doi: 10.1161/CIRCULATIONAHA.107.706820
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(Circulation. 2008;117:1028-1036.)
© 2008 American Heart Association, Inc.
Health Services and Outcomes Research |
Prevalence, Predictors, and Outcomes of Primary Nonadherence After Acute Myocardial Infarction
From the University Health Network (C.A.J.) and Department of Health Policy, Management, and Evaluation (C.A.J., J.V.T.), Faculty of Medicine, University of Toronto, and Division of General Internal Medicine and Cardiology, Sunnybrook Health Sciences Centre (J.V.T.), Toronto, Ontario, Canada; Department of Pharmacy Practice, College of Pharmacy, Western University of Health Sciences, Pomona, Calif (C.A.J.); and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (P.L., J.V.T.).
Reprint requests to Cynthia Jackevicius, BSc, MSc, PharmD, BCPS, FCSHP, Pharmacy Department, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4. E-mail Cynthia.Jackevicius{at}uhn.on.ca
Received March 31, 2007; accepted December 28, 2007.
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Abstract |
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Background— Secondary prevention after acute myocardial infarction (AMI) is achieved primarily through medications. However, patients must take their medications to benefit. Medication adherence research has focused primarily on continuation of medications rather than not filling the first prescription written (primary nonadherence). Our objectives were to characterize, to determine factors of, and to measure outcomes associated with primary nonadherence after AMI.
Methods and Results— We conducted a population-based cohort study using an AMI registry linked with administrative data in Ontario, Canada. The primary outcome was 1-year mortality. There were 4591 post-AMI patients >65 years of age included with 12 832 prescriptions written, of which 73% and 79% were filled within 7 and 120 days, respectively. By 120 days after discharge, more cardiac than noncardiac prescriptions were filled (82% versus 35%, respectively; P<0.0001). Only 74% of patients filled all their discharge prescriptions by 120 days after discharge after the exclusion of acetylsalicylic acid, which is also available over the counter in Ontario. Factors associated with filling all compared with filling no discharge prescriptions included younger age, low income, discharge medication counseling, in-hospital attending cardiologist, and fewer medications before AMI. The adjusted 1-year mortality rate was higher in patients who filled some versus all (odds ratio, 1.44; 95% confidence interval, 1.15 to 1.79; P=0.001) and none versus all (odds ratio, 1.80; 95% confidence interval, 1.35 to 2.42; P<0.0001) of their discharge medications.
Conclusions— Patients fill most of their discharge prescriptions within 1 week after AMI. The 1-year mortality rate was higher for those patients who did not fill all of their discharge medications after AMI. Factors such as discharge medication counseling and postdischarge follow-up may help to increase the filling rate of medications after AMI.
Key Words: drugs • mortality • myocardial infarction • prevention
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Introduction |
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Medication nonadherence may occur at different points in a patient’s decision-making process.1 It may occur at the start of therapy if a patient receives the initial prescription but does not fill it (primary nonadherence), or it may occur after therapy has started if the patient fails to follow the instructions or fails to refill the prescription (secondary nonadherence).2,3 Both types of nonadherence are important. Primary nonadherence may be seen as a more severe form of nonadherence in that the patient fails to comply with the physician’s treatment plan from the outset by not filling the initial prescription. Patients give varied reasons for not filling prescriptions, ranging from lack of perceived need to concern about costs or adverse effects.4,5
Clinical Perspective p 1036
Most adherence research has been related to secondary rather than primary nonadherence.6–8 This literature suggests that many patients do not continue their medications, particularly for long-term preventive therapies for dyslipidemia and hypertension. For example, a large cohort study of older patients found that 2-year statin adherence rates were 
40% for acute coronary syndrome patients, 36% for chronic coronary artery disease, and 25% for primary prevention.7 Several studies of various designs and populations have assessed primary nonadherence and found between 1% and 21% of prescriptions unfilled or unclaimed within pharmacies when the window for claiming the prescription was 2 to 4 weeks after being prescribed or filled.9–15
Secondary nonadherence has been shown to increase mortality, hospitalizations, and costs.16–19 To the best of our knowledge, the impact of primary nonadherence on patient outcomes has not been studied. Primary nonadherence often is overlooked as a potential significant contributor to failed or suboptimal therapy, and this aspect of nonadherence deserves further study. Given the importance of initiating evidence-based therapies for secondary prevention after acute myocardial infarction (AMI) and the inherent risks of nonadherence in this population, investigation of factors associated with and outcomes of primary nonadherence is paramount to achieve the substantial benefits possible from therapy.20 In this study, we characterized primary nonadherence in a large, population-based post-MI cohort and determined its association with patient and provider characteristics and 1-year mortality.
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Methods |
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Patient Population
We conducted a retrospective cohort study using a population-based AMI registry with linkage to prescription drug claims, vital statistics, physician services use, and hospital discharge abstract databases. The primary data source for patient identification was the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) study registry, which includes retrospectively collected hospital-level data from charts of AMI patients from 104 acute care hospitals in Ontario from 1999/2000 to 2000/2001. Hospitals were representative of the province in terms of type, size, and geography. Up to 125 AMI charts were abstracted per hospital, including a comprehensive set of clinical risk factors, medications, and cardiac quality indicators. If the hospital identified >125 AMI charts during the study period, a random sample of 125 charts was abstracted. If the hospital identified
125, all charts were abstracted. The EFFECT study identified AMI patients using International Classification of Diseases, ninth revision, code 410 as the most responsible diagnosis, using exclusion criteria that have been previously described.21 Eligible subjects were those enrolled in EFFECT who were 
66 years at the time of hospital discharge after AMI. The analysis of adherence required linkage to the Ontario Drug Benefit (ODB) prescription claims database; therefore, non-Ontario residents were excluded. To limit subjects’ prior exposure to the discharge medications and to minimize the potential effect of preexisting drug supplies on postdischarge prescription-filling behavior, prescriptions for medications dispensed to subjects in the 120 days before the index admission and those patients documented in the EFFECT database to have been taking that medication before admission were excluded. To focus on community-dwelling seniors, those admitted to a long-term care institution were excluded. Because of a data coding issue in the EFFECT data, all prescriptions for felodipine were excluded.
Sources of Data
Four separate population-based data sources were deterministically linked to the EFFECT data using common encrypted identifiers: the Canadian Institutes of Health Information hospital discharge abstract database, the Ontario Health Insurance Plan database, the Ontario Registered Persons Database, and the ODB prescription claims database (Figure). Canadian Institutes of Health Information abstracts contain information pertaining to the hospital admission, demographics, coexisting illnesses, in-hospital procedures, and mortality; the Ontario Health Insurance Plan database contains physicians’ claims information; and the Ontario Registered Persons Database contains vital status information. The ODB database contains information on outpatient prescriptions dispensed for all elderly residents of Ontario. Residents may fill prescriptions at any pharmacy within Ontario and have a minimal copayment (Can $2 per prescription or yearly deductible of Can $100 and then Can $6.11 per prescription for higher-income seniors).
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Prescription Claims Data and Linkage
Each subject’s discharge medication information was obtained from the EFFECT database, which served as the gold standard for medication data. Information available for each medication included medication name, dosage, and directions. A universally used unique drug identification number (DIN) was assigned to each discharge medication using the DIN registered for each medication–pill strength combination by Health Canada.22 Each prescription claim submitted to ODB for reimbursement contains the DIN, the quantity dispensed, and the days’ supply, which allowed assessment of concordance between the discharge medication and what was dispensed. For each subject, the ODB database was searched for linkable claims for 7, 14, 30, 90, and 120 days after discharge. A prescription was considered unfilled if no claim was processed in the ODB database within 120 days after discharge. The discharge date after AMI served as the index date.
Patient and Prescriber Characteristics
We examined the association of several patient-specific characteristics and primary nonadherence, including age, sex, socioeconomic status, number of prescriptions before the index date, receipt of discharge medication counseling, history of diabetes, and number of physicians. Socioeconomic status was determined using the low-income code indicator in ODB.23 Preindex medications were defined as the number of different DIN prescriptions dispensed 120 days before the index date. Documentation of any form of predischarge counseling about medication indications or side effects by any health professional was verified through chart review. The number of different physicians was defined by the number of different physician identifier codes in the Ontario Health Insurance Plan within the year before the index date. To assess the in-hospital physician effect, the most responsible physician type for the index AMI admission was assigned to each patient (the attending physician most responsible for the care of the patient and/or for the longest length of stay). Physicians were grouped into practice specialty: specialist (internist, cardiologist) or nonspecialist (family practitioner, other physicians). Patients were classified as to whether they were admitted to a teaching or nonteaching hospital and were categorized by whether they were admitted to a hospital with catheterization facilities according to a categorization scheme previously described.24
Outcomes
The outcome of interest was death within 1 year after the discharge date. Primary nonadherence was separated into 3 categories: those patients who filled all, some, and none of their discharge prescriptions within 120 days after discharge. The risk factor of interest was filling discharge prescriptions within 120 days after discharge, with filling all discharge prescriptions as the reference group. Prescriptions for acetylsalicylic acid were excluded from the outcomes analysis because at least 20% to 25% of patients obtain acetylsalicylic acid over the counter without a prescription, which may confound the results.
Statistical Analysis
Descriptive statistics were used to portray the characteristics of the population and of the unfilled prescriptions. Unfilled prescriptions were calculated overall and by drug class. The timing of prescription filling was based on the first ODB claim for that drug class after discharge. Mixed-effects regression models, used to determine characteristics of patients who filled and who did not fill their prescriptions, evaluated the relationship between primary nonadherence and 1-year mortality while adjusting for potentially confounding patient, prescriber, and hospital variables. We also adjusted for patient characteristics using the variables from the Global Registry of Acute Coronary Events acute coronary syndrome prediction model for mortality, which was validated in the EFFECT data set.25 These variables, from the EFFECT database, included heart failure history; MI history; admission values for serum creatinine, heart rate, and systolic blood pressure, ST-segment depression, and positive cardiac enzymes; and use of in-hospital percutaneous coronary intervention. Data were analyzed with SAS version 9.1 (SAS Institute Inc, Cary, NC). This study was approved by the Research Ethics Board at Sunnybrook Health Sciences Centre in Toronto.
The authors had full access to and take responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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There were 4591 post-AMI patients in the cohort; 45% were female, and the mean age was 76.33±7.23 years (Table 1). There were 12 832 discharge prescriptions written, of which 92.3% were for cardiac medications. The majority of patients (59.5%) had
10 prescriptions filled within 120 days after discharge. Only 74% of patients filled all of their discharge prescriptions by 120 days after discharge after exclusion of acetylsalicylic acid, which is also available over the counter, whereas 10% filled no discharge prescriptions. In the first week after discharge, 73.0% of prescriptions were dispensed, and by 120 days, 21.4% remained unfilled. By 120 days after discharge, more cardiac than noncardiac prescriptions were filled (82.3% versus 34.6%, respectively; P<0.0001; Table 2). Of the cardiac prescriptions, the lowest fill rates by 120 days were for injectable anticoagulants (eg, low-molecular-weight heparin; 13.3%) and antiplatelets (55.7%; Table 3). At least 90% of patients filled prescriptions for angiotensin-converting enzyme inhibitors by 7 days; for statins by 30 days; and for β-blockers, nitrates, calcium channel blockers, and lipid-lowering agents by 90 days after discharge (Table 2). Of the noncardiac prescriptions, supplements (eg, calcium, potassium; 4.9%), antibiotics (22.1%), antidepressants (67.4%), and respiratory medications (76.6%) had the lowest fill rates at 120 days.
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We assessed factors associated with filling medications overall, filling cardiac medications only, and filling rates by cardiac medication class. Significant factors associated with filling all compared with filling no discharge prescriptions included younger age, low income status, having a cardiologist as the most responsible physician, documentation of receipt of discharge medication counseling, and a lower number of prescriptions before AMI (Table 4). There was more variability in the factors associated with filling discharge prescriptions for specific cardiac medication classes. However, a relatively consistent factor associated with a slightly higher likelihood of filling discharge prescriptions for angiotensin-converting enzyme inhibitors, statins, and calcium channel blockers was a higher number of pre-AMI medications (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.00 to 1.18; OR, 1.18; 95% CI, 1.03 to 1.35; and OR, 1.21; 95% CI, 1.06 to 1.38, respectively).
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Crude 1-year mortality rates for patients who filled all, some, or none of their discharge prescriptions were 12.8%, 20.5%, and 30.4%, respectively. In the mixed-effects regression model, the adjusted 1-year mortality rate was higher in patients who filled some versus all (OR, 1.44; 95% CI, 1.15 to 1.79; P=0.001) and none versus all (OR, 1.80; 95% CI, 1.35 to 2.42; P<0.0001) of their discharge medications within 120 days after the index date (Table 5). Other variables significantly associated with increased 1-year mortality include older age, history of diabetes, greater number of physicians before AMI, greater number of pre-AMI prescriptions, history of heart failure, high serum creatinine, high heart rate, and ST-segment depression. The only variables significantly associated with reduced 1-year mortality rate were documentation of receipt of discharge medication counseling, low heart rate, and high systolic blood pressure.
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Discussion |
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We found that primary nonadherence was associated with an increased risk of death at 1 year after AMI even after adjusting for other known factors that may be associated with mortality. Patients who filled none of their discharge medications within 120 days after AMI had an 80% increased odds of death; those who filled only some of their medications had a 44% increased odds of death. Although secondary nonadherence has been associated with adverse clinical outcomes, to the best of our knowledge, this is the first study to report adverse outcomes associated with primary nonadherence.8,16–18 Studies have demonstrated that patients who do not adhere to either placebo or treatment have worse outcomes than patients who adhere to either regimen.19,26,27 It is possible that poor adherence may be a marker for worse outcomes as a result of specific health-related behaviors. Increased mortality with primary nonadherence may represent the converse of the "healthy adherer" effect and relate to a purposeful behavior.19 Readiness to change such as starting a discharge medication involves the patient’s personal values and expectations of the importance of change, as well as their level of confidence or self-efficacy. Although it may not appear to be wise to be nonadherent with the initial discharge medication, the patient is making a clear decision when an initial prescription remains unfilled, rejecting this aspect of the treatment plan. Some reasons for intentional nonadherence include believing the medication is not needed, the perceived ineffectiveness of therapy, the complexity of the regimen, and an inability to afford the medication.28,29 Patients who did not fill discharge prescriptions of medications they were receiving in hospital would be at risk of adverse effects from medication discontinuation. Although prior studies have documented adverse outcomes associated with discontinuation of β-blockers and clopidogrel, adverse effects also may be possible with other medications.30–32
Patients who received discharge medication counseling as documented in their charts had a significantly lower risk of 1-year mortality. The impact of medication counseling on adherence and outcomes has been inconsistent in the literature. Some studies have shown medication counseling to be associated with improved patient outcomes, but usually when combined with other adherence interventions.33,34 Some evidence supports discharge planning and counseling in improving outcomes. Discharge medication counseling by pharmacists has been associated with improved drug knowledge and compliance, together with reduced unplanned physician visits and readmissions in elderly patients, whereas discharge education by nurse-educators has been associated with improved clinical outcomes and reduced costs in patients with chronic heart failure.35,36 Some recent studies such as the Federal Study of Adherence to Medications in the Elderly (FAME) showed that ongoing pharmacist intervention, along with blister packaging, was necessary to maintain long-term adherence; however, important differences in the patient populations and settings between FAME and our study may account for the different findings.37 It has been demonstrated that an intervention such as starting medications at the time of an acute event may improve adherence, and perhaps the same holds true for other interventions. Thus, receipt of predischarge medication counseling at the time of an acute event may have a greater-than-anticipated association with outcomes because the patient may be more ready to accept behavior change.38
One in 5 discharge post-AMI prescriptions was unfilled by 120 days after discharge. Most prescriptions were filled within 1 week, with <6% of additional prescriptions filled between 8 and 120 days. Several studies, primarily surveys or assessment of electronic prescription transmission, found 1% to 21% unclaimed prescriptions within pharmacies when the window for claiming the prescription was 2 to 4 weeks.9–15 We recently conducted a small single-center study to assess database validity and estimated a rate of unfilled prescriptions in post-AMI patients of 18%, similar to the present study.15 Filling the first prescription is an important decision for the patient, and its importance is likely underestimated. Clinicians often assume that patients fill their prescriptions once written, but our study shows this may be incorrect in a sizable proportion of cases.
Prescriptions for cardiac medications, which made up the vast majority of prescriptions, were more likely to be filled than noncardiac prescriptions. Patients likely recognized the need for cardiac more than noncardiac medications given their recent AMI. Evidence-based cardiac medications such as angiotensin-converting enzyme inhibitors, β-blockers, and statins had high fill rates. However, 8% of patients did not fill their β-blocker prescriptions within 120 days after AMI discharge. Patients receiving a β-blocker in hospital who do not fill their discharge prescription are at risk of β-blocker withdrawal, which has been associated with reinfarction or death.30 The lowest fill rate for cardiac medications was for antiplatelets. Only 44% of patients filled their antiplatelet prescription. However, those patients prescribed acetylsalicylic acid may easily have obtained it over the counter because it is usually less expensive when purchased in this manner. At the time of this study, clopidogrel was restricted on the provincial drug formulary, requiring individual clinical review, which limited timely access. Patients would have had to pay for their initial prescription until their review was completed, and this process may have provided a barrier to those patients unable or unwilling to pay for this expensive medication. Because drug-eluting stents were not used during the study period, the usual duration for clopidogrel in AMI patients undergoing percutaneous coronary intervention was 1 month. Some institutions also had programs to supply clopidogrel samples at discharge to avoid gaps in therapy. This may explain some but not all of the unfilled clopidogrel prescriptions. These patients may be at risk of thrombosis because thrombosis has been documented after clopidogrel discontinuation.31,32
Noncardiac medications had much lower fill rates, with nearly 2 of every 3 discharge prescriptions remaining unfilled by 120 days after AMI. Supplements such as calcium, magnesium, and potassium were the most common category. Oral potassium tablets and magnesium supplements were not covered by the drug plan at the time of this study. This may account for some of the unfilled prescriptions because patients were able to purchase them over the counter. More concerning is that nearly one third of antidepressant, four fifths of antibiotic, and one fourth of respiratory prescriptions were unfilled. In prior studies of general populations, the most common unclaimed categories were antiinfectives, antiinflammatories, gastrointestinals, topicals, and perinatal supplements.9–14 It is possible that with the focus on their cardiac condition, patients failed to perceive the importance of medications for concomitant conditions.
At least 1 in 4 patients is partially or totally nonadherent in filling discharge prescriptions. Although some discharge prescriptions in our study may have been purchased directly over the counter (especially by wealthier individuals) or with private insurance, data are not available to explore these hypotheses. The private insurance market for elderly patients in Ontario is likely extremely small because the ODB formulary is quite comprehensive in its drug coverage and has minimal copayments, providing few barriers to medication access.
We found several factors associated with primary nonadherence. Patients identified as low income, those with a cardiologist as the most responsible physician, and those who received discharge medication counseling were more likely to fill their prescriptions. These factors have not been assessed previously in relation to primary nonadherence. Before discharge, recognizing the possibility of primary nonadherence while providing discharge medication counseling may help improve fill rates. Most prescriptions were filled in the first week after discharge. To reduce primary nonadherence, it would be prudent to follow up with patients 1 to 2 weeks after discharge. Although low income has been associated with nonadherence, this factor is not consistent in its association with nonadherence.39 Our low-income patients may differ from those in other studies in that our patients were seniors with a relatively comprehensive prescription plan with a small Can $2 copay per prescription.39 This small copay may not present a large enough barrier to prevent low-income seniors from filling their necessary prescriptions. Although specialists, including cardiologists, have been noted to have higher rates of evidence-based prescribing in various cardiovascular diseases, they also may be more influential with patients in terms of adhering to the initial prescribed regimen after AMI as demonstrated by our findings.40
Older patients were less likely to fill their prescriptions, so special attention to these patients may help target those least likely to comply. Patients with more pre-AMI prescriptions had a decreased likelihood of filling medications overall; however, having more baseline prescriptions was associated with a higher fill rate when individual cardiac medications were assessed. Although this may sound counterintuitive, we had consistent findings when we assessed multidrug secondary adherence of evidence-based medications after AMI.41 Secondary adherence studies also have found conflicting results regarding the number of concomitant medications and adherence.42 Further assessment of possible predictors associated with nonadherence using qualitative research is warranted to further explore and complement our findings.
Study Limitations
We used the marker of a patient filling a prescription as adherence; however, we do not know whether patients actually took their medications after filling their prescriptions. The discharge medication information from the EFFECT study was taken from the discharge information documented in the patient’s medical chart. It is possible that patients may have received different medication instructions from their physicians at discharge that was undocumented. It should be noted that we did not have data on the quality of the medication counseling provided, and some providers may have offered counseling without documenting it in the patient’s chart. Our study was restricted to elderly patients because of prescription claims data availability; primary nonadherence rates may differ in a younger population. We were not able to capture whether patients had obtained their medications over the counter or by private insurance. In the multiple regression model for mortality, we may not have adjusted for all possible covariates that may have been associated with mortality.
Conclusions
Post-AMI patients are more likely to fill their cardiac than their noncardiac discharge prescriptions. If patients fill their discharge prescriptions, the vast majority are filled in the first week after discharge. Patients who do not fill all of their discharge medications after AMI have an increased risk of death at 1 year. Recognition of factors associated with filling discharge prescriptions in the post-AMI population may aid in targeting interventions such as discharge medication counseling and postdischarge follow-up to improve primary nonadherence and mortality.
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Acknowledgments |
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Sources of Funding
Dr Tu is supported by a Canada Research Chair in Health Services Research and by a Career Investigator Award of the Heart and Stroke Foundation of Ontario, Toronto, Ontario. The EFFECT study was funded by a grant to the Canadian Cardiovascular Outcomes Research Team from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada. The Institute for Clinical Evaluative Sciences is supported by an operating grant from the Ontario Ministry of Health and Long-Term Care, Toronto, Ontario.
Disclosures
None.
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Footnotes |
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Clinical Summaries
Circulation 2008 117: 987-989.[Extract] [Full Text]
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