Patient-focused intervention to improve long-term adherence to ...

Outcomes, Health Policy, and Managed Care

Patient-focused intervention to improve long-term adherence to evidence-based medications: A randomized trial Sara Bristol Calvert, PharmD, a Judith M. Kramer, MD, MS, a,b,c Kevin J. Anstrom, PhD, a Lisa A. Kaltenbach, MS, a Judith A. Stafford, MS, a and Nancy M. Allen LaPointe, PharmD a,b Durham, NC

Background Nonadherence to cardiovascular medications is a significant public health problem. This randomized study evaluated the effect on medication adherence of linking hospital and community pharmacists. Methods

Hospitalized patients with coronary artery disease discharged on aspirin, β-blocker, and statin who used a participating pharmacy were randomized to usual care or intervention. The usual care group received discharge counseling and a letter to the community physician; the intervention group received enhanced in-hospital counseling, attention to adherence barriers, communication of discharge medications to community pharmacists and physicians, and ongoing assessment of adherence by community pharmacists. The primary end point was self-reported use of aspirin, β-blocker, and statin at 6 months postdischarge; the secondary end point was a ≥75% proportion of days covered (PDC) for β-blocker and statin through 6 months postdischarge.

Results Of 143 enrolled patients, 108 (76%) completed 6-month follow-up, and 115 (80%) had 6-month refill records. There was no difference between intervention and control groups in self-reported adherence (91% vs 94%, respectively, P = .50). Using the PDC to determine adherence to β-blockers and statins, there was better adherence in the intervention versus control arm, but the difference was not statistically significant (53% vs 38%, respectively, P = .11). Adherence to β-blockers was statistically significantly better in intervention versus control (71% vs 49%, respectively, P = .03). Of 85 patients who self-reported adherence and had refill records, only 42 (49%) were also adherent by PDC. Conclusions The trend toward better adherence by refill records with the intervention should encourage further investigation of engaging pharmacists to improve continuity of care. (Am Heart J 2012;163:657-665.e1.)

Medications such as aspirin, β-blockers, and statins have been shown to reduce morbidity and mortality in patients with acute coronary syndrome. Several national quality improvement initiatives have focused on improving prescribing of these medications at hospital discharge in patients with acute coronary syndrome. 1-4 Although From the aDuke Clinical Research Institute, Duke University Medical Center, Durham, NC, b Division of Clinical Pharmacology, Department of Medicine, Duke University Medical Center, Durham, NC, and cDivision of General Internal Medicine, Department of Medicine, Duke University Medical Center, Durham, NC. RCT eg number NCT00323258. This investigator-initiated study received funding from a grant from Pfizer, Inc, New York, NY, and from grant number U18HS10548 from the Agency for Healthcare Research and Quality, US Department of Health and Human Services, Rockville, MD (awarded to the Duke Center for Education and Research on Therapeutics). Padmaja Kaul, PhD served as guest editor for this article. Submitted August 22, 2011; accepted January 25, 2012. Reprint requests: Sara Bristol Calvert, PharmD, 300 West Morgan St, Suite 800, Durham, NC 27701. E-mail: [email protected] 0002-8703/$ - see front matter © 2012, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2012.01.019

critical to achieving long-term benefit, adherence to these medications after hospital discharge has received less attention. Research at Duke University Medical Center has shown in a population with documented coronary artery disease (CAD) that the percentage of patients who reported consistent, long-term use was 71% for aspirin; 46% for β-blockers; 44% for lipid-lowering therapy; and 21% for triple therapy with aspirin, β-blockers, and lipidlowering therapy. 5 Other research studies also have shown outpatient adherence to be poor, and nonadherence has been associated with increased mortality. 5-9 The most successful interventions to improve patient medication adherence typically address multiple factors associated with nonadherence, including lack of patient knowledge or perceived benefits, perceived harms of medications, poor medication management skills, and inadequate social support. 10,11 However, even those interventions considered successful have demonstrated only modest improvements in medication adherence. 12 Clearly, there is need for development and testing of new intervention strategies.

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The PILOT-EBM study was a prospective, randomized study coordinated through Duke University Medical Center that tested a multifaceted intervention to improve postdischarge adherence to evidence-based medications for CAD. The intervention included patient education, adherence aids, and expanded communication linkages between hospital-based and community pharmacists, physicians, and patients, beyond what usually exists in the US health care system.

Methods Patients hospitalized at Duke University Hospital (Durham, NC) were screened for study enrollment from July 5, 2006, through July 2, 2009. To increase enrollment, the study was opened to enrollment at Southeastern Regional Medical Center (Lumberton, NC) on May 27, 2008. This study was reviewed and approved by the institutional review boards of the Duke University Health System and Southeastern Regional Medical Center and is registered at clinicaltrials.gov (NCT00323258).

Patient population Hospitalized patients on any nonsurgical cardiology service were eligible if they were ≥18 years old and had documented CAD as determined by one of the following: a diagnosis of unstable angina or acute myocardial infarction; presence of ≥50% coronary occlusion on cardiac catheterization; or prior angioplasty, coronary artery stent, or coronary artery bypass graft surgery. At hospital discharge, patients had to be prescribed triple therapy (aspirin or another antiplatelet drug, a β-blocker, and a statin), unless contraindicated. Patients were required to have their prescription medications filled by only one of the participating pharmacies for 6 months after hospital discharge. Patients were excluded from the study if any of the following criteria were met (Figure 1): hospital stay shorter than needed for enrollment; inability to provide informed consent (cognitively impaired, non–English-speaking, or altered mental status); plan for coronary artery bypass graft surgery during hospitalization; terminal condition with low likelihood of 6-month survival; residence in a correctional or long-term care facility; inability to participate in a follow-up telephone call; participant in the Duke Heart Failure Disease Management Program; or employee/patient of key study personnel.

Participating pharmacies All pharmacies located in the North Carolina counties of Durham, Robeson, Person, Granville, and Vance were invited to participate. Fifty-nine (72%) of 82 candidate pharmacies agreed to participate in the study. Contractual agreements were established with each pharmacy or pharmacy chain. Each pharmacy site received a detailed orientation to study procedures before patients using that pharmacy could be enrolled.

Study design and procedures After receiving approval for the study from the medical directors, hospital physicians and staff were informed about the study and the role of the hospital-based study pharmacist, henceforth referred to as the study pharmacist. Eligible patients

who agreed to participate in the study provided written informed consent. The study pharmacist collected baseline demographics, medical history, medication history, potential barriers to medication adherence, local pharmacy name, and physicians' contact information from the patients' medical records and through patient interviews. The Beliefs about Medicines Questionnaire (BMQ) was completed to assess potential barriers to adherence. 13,14 Patients were randomized to the intervention or usual care arm in a 1:1 ratio using a computer-generated random number sequence and with treatment codes placed in sealed envelopes. Patients were stratified by the county in which their pharmacy was located. Both treatment groups received routine discharge counseling performed by the patient-care nurse and a letter/ discharge summary from the hospital physician to the community physician listing the discharge medications, procedures, and recommendations. Enrolled patients in the usual care arm were not disclosed to the community pharmacy until the end of the study period when refill records were requested. Patients in the intervention group also received standardized counseling from the study pharmacist on the importance of adherence to their cardiovascular medications and review of the purpose for each medication. In coordination with the hospital physician and staff, the study pharmacist addressed identified barriers to medication adherence. A pocket medication card, a list of tips for remembering to take medications, and a pillbox were provided. Before hospital discharge, the study pharmacist contacted the patient's specified community pharmacy and discussed the identified barriers to medication adherence with the community pharmacist. At the time of hospital discharge, the patient's discharge medication regimen, barriers to medication adherence, and contact information for the patient and the patient's physician(s) were faxed to the patient's pharmacy. In addition, a letter was faxed to the patient's local physician indicating that the patient had been enrolled in the intervention arm of the study and providing the contact information for the community pharmacist and study pharmacist. The study pharmacist called each patient 1 to 2 weeks after hospital discharge to verify that the patient had filled all discharge prescriptions and to confirm which pharmacy the patient used. Community pharmacists were reminded to verify the intervention patient's adherence to triple therapy immediately after discharge and at 6, 12, 18, and 24 weeks postdischarge. When a medication was not filled on time or stopped, the pharmacist was asked to elicit the reason from the patient and to contact the physician about nonadherence as necessary. Interventions made by the community pharmacist were documented and faxed to the study investigators. Pharmacies were reimbursed for completion of postdischarge assessment forms: $30 for the first visit form and $20 for each additional form and for a refill record report, for a total of $130 per patient. See online Appendix A for a table showing differences in activities between the treatment groups.

Six-month follow-up telephone call All patients in both study arms were contacted by telephone 6 months after hospital discharge by a pharmacist who was blinded to treatment group. The blinded pharmacist followed a script to determine all current medications, reasons for discontinuing medications of interest, pharmacy(s) used, and

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Figure 1

Patient enrollment and completion of study. (CABG, Coronary artery bypass graft surgery; f/u, follow-up.)

patient satisfaction with the pharmacy and health care providers. The 4-item Morisky Adherence Scale (MAS) using a 5-item Likert scale was also administered (score range, 4-20, with higher scores indicating greater adherence). 15-17 The primary end point was the percentage of patients in each group who self-reported taking all prescribed components of triple therapy 6 months after discharge. Patient self-report was chosen for the primary end point to capture information on aspirin use, an over-the-counter medication. If, during the follow-up telephone call, a patient in either study arm reported that a medication of interest was discontinued by his or her

physician, the physician was contacted by fax to confirm and obtain the reason for the discontinuation. Patients were considered adherent if their physician verified discontinuing the medication(s). For patients unable to be reached using the provided contact information, the Social Security Death Index was used to determine if they were deceased.

Prescription refill records Prescription records were requested from participating pharmacies for patients in both study arms, covering 90 days before hospital


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discharge to 180 days after hospital discharge. For the secondary end point, a patient was considered adherent by prescription records if the proportion of days covered (PDC) was ≥75% for βblocker and statin from discharge to 180 days after discharge. The PDC value of ≥75% was selected based on prior studies showing increased mortality in post myocardial infarction patients with a PDC b75% as compared with those with a PDC ≥75%.18,19 See online Appendix B for details on the calculation of PDC.

Statistical analysis Characteristics and outcomes of patients randomized to the intervention and control groups were compared using Pearson χ 2 tests for all categorical variables and Wilcoxon rank sum tests for all continuous variables. Medians with 25th and 75th percentiles are reported for continuous variables, and numbers and percentages are reported for all categorical variables. P b .05 was considered statistically significant for all tests. Analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC). In the primary analysis, the number of patients with selfreported adherence to triple therapy (or all components of triple therapy that were prescribed at time of hospital discharge) at 6 months postdischarge was compared between the intervention and control arms. Patients with a missing 6-month follow-up telephone assessment were excluded from the analysis. All randomized patients who completed the 6-month follow-up telephone assessment were included in the analysis regardless of whether community pharmacists completed and documented all follow-up assessments. In the secondary analysis, the number of patients by refill records with a PDC ≥75% for both β-blockers and statins during the 6 months after index hospitalization was compared between the intervention and control arms. Patients who died before 180 days and those with missing refill records were excluded from the analysis. Additional prespecified analyses of adherence by self-report and pharmacy medication records were also performed for individual drug classes. The 2 methods for capturing adherence were compared using a simple κ statistic to account for chance agreement between methods. In addition, because decreased mortality has been shown in those adhering to statins at a PDC ≥80% compared with b80%, 20 a sensitivity analysis was conducted in which patients were considered adherent if PDC was ≥80% for βblocker and statins prescribed at hospital discharge. Median PDC, with percentages truncated at 100%, are also reported. Based on an estimated absolute improvement in medication adherence of 10% in the intervention group (eg, 80% in the intervention group, 70% in the control group), a 2-sided test with α level of .05, a 15% dropout rate, and power of 0.80, the targeted sample size was 692 patients (346 patients per group). Because of concerns about slow enrollment after only 37 patients had been enrolled in 7 months, the sample size was re-estimated assuming a larger absolute improvement in medication adherence of 15%. As a result of that calculation, the protocol was amended to specify a smaller overall sample size of 286 patients (143 patients per group). In the end, continued slow accrual of patients led to termination of the study 3 years after study initiation but before the target enrollment had been reached. PILOT-EBM was a Duke investigator-initiated protocol funded both by grant number U18HS10548 from the Agency for Healthcare Research and Quality, US Department of Health

Table I. Baseline patient characteristics Characteristic n (%), unless otherwise noted

Intervention (n = 71)

Control (n = 72)

Age, median (25th-75th percentile) Male Race White Black Native American Other Highest education level completed Advanced degree College graduate Some college High school graduate Some high school Middle school Up to sixth grade Married Medical insurance Prescription coverage Pharmacy location (county) Vance Granville Person Durham Robeson Type of pharmacy Retail chain Independent Clinic pharmacy BMQ necessity-concerns differential,⁎ median (25th-75th percentile) Medical history Heart failure Depression COPD Cerebral vascular disease Diabetes mellitus Hypertension Obesity Renal disease Current smoker First hospitalization for heart disease Medication prescribed at discharge Statin β-Blocker Aspirin ACE inhibitor Angiotensin receptor blocker Antiplatelet other than aspirin

63 (54-71) 47 (66)

62 (52-70) 44 (61)

36 (51) 24 (34) 11 (15) 0 (0)

37 25 9 1

(51) (35) (13) (1)

7 7 13 24 10 8 2 41 65 61

(10) (10) (18) (34) (14) (11) (3) (58) (92) (86)

5 12 24 11 13 5 2 45 65 63

(7) (17) (33) (15) (18) (7) (3) (63) (90) (88)

2 6 11 32 20

(3) (8) (15) (45) (28)

1 7 12 32 20

(1) (10) (17) (44) (28)

57 11 3 7

(80) (15) (4) (5-10)

62 7 3 6

(86) (10) (4) (3-10)

17 14 6 12 31 63 12 13 12 25

(24) (20) (8) (17) (44) (89) (17) (18) (17) (35)

29 12 9 10 34 66 8 12 22 16

(40) (17) (13) (14) (47) (92) (11) (17) (31) (22)

65(92) 65(92) 69 (97) 54(76) 8(11) 47 (66)

66(92) 65(90) 72 (100) 57(79) 9(13) 45(63)

COPD, Chronic obstructive pulmonary disease; ACE, angiotensin-converting enzyme. ⁎ The BMQ necessity score minus BMQ concerns score (scores above 0 indicate greater perceived necessity for medications than perceived concerns about medications, scale −20 to 20).

and Human Services, Rockville, MD (principal investigator, Judith M. Kramer, for the Duke Center for Education and Research on Therapeutics) and by a grant from Pfizer, Inc., New York, NY. The authors are solely responsible for the design and conduct of the study, all study analyses, and the drafting and editing of the manuscript. Amanda McMillan, MPH, MA, provided editorial assistance; Susan H. Corbett, PharmD, conducted the follow-up telephone calls with study participants.


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Figure 2

Patient-reported adherence to cardiovascular medications at 6 months.

Figure 3

Adherence to cardiovascular medications based on prescription refill records through 6 months.


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Results Of the 5,988 patients screened, 207 met all inclusion criteria and were approached for participation in the study. Of these, 64 (31%) declined to participate (Figure 1). There were no statistically significant differences in sex, race or ethnicity, educational level, marital status, or pharmacy location between those who declined and those who agreed to participate. However, those who declined were significantly older than participants (median age 69 vs 62 years, respectively, P = .003). Of the 143 patients enrolled in the study, 71 were randomized to the intervention arm and 72 to the control arm. Comparisons of characteristics between the study arms indicated the groups were well matched (Table I). Three patients (2%) died after randomization but before completion of the 6-month follow-up period (1 in the intervention arm and 2 in the control arm) (Figure 1).

Patient-reported adherence at 6 months Of the 140 patients who survived to 6-month followup, 32 (23%) did not complete the 6-month follow-up telephone call (Figure 1). In the remaining 108 patients, self-reported adherence to aspirin, β-blockers, and statins was very high in both groups (Figure 2). There was no statistically significant difference in overall adherence between the intervention and control arms (91% vs 94%, respectively, P = .50). Likewise, there was no statistically significant difference in MAS between the intervention and control groups (median score 19 in both groups, P = .40). Adherence determined by prescription refill records through 6 months Of the 140 patients who survived to the 6-month followup, 25 (18%) did not have prescription refill records available (Figure 1). In the remaining 115 patients, the prespecified secondary end point of percentage of patients adherent by prescription records (ie, ≥75% PDC for both βblockers and statins) was 53% for the intervention group and 38% for the control group (P = .11) (Figure 3). Analyses of the individual drug classes revealed a larger proportion of patients adherent in the intervention versus control groups for β-blockers (71% vs 49%, P = .03) and for statins (58% vs 49%, P = .34). In the sensitivity analysis using a PDC ≥80% to determine adherence, a larger proportion of patients was adherent in the intervention versus control groups to both β-blockers and statins (51% vs 33%, P = .05), to β-blockers alone (67% vs 47%, P = .05), and to statins alone (58% vs 44%, P = .13). The median PDCs were higher in the intervention versus control groups for combined β-blockers and statins (median [interquartile range] 91% [56%-98%] vs 68% [33%-93%], respectively, P = .08), for β-blockers

alone (94% [71%-100%] vs 75% [51%-98%], P = .03), and for statins alone (85% [50%-98%] vs 74% [17%-98%], P = .30).

Comparison of patient-reported adherence and adherence according to prescription records Of the 85 patients who self-reported that they were adherent to triple therapy and had prescription refill records obtained, only 42 (49%) were also found to be adherent to β-blocker and statin using the prescription refill records (Table II). The level of agreement between the 2 approaches for measuring adherence was very poor (κ = 0.04). In contrast, of the 4 patients self-reporting nonadherence who also had prescription records obtained, 3 (75%) were also found to be nonadherent by the prescription records.

Discussion The intervention used in this study is unique in that it expanded roles and lines of communication for hospitalbased and community pharmacists in a traditional, nonintegrated US health care system. Although the primary end point of patient self-reported adherence was not statistically significant, the prespecified secondary end point using prescription refill records documented both overestimation of adherence by patients' selfreport and a trend toward improvement in adherence to β-blockers and statins with the intervention. These results fulfill a tenet of recently proposed healthcare reforms that require improved continuity of care transcending traditional institutional and practice boundaries. Widespread implementation of this type of intervention would require practice and policy changes in the health care system. This study tested the principle that hospital and community pharmacists can assist in improving continuity of treatment between the hospital and community setting and in monitoring and supporting adherence to life-saving medications. Further corroboration of this finding would be necessary before health system changes could be recommended to support changes in the pharmacist's role. Community pharmacists are uniquely positioned to interact with patients at more frequent intervals than most other health care providers and can promote effective medication-taking behavior through a variety of mechanisms including education, adherence aids, support, and feedback/reminders. They also have immediate access to medication refill information to ascertain medication adherence. However, because they are typically outside of closed health care systems, they do not usually have access to a patient's medical history, which may limit the extent of service that they can provide. In addition, community pharmacists do not typically engage prescribers nor are they engaged by prescribers to identify and resolve adherence issues.


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Table II. Comparison of adherence by self-report to adherence determined by prescription refill records Refill records

Self-reported

Adherent

Nonadherent

Missing

Total

42 1 9 52

43 3 17 63

15 4 6 25

100 8 32 140

Adherent Nonadherent Missing Total

κ = 0.04 (P = .17) for agreement between self-report and refill records.

Thus, the pharmacist has access to medication adherence patterns but not medical history, and the prescriber has access to medical history but not medication adherence patterns, leading to a less-thanoptimal system. This study sought to bridge the gaps by establishing virtual networks among hospital and community physicians and pharmacists for each patient. Previous studies using pharmacists to improve patient medication adherence have been typically limited to a single health care setting (hospital 21-27 or community 28-31), small number of participating pharmacies, or single pharmacy chain 32-35 or were conducted outside the United States in health care systems with preexisting integration between hospital and community providers. 29,36,37 To our knowledge, this is the first intervention of this type and magnitude to be implemented and tested to improve medication adherence outside a closed health care system. In considering replication and expansion of this intervention, there are several lessons about process and evaluation that may be useful. The establishment of the virtual network required some health care providers, such as the study pharmacist and community pharmacist, to alter their scope of work or the delivery of services. Within the context of a research study, these new or expanded activities were encouraged, implemented, and funded outside the existing health care infrastructure. To embed these new activities within current health care processes, changes would be required to obviate the need both for continual re-engagement/education to account for pharmacist turnover in community settings and for external payments for “extra” services such as provision of medication therapy management. Participating health care providers may be more receptive to new relationships with other health care providers and new processes if the relationships became part of standard operating procedures rather than a component of a research study. Another important finding was the discrepancy between proportion of patients determined to be adherent using the 2 assessment methods. Adherence as determined by prescription refill data was substantially lower than that determined by patient self-report of use at one point in time. Although these are not necessarily new findings, 38,39 the substantial discrepancy that was docu-

mented is important to communicate to those about to embark on research on medication adherence. Although neither assessment method measured actual day-to-day use, achieving adherence as measured by refill records required more evidence of effort by the patients than affirming verbally that they had drug available to them at a single point in time. Adherence to cardiovascular medications was found to be very low in this population of patients, which was very diverse and had substantial rates of comorbid conditions, including hypertension, diabetes, renal disease, cerebrovascular disease, heart failure, obesity, depression, and smoking. These results not only highlight the need for interventions to improve adherence but also emphasize the need to use robust methods to assess adherence in research studies and clinical practice. There are several limitations to this study. The choice of patient self-report of adherence as the primary end point and the noted discrepancy between self-reported adherence and adherence determined by refill records have already been described. The study also was not able to recruit the targeted number of patients, resulting in lower power to detect a difference between the study arms. In addition, because follow-up interviews were not available for all patients with prescription refill records, physician-directed medication discontinuations were not able to be included in the assessment of adherence using refill data. Thus, patients would have been considered nonadherent if their physician had purposely discontinued β-blocker or statin, resulting in an overestimate of nonadherence by that measure in our analysis. Despite the lack of a statistically significant difference in self-reported adherence between the intervention and control arms, the results of the prespecified secondary end point using prescription refill data as the method for assessing adherence provide encouraging evidence to support further evaluation of such a multifaceted, combined hospital and community-based strategy to improve medication adherence.

Disclosures Drs Bristol Calvert, Allen LaPointe, and Kramer have received research and salary support from Pfizer. Dr

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Kramer is the executive director of a Food and Drug Administration (FDA)–initiated public-private partnership, the Clinical Trials Transformation Initiative (CTTI), which Duke is hosting according to a memorandum of understanding between Duke and FDA. There are N60 member organizations, all of which pay a membership fee based on the type of organization. Fees are publicly posted on the CTTI Web site: https:// www.ctti-clinicaltrials.org/about/membership/ membership-categories-and-fees. Only government organizations, invited patient representatives, and the invited at-large representative do not pay membership fees. Dr Kramer receives partial salary support derived from membership fees and partial salary support from an FDA-issued cooperative agreement (U-19FD003800), of which Dr Kramer is the principal investigator. Of note, Dr Kramer's salary is determined by Duke University and is not affected by her role as executive director of CTTI. Dr Anstrom has received research and salary support from Alexion, AstraZeneca, Bristol-Myers Squibb, Lilly, Innocoll Pharmaceuticals, Medtronic, Pfizer, and Proctor & Gamble. Dr Anstrom has served on data safety monitoring boards for Pfizer and Vertex; he has also provided consulting services for Pacific Therapeutics, Bristol-Myers Squibb, and AstraZeneca. All data safety monitoring board and consulting services financial relationships involve b$10,000. Ms Kaltenbach and Ms Stafford report no financial disclosures.

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Appendix A. Comparison of activities in usual care versus intervention arms Usual care Intervention Written patient informed consent Baseline demographic and medical history collected from patient and medical record Administration of BMQ Routine discharge counseling from patient-care nurse Standard discharge summary sent to community physician Study pharmacist provided additional counseling on the importance of medication adherence and review of the purpose of medications Study pharmacist addressed barriers to adherence and communicated to hospital team as needed Pocket medication card, pill box, and list of tips for remembering to take medications provided to patient Study pharmacist called pharmacy to relay that the patient had been enrolled in the intervention arm of the study and to share any identified barriers to medication adherence Study pharmacist sent a fax to the patient's pharmacy providing information regarding discharge medications, identified barriers to medication adherence, and contact information for the patient and the patient's physician(s) Study pharmacist faxed the patient's local physician a letter with notification of enrollment in the intervention arm of the study, study description, and contact information for the community pharmacist and study pharmacist Study pharmacist called patient 1-2 wk after discharge to review medications and importance of adherence Community pharmacist verified patient's adherence to medications of interest immediately after discharge and at 6, 12, 18, and 24 wk after discharge Community pharmacist called patient if nonadherence discovered; physician or study pharmacist notified as needed Blinded pharmacist called patient to determine medication use 6 m after hospital discharge Administration of MAS Refill records requested from patient's community pharmacy

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Appendix B. Calculation of percent days covered The following equation was used: Number of days’ supply ðfrom hospital discharge through day 180Þ PDCð%Þ = 100 180 days

For prescriptions of β-blockers or statins filled before the index hospitalization, only the number of days' supply that would have been available after hospital discharge were included in the equation above. Therefore, if a prescription fill or refill preceded the index hospitalization admission date by more than the dispensed days' supply, it was not used in the PDC calculation. If 1 of the medication classes, statin or β-blocker, was not prescribed at discharge, the PDC to only the prescribed class was used to determine overall adherence. To be classified as having overall adherence, the patient must have a PDC ≥75% for each medication class (statin and β-blocker). For example, if the patient's PDC for β-blocker was 95% but PDC for statin was 50%, the overall classification would be nonadherent. If a patient switched pharmacies during the study period and the new pharmacy was a participating pharmacy, both pharmacies were contacted for refill records. If the patient switched to a nonparticipating pharmacy, no attempt was made to obtain prescription records from the nonparticipating pharmacy, and the patient was considered to have missing prescription refill records. The methodology of the sensitivity analysis was identical to that used to calculate PDC with a cutoff of ≥75%, with the exception of changing the cutoff to ≥80%. Adherence as a continuous variable was also calculated with the equation above. Adherence rates N100% were truncated at 100%. The adherence rate for β-blocker and statin were averaged to give the combined adherence rate.