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The American Journal of Managed Care March 2012
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Adherence and Dosing Frequency of Common Medications for Cardiovascular Patients
Jay P. Bae, PhD; Paul P. Dobesh, PharmD; Donald G. Klepser, PhD, MBA; Johnna D. Anderson, MS; Anthony J. Zagar, MS; Patrick L. McCollam, PharmD; and Molly E. Tomlin, MS
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Joanne Spetz, PhD; James F. Burgess, Jr, PhD; and Ciaran S. Phibbs, PhD
IT-Enabled Systems Engineering Approach to Monitoring and Reducing ADEs
Ranjit Singh, MD; Diana Anderson, EdM; Elizabeth McLean-Plunkett, MA; Ron Brooks, BS; Angela Wisniewski, PharmD; Nikhil Satchidanand, PhD; and Gurdev Singh, PhD
The Promise and Peril of Healthcare Forecasting
J. Frank Wharam, MB, BCh, BAO, MPH; and Jonathan P. Weiner, DrPH
Impact of an Online Prescription Management Account on Medication Adherence
John G. Hou, PhD; Patricia Murphy, MPH; Andrew W. Tang, MS; Nikhil Khandelwal, PhD; Ian Duncan, FSA, FIA, FCIA, MAAA; and Cheryl L. Pegus, MD, MPH
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Deepika Mohan, MD, MPH; Amber E. Barnato, MD, MPH, MS; Matthew R. Rosengart, MD, MPH; Derek C. Angus, MD, MPH, FRCP; and Kenneth J. Smith, MD, MS
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Adherence and Dosing Frequency of Common Medications for Cardiovascular Patients

Jay P. Bae, PhD; Paul P. Dobesh, PharmD; Donald G. Klepser, PhD, MBA; Johnna D. Anderson, MS; Anthony J. Zagar, MS; Patrick L. McCollam, PharmD; and Molly E. Tomlin, MS
In this database analysis, greater adherence was observed for once-daily dosing compared with twice-daily dosing with chronic-use prescription medications used by patients with cardiovascular disease.
Objectives: To compare adherence between oncedaily (QD) and twice-daily (BID) dosing with chronic-use prescription medications used by patients with cardiovascular disease.

Study Design: Retrospective cohort database analysis.

Methods: Analysis consisted of 1,077,474 patients aged >18 years with a prescription index date from January 1 to December 31, 2007, for an antidiabetic, antihyperlipidemic, antiplatelet, or cardiac agent with QD or BID dosing. Adherence (medication possession ratio [MPR]) was the number of days of medication supplied between the first prescription fi ll date and the subsequent 365 days divided by 365 days. Overall mean MPR and comparisons between dosing frequency groups were assessed with a generalized estimating equation. Covariates included age at index date, gender, Charlson comorbidity index, therapeutic class, dosing frequency, and the interaction between therapeutic class and dosing frequency group.

Results: Overall, the adjusted mean MPR ± standard error (SE) value for QD agents was 13.6% greater than BID agents (0.66 ± 0.0006 vs 0.57 ± 0.0016; P <.01). The adjusted mean MPR value for QD agents was 2.9%, 17.5%, and 29.4% greater than BID agents in the antidiabetic, antihyperlipidemic, and antiplatelet therapeutic classes, respectively. For cardiac agents, the adjusted mean MPR value was similar between QD and BID agents. Carvedilol represented approximately 80% of the cardiac agents in the BID group. The adjusted mean MPR ± SE for carvedilol phosphate QD was 0.73 ± 0.0024 and 0.65 ± 0.0027 for carvedilol BID (11% difference; P <.01).

Conclusions: In this large analysis, the QD dosing regimen was related to greater adherence versus a BID regimen.

(Am J Manag Care. 2012;18(3):139-146)
The current study is the first large-scale effort to validate the often-held assumption that the complexity of a cardiovascular dosing regimen impacts medication adherence.

  •  Across the 4 therapeutic classes studied (antidiabetic, antihyperlipidemic, antiplatelet, and cardiac), adherence for once-a-day regimens was 14% higher than for twice-daily agents.

  •  Regardless of dosing regimen, adherence for many patients remains suboptimal.

  •  Providing patients with access to simplifi ed dosing regimens may be an important factor in maximizing therapeutic success.
Cardiovascular disease (CVD) continues to be the leading cause of mortality in the western world. In the United States alone, more than 830,000 people die each year from CVD, which accounted for 34.3% of all deaths in 2006.1 The prevalence of CVD in the US population is staggering, with 17.6 million, 5.8 million, and 6.4 million individuals living with coronary heart disease, heart failure, or a history of stroke, respectively.1 These numbers are likely to rise with the increasing elderly population, which is anticipated to be 20% of the US population by 2030.2

Over the last decade, numerous clinical trials of medications have demonstrated signifi cant benefi t in treating patients with CVD and associated risk factors, such as diabetes mellitus, and are now highly recommended in clinical guidelines.3-7 For these medications to provide their benefi ts, patients need to be adherent to the prescribed regimen. Adherence, as defi ned by the International Society for Pharmacoeconomics and Outcomes Research, is “the degree or extent of conformity to the recommendations about day-to-day treatment by the provider with respect to the timing, dosage, and frequency. It may be defi ned as ‘the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen.’”8 While this is one defi nition of adherence, it can basically be explained as “Does the patient take the medication as prescribed?”

Despite evidence of signifi cant clinical benefit, for patients with CVD, adherence is often suboptimal.9-16 It has been estimated that 40% to 50% of patients with CVD may be nonadherent, and this reduction in adherence may be seen at approximately 3 to 6 months of therapy.10-12 Medication nonadherence is a commonly recognized source of adverse patient outcomes and use of healthcare and associated costs.16,17 Studies have demonstrated that nonadherence to therapies for hypertension, dyslipidemia, or chronic stable angina results in greater morbidity, increased risk for hospitalization, or greater mortality. 14,18-25 For example, data from the PREMIER (Prospective Registry Evaluating Myocardial Infarction: Events and Recovery) registry have demonstrated that lack of adherence with the antiplatelet agent clopidogrel in patients with acute myocardial infarction was associated with a 10-fold increase in mortality (0.7% vs 7.5%; P <.0001) and increase in cardiac hospitalizations (14% vs 23%; P = .08) atthe end of 1 year.26

A number of factors may infl uence adherence, one being the complexity of the medication regimen.10,27-30 Complexity of a prescribed medication regimen has been shown to be inversely related to patient adherence.10,29 The complexity consists of 3 major domains: the number of medications prescribed, the complexity of administration, and daily dosing frequency.30 For patients with CVD, who often take multiple medications, including the use of combination products, it can be diffi cult to signifi cantly reduce the number of medications needed for optimal patient outcomes. The complexity of the administrations is not typically an issue in the management of chronic CVD since most medications are taken orally. Subsequently, the simplifi cation of daily dosing frequency may have the most potential to improve drug adherence in patients with CVD.

While it may seem intuitive that a simplifi ed dosing schedule would improve adherence, the literature investigating the relationship between adherence and daily dosing frequency is limited to smaller studies that are fairly old and meta-analyses of these previous studies.16,30,31 The research has suggested that patients are more adherent to drugs with a once-daily (QD) dosing schedule compared with drugs requiring more frequent dosing, but there are concerns about the generalizability of the results. Another major limitation of the current data is that much of the data focus on a single drug or drug class. Additionally, the data are limited to the assessment of adherence of a single therapeutic class, such as only hypertension, dyslipidemia, or diabetes. There have been studies that have compared medication adherence across a variety of different disease states, but these analyses often included disease states that are unrelated, such as epilepsy, hypertension, and osteoporosis. 32,33 Recognizing the scarcity of broad-based multitherapeutic evidence related to adherence and the need to generate relevant data for the patients with CVD, this study attempts to estimate adherence from the broader multi-therapeutic perspective of classes of medications that are commonly used by patients with CVD. The objective of this study is to compare patient adherence between QD and twice-daily (BID) dosing with chronic-use prescription medications commonly used by patients across the spectrum of CVD with a large, recent, commercial database.


Data Source and Data Selection

The study data are from the Thomson Reuters MarketScan Research Databases (Ann Arbor, Michigan). The MarketScan Commercial Claims and Encounters plus the Medicare Supplemental databases are large insurance claims databases with both working age employer-sponsored insurance and patients with Medicare Supplemental Insurance. Pharmacy claims contained quantities of drug dispensed, days supply, and costs.

Data were from July 1, 2006, to December 31, 2008. The first prescription fi ll date, or index date, for 1 or more of the drugs of interest, as described below, occurred between January 1 and December 31, 2007, and prescription data needed to be available for the entire period of time between 6 months prior to and 12 months after the index date. The unit of analysis was drug therapy for 1 year; therefore, patients were permitted to have prescription claims for more than 1 drug in this analysis.

Drugs were selected for inclusion in the study if they were in capsule or tablet form and could be grouped into 1 of the following therapeutic classes: antidiabetic (eg, metformin, thiazolidinediones, sulfonylureas), antihyperlipidemic (eg, statins, fi brates), antiplatelet (eg, clopidogrel, aspirin/dipyridamole, cilostazol), or cardiac agents (eg, ACE inhibitors, antiarrhythmic agents, alpha-beta blockers, calcium channel blockers). For each prescription claim, the quantity of pills per day was calculated. A drug was designated as having either QD or BID dosing if >80% of the claims had a quantity per day of either 1 or 2, respectively.

Patients in the analysis were 18 years or older and were required to be continuously enrolled in a health plan for inclusion in the study. Patient baseline comorbidities were quantified with a simple unweighted Charlson index score.34 Patients with catastrophic healthcare costs (eg, index drug costs greater than $1000, pre-index prescription costs greater than $10,000, or pre-index medical costs greater than $100,000) were excluded from the analysis in order to capture a typical healthcare experience. Patients with prescription claims for less than a 30-day supply were excluded.

Adherence Measures

The adherence measure used in this analysis was the medication possession ratio (MPR). The MPR was defi ned as the number of days of medication supplied from the fi rst prescription fill date up to 365 days divided by 365 days. Calculations of MPR greater than 1.0 were set to 1.0.

Statistical Analyses

The primary objective was to compare the mean MPR values between the QD and BID groups. A generalized estimating equation (GEE) was used to estimate the mean MPR and to compare the dosing frequency groups. The GEE accounted for the correlations resulting from a patient presenting data for multiple drugs either within a therapeutic class or in different therapeutic classes. An exchangeable correlation structure was used in the GEE. Alternative to mean, MPR greater than 80% has been suggested as a measure of adherence and was also calculated. To account for differences in patient demographic and clinical characteristics, the multivariate model adjusted for the potential confounding variables (age at index date, gender, and Charlson comorbidity index) and included therapeutic class, dosing frequency (QD or BID), and the interaction between therapeutic class and dosing frequency group.

The mean MPR adjusted for the model covariates and the standard error (SE) are presented, unless noted otherwise. P values less than or equal to 0.05 were considered statistically significant. No adjustments were made for multiplicity. All analyses were conducted with SAS (SAS Institute, Inc, Cary, North Carolina) version 9.2.


The sample sizes for the analysis, after applying the study inclusion and exclusion criteria, are presented in the Figure. The final analysis database contained 1,440,254 (QD: 1,384,226 and BID: 56,028) therapy observations. This represented 1,077,474 patients, and their baseline characteristics at the index event for a therapy are presented in Table 1. The average age of patients was 59 years for patients taking QD medications and 61 years for patients with BID medications. Approximately 45% and 30% of the patients were in the Southern and North Central regions of the United States, respectively. Across the therapeutic classes, the average Charlson index score ranged from an average of 0.5 to 1.6 and the number of concomitant medications ranged from an average of 3 to 6. Approximately 80% of patients who took antidiabetic agents had a diagnosis of diabetes. Of patients in the antiplatelet agent class with a QD dosing frequency, 65% had a diagnosis of ischemic heart disease, and approximately 50% of patients in the cardiac agent class had a diagnosis of hypertension. For all patients, one-third had a diagnosis of hyperlipidemia. Approximately 50% of patients participated in a preferred provider organization insurance plan. For healthcare costs, the average cost of the index drug ranged from $30 for the antihyperlipidemic agent class with a BID dosing frequency to $255 for the antidiabetic agent class with the QD dosing frequency. Inpatient and outpatient pre-index medical costs ranged from an average of $3041 for patients in the antidiabetic agent class with a BID dosing frequency to $18,522 for patients in the antiplatelet agent class with a QD dosing frequency.

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