wallace Kettering Neuroscience Institute at Kettering Medical Center, Jeanne Robinson, Nancy Wiech; Washington Hospital Healthcare System, Ash Jain, Douglas Van Houten; Westchester Medical Center ,Stephen Marks, Kathryn D'Aquila; Wyoming Medical Center, David Wheeler, Melissa Tapp; York Hospital/Wellspan Health, Marta Jimenez, Brenda Chapman.