BACKGROUND/RATIONALE:
Acute coronary syndrome, including acute myocardial infarction (MI), is one of the leading causes of hospitalization for veterans. Recent advances in the treatment of acute MI have led to declines in hospital mortality. Despite this, the risk of recurrent events and mortality after the index MI hospitalization remains substantial in the following year. Non-adherence to proven cardioprotective medications is a potentially modifiable risk factor that contributes to the persistently high risk of adverse outcomes following MI hospitalization. Prior interventions to improve medication adherence in cardiovascular populations have produced mixed results and have not specifically targeted patients after acute coronary syndrome (ACS) hospital discharge. It is currently unknown if interventions targeting medication non-adherence in the year after ACS discharge will improve medication adherence and intermediate outcomes, or will be cost-effective.


OBJECTIVE(S):
We proposed to test the effectiveness of a multi-faceted patient-centered adherence intervention among veterans following ACS hospitalization, to improve adherence to cardioprotective medications (primary aim). Secondary aims will assess whether the intervention improves achievement of secondary prevention blood pressure (BP) and LDL-cholesterol goals, reduces cardiac endpoints (MI hospitalization, coronary revascularization, all-cause mortality) and is cost-effective.


METHODS:
We proposed a 3-year, multi-site patient-level randomized controlled trial to evaluate, relative to usual care, a multi-faceted patient-centered intervention to improve adherence to cardioprotective medication among veterans following ACS hospital discharge. The study will enroll 280 patients to either the intervention or usual care for 12 months, at three VA Medical Centers (Eastern Colorado, Puget Sound, and Central Arkansas). The proposed intervention will be based on several conceptual frameworks (Chronic Care Model and Medication Adherence Model), and will adapt elements of prior successful adherence interventions, including: collaborative care, patient education, tailoring of medication regimens, and tele-monitoring. The primary analyses will be a comparison of adherence to cardioprotective medications using pharmacy refill records based on the ReCOMP adherence measure developed in the VA. Secondary analyses will compare achievement of secondary prevention BP and LDL cholesterol goals and cardiac events. In addition, cost-effectiveness analysis will be performed. All analyses will be intention to treat.


FINDINGS/RESULTS:
Of 789 patients screened, 394 patients were potentially eligible and 253 patients were randomized, 129 to intervention and 124 to usual care (Figure 1). The patients were predominantly male (~98%), and the average age was ~64 years. Baseline characteristics of the patients were comparable. Almost half of the patients (~45%) had diabetes and two-thirds had a history of coronary artery disease. During the hospitalization, approximately 40% in each group underwent PCI. Usual care patients were more likely to undergo CABG (17.1% vs. 6.7%; p=0.02).

For the primary outcome of medication adherence based on the 4 classes of medications, a greater proportion of intervention patients were adherent compared to usual care patients (89.3% vs. 73.9%; p=0.003) (Table 2). The mean PDC for the 4 medications combined was greater for intervention patients (0.94 vs. 0.87; p<0.001). Further, a statistically significant greater proportion of intervention patients were classified as adherent for statins (93% vs. 82%; p<0.001), ACE /ARB (93% vs. 82%; p=0.03); and clopidogrel (87% vs. 71%; p=0.03). For beta-blockers, the proportion of adherent patients was comparable between the 2 groups (88% vs. 85%; p=0.59). The PDC for each class of medications are listed in Table 2 and demonstrated a 6-11% greater PDC in the intervention group except for beta-blockers.

For the secondary outcomes, there was no statistically significant differences in the proportion of patients reaching BP (p=0.23) or LDL (p=0.14) targets. There was a trend towards greater BP control (59% vs. 49%), decline in systolic BP (-12 vs. -4 mm hg), and decline in diastolic BP (-5 vs. -3 mm hg) for intervention patients, however, these comparisons were not statistically significantly different (Table 3). For the LDL outcome, over one-third (37%) of patients did not have a follow-up lab which was differential by study arm (33.6% vs. 40.3%; intervention versus usual care). Patients with missing LDL levels were less adherent to statin medications compared to those with a follow-up lab (74% vs. 96%; p=0.02). There were no statistically significant difference in LDL change (-13 vs -12 mg/dl) between intervention and usual care. When LDL change was stratified by randomization group and adherence categories, adherent patients in the intervention (-15.5 mg/dl) and usual care (-13.1 mg/dl) groups had similar magnitudes of LDL decline. Interestingly, non-adherent usual care patients also had a decline in LDL (-9.3 mg/dl) while non-adherent intervention patients had a LDL increase (+15.4 mg/dl) (Table 4). Finally, there were no statistically significant differences between the 2 groups for re-hospitalization for MI, revascularization or death (Table 3).

Over 12 months, each intervention patient received an average of 3 hours, 51 minutes of additional pharmacist time (valued at $62.02 hourly), 35 minutes of additional cardiologist time, (valued at $186.97 per hour), and a pill box (valued at $5.00) for a total of $359.77 in costs directly related to the intervention. The difference in median cost for the two groups for all medications, ACS and non-ACS related medications was very small and not statistically different (Table 3). Median ACS-related medication costs were approximately $0.78 per covered day (IQR $0.42 to $1.59), and median overall medication costs were $8 per covered day (IQR $4.27-$14.32). There were no statistically significant differences between the two groups in median number of VA outpatient visits (49 and 54, respectively) during the year (p=0.11), which translated into similar costs. Further, there were no differences in inpatient costs, stays, or costs per inpatient day between the two groups. Including the direct costs of the intervention, annual costs for intervention and usual care patients were similar

IMPACT:
The objective of this study was to test the effectiveness of a multifaceted intervention to improve adherence to cardioprotective medications in the year after ACS hospital discharge. We found that our intervention comprised of pharmacist-led medication reconciliation and tailoring, patient education, collaborative care involving pharmacists, and automated telephone voice messaging calls improved the proportion of adherent patients by ~15% and the mean adherence to the 4 medications combined by ~7%. There was no statistically significant difference in the secondary prevention measures or clinical outcomes over the 12 months of the study.

There have been few prior studies that have focused on improving medication adherence among patients discharged following ACS hospitalization. Smith, et al. demonstrated that 2 mailed communications to patients after MI discharge improved adherence to beta-blockers by 4.3% (9). Choudhry, et al. showed reductions in adherence of 4 to 6% and in vascular events and revascularization with elimination of copayments for cardiovascular medications (i.e., beta-blockers, statins or ACE/ARB) after MI discharge (10). Important differences should be highlighted of our study compared to these studies. First, we obtained informed consent from each study participant in contrast to prior studies where cluster randomization occurred and individual patient consent was not required. Because of this, the patients in our study were more adherent since they volunteered to participate in a study and this is reflected in the high adherence rates in the usual care patients (PDC of 0.87). Next, we only followed patients for 12 months after hospital discharge and did not see a statistically significant difference in clinical events. In the Choudhry study, the differences in clinical endpoints between full and usual prescription coverage began to diverge after 12-months. It will be important for us to continue to follow patients longer to assess whether the higher adherence in the intervention group translates into improved clinical outcomes. Despite these differences, we were able to demonstrate a similar magnitude of improvement in adherence compared to the prior studies. Together, these studies provide an increasing evidence-base of interventions to improve adherence to cardiac medications after ACS discharge.

Our intervention included multiple components, all of which have been shown to improve adherence to medications among patients with cardiovascular diseases (11-14). While our study was conducted within an integrated health care delivery system, none of the components were unique to it and can be replicated in other health care settings. In the study, a pharmacist reconciled pre and post-hospital medications within 7 to 10 days of discharge, contacted patients at 30 days to address any interim medication issues and then contact thereafter was based on patient needs. The pharmacist notified the patient's primary care provider or cardiologist of any interim changes and provided education to patients focusing on the importance of adherence. These findings add to a prior VA study focused on collaborative care between PCPs and specialists for patients with chronic stable angina by demonstrating that a multi-model intervention, with one component involving collaborative care improves adherence to secondary prevention medications. Finally, automated calls both educational and reminders about medication refills were delivered to patients. Delivery of these intervention components is likely facilitated within an integrated health care delivery system but each of the components should be able to be implemented elsewhere. It will be important to replicate this intervention in other health care delivery systems as well as determine if a single component has the greatest impact on adherence.
The annual incremental program cost to the VA for the multi-faceted intervention was modest at $360 per patient. Most of the costs were related to pharmacist time to review medications and to meet with the patient soon after ACS discharge. Increased medication adherence in our study did not lead to more medication costs for the intervention group. Including the costs of the intervention, median total VA costs over 12 months for the patients in the intervention were approximately the same as costs for usual care, suggesting that the intervention improved medication adherence without increasing VA costs. These results contrast the study by Choudhry et al., where there were higher medication costs for the insurance company but no difference in total healthcare spending between full and usual prescription coverage groups. We plan to continue follow-up of patients beyond the initial 12 months to assess whether there are differences in outcomes and costs longer term. In the interim, the modest costs associated with the intervention suggest that the intervention may be feasible to implement more broadly. Individual healthcare systems will need to weigh the costs and benefits of such an intervention to improve adherence.

There are several limitations which should be acknowledged. This study was conducted at 4 VA Medical Centers which is comprised of males predominantly and may not be generalizable to other patient populations. While prior studies have shown that male patients may be less adherent compared to females, adherence rates overall in this study for both groups were very high and prior studies have not demonstrated a differential intervention effect in adherence by gender (15). Second, we used pharmacy refill data to assess adherence in contrast to clinical trials that have traditionally used pill counts and refilling a prescription does not mean the patient actually ingested the medication. However, the use of pharmacy refill data has been validated as a measure of adherence and used in multiple other adherence intervention studies (15). Further, in our assessment of adherence, we were able to account for medication discontinuation and hospitalized days in the VA which improves our estimate of adherence. Third, we included all patients who consented to participate in the study regardless of their prior adherence behavior. Consideration should be given in the future about targeting patients who have exhibited non-adherence to medications as these patients may obtain a greater benefit with an adherence intervention. Finally, there was no statistically significant difference in the proportion of patients achieving BP and LDL targets which were the a priori secondary outcomes. However, our sensitivity analyses of the BP results suggest that intervention patients had greater declines in systolic and diastolic BPs. Regarding LDL cholesterol, adherent patients were more likely to get follow-up LDL labs and accordingly, we saw declines in LDL levels in both intervention and usual care patients which may have attenuated the intervention effect on LDL levels. Additonal studies are needed to assess the association between adherence and these clinical outcomes in a larger patient sample.

In conclusion, we demonstrated an improvement in adherence to cardioprotective medications after ACS hospital discharge with use of a multi-faceted intervention but not a change in LDL or BP levels. Additional studies are needed to understand the impact of the magnitude of adherence improvement shown in our study on clinical outcomes prior to broader dissemination of such an adherence program.

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External Links for this Project

NIH Reporter

Grant Number: I01HX000165-01
Link: https://reporter.nih.gov/project-details/7749766

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PUBLICATIONS:

Journal Articles

1. Writing Committee Members, Drozda JP, Ferguson TB, Jneid H, Krumholz HM, Nallamothu BK, Olin JW, Ting HH, ACC/AHATask Force On Performance Measures, Heidenreich PA, Albert NM, Chan PS, Curtis LH, Ferguson TB, Fonarow GC, Ho PM, O'Brien S, Russo AM, Thomas RJ, Ting HH, Varosy PD. 2015 ACC/AHA Focused Update of Secondary Prevention Lipid Performance Measures: A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures. Circulation. Cardiovascular quality and outcomes. 2016 Jan 1; 9(1):68-95. [view]
2. Kureshi F, Kennedy KF, Jones PG, Thomas RJ, Arnold SV, Sharma P, Fendler T, Buchanan DM, Qintar M, Ho PM, Nallamothu BK, Oldridge NB, Spertus JA. Association Between Cardiac Rehabilitation Participation and Health Status Outcomes After Acute Myocardial Infarction. JAMA cardiology. 2016 Dec 1; 1(9):980-988. [view]
3. Branch-Elliman W, Stanislawski M, Strymish J, Barón AE, Gupta K, Varosy PD, Gold HS, Ho PM. Cardiac Electrophysiology Laboratories: A Potential Target for Antimicrobial Stewardship and Quality Improvement? Infection control and hospital epidemiology. 2016 Sep 1; 37(9):1005-11. [view]
4. Kini V, McCarthy FH, Dayoub E, Bradley SM, Masoudi FA, Ho PM, Groeneveld PW. Cardiac Stress Test Trends Among US Patients Younger Than 65 Years, 2005-2012. JAMA cardiology. 2016 Dec 1; 1(9):1038-1042. [view]
5. Navarro MA, Gosch KL, Spertus JA, Rumsfeld JS, Ho PM. Chronic Kidney Disease and Health Status Outcomes Following Acute Myocardial Infarction. Journal of the American Heart Association. 2016 May 23; 5(5). [view]
6. Marzec LN, Carey EP, Lambert-Kerzner AC, Del Giacco EJ, Melnyk SD, Bryson CL, Fahdi IE, Bosworth HB, Fiocchi F, Ho PM. Cognitive dysfunction and poor health literacy are common in veterans presenting with acute coronary syndrome: insights from the MEDICATION study. Patient preference and adherence. 2015 Jun 8; 9(June 8):745-51. [view]
7. Smolderen KG, Buchanan DM, Gosch K, Whooley M, Chan PS, Vaccarino V, Parashar S, Shah AJ, Ho PM, Spertus JA. Depression Treatment and 1-Year Mortality After Acute Myocardial Infarction: Insights From the TRIUMPH Registry (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status). Circulation. 2017 May 2; 135(18):1681-1689. [view]
8. Doll JA, Hellkamp A, Thomas L, Ho PM, Kontos MC, Whooley MA, Boyden TF, Peterson ED, Wang TY. Effectiveness of cardiac rehabilitation among older patients after acute myocardial infarction. American heart journal. 2015 Nov 1; 170(5):855-64. [view]
9. Schopfer DW, Priano S, Allsup K, Helfrich CD, Ho PM, Rumsfeld JS, Forman DE, Whooley MA. Factors Associated With Utilization of Cardiac Rehabilitation Among Patients With Ischemic Heart Disease in the Veterans Health Administration: A QUALITATIVE STUDY. Journal of cardiopulmonary rehabilitation and prevention. 2016 May 1; 36(3):167-73. [view]
10. Maddox TM, Ho PM. Health Services Research in Improving the Delivery of Care for Patients with Cardiovascular Diseases: Moving From Observation to Innovation to Action. Circulation. 2017 Jan 31; 135(5):403-405. [view]
11. Shore S, Smolderen KG, Kennedy KF, Jones PG, Arnold SV, Cohen DJ, Stolker JM, Zhao Z, Wang TY, Ho PM, Spertus JA. Health Status Outcomes in Patients With Acute Myocardial Infarction After Rehospitalization. Circulation. Cardiovascular quality and outcomes. 2016 Nov 1; 9(6):777-784. [view]
12. Valle JA, Ho PM. Medication adherence in secondary prevention post-myocardial infarction. Current Treatment Options in Cardiovascular Medicine. 2014 Dec 1; 16(12):349. [view]
13. Ho PM, Lambert-Kerzner A, Carey EP, Fahdi IE, Bryson CL, Melnyk SD, Bosworth HB, Radcliff T, Davis R, Mun H, Weaver J, Barnett C, Barón A, Del Giacco EJ. Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge: a randomized clinical trial. JAMA internal medicine. 2014 Feb 1; 174(2):186-93. [view]
14. Lambert-Kerzner A, Del Giacco EJ, Fahdi IE, Bryson CL, Melnyk SD, Bosworth HB, Davis R, Mun H, Weaver J, Barnett C, Radcliff T, Hubbard A, Bosket KD, Carey E, Virchow A, Mihalko-Corbitt R, Kaufman A, Marchant-Miros K, Ho PM, Multifaceted Intervention to Improve Cardiac Medication Adherence and Secondary Prevention Measures (Medication) Study Investigators. Patient-centered adherence intervention after acute coronary syndrome hospitalization. Circulation. Cardiovascular quality and outcomes. 2012 Jul 1; 5(4):571-6. [view]
15. Yong C, Azarbal F, Abnousi F, Heidenreich PA, Schmitt S, Fan J, Than CT, Ullal AJ, Yang F, Phibbs CS, Frayne SM, Ho PM, Shore S, Mahaffey KW, Turakhia MP. Racial Differences in Quality of Anticoagulation Therapy for Atrial Fibrillation (from the TREAT-AF Study). The American journal of cardiology. 2016 Jan 1; 117(1):61-8. [view]
16. Sandhu A, Ho PM, Asche S, Magid DJ, Margolis KL, Sperl-Hillen J, Rush B, Price DW, Ekstrom H, Tavel H, Godlevsky O, O'Connor PJ. Recidivism to uncontrolled blood pressure in patients with previously controlled hypertension. American heart journal. 2015 Jun 1; 169(6):791-7. [view]

VA Cyberseminars

1. Ho M, Glorioso T. Lessons Learned from the Partnered Evaluation with the Office of Specialty Care. Using Data and Information Systems in Partnered Research [Cyberseminar]. HSR&D. 2016 Sep 28. [view]

Conference Presentations

1. Fagan KM, Lambert-Kerzner A, Carey EP, Del Giacco EJ, Mihalko-Corbitt R, Fahdi IE, Bosworth HB, Melnyk D, Bryson CL, Rumsfeld JS, Ho M. Depression Does Not Predict Longitudinal Medication Adherence in an Acute Coronary Syndrome Population. Poster session presented at: American Heart Association Quality of Care and Outcomes Research Council Annual Scientific Session; 2014 Jun 2; Baltimore, MD. [view]
2. Ho M. Importance of Medication Adherence in Cardiovascular Disease. Paper presented at: Montana Cardiovascular Health Summit; 2010 Apr 9; Missoula, MT. [view]
3. Ho M, McCreight M. Patient and provider perceptions about a clopidogrel adherence intervention in the Veterans Health Administration. Paper presented at: American Public Health Association Annual Meeting and Exposition; 2016 Oct 29; Denver, CO. [view]

DRA: Cardiovascular Disease, Health Systems Science
DRE: Prevention
Keywords: Adherence, Ischemic Heart Disease
MeSH Terms: none