The Pennsylvania State University

The Graduate School

College of Health and Human Development

PREDICTORS AND HEALTH OUTCOMES OF MEDICATION NON-ADHERENCE

ACROSS MULTIPLE THERAPEUTIC CLASSES AMONG ELDERLY

A Dissertation in

Biobehavioral Health

by

Jian Ding

2010 Jian Ding

Submitted in Partial Fulfillment

of the Requirements

for the Degree of

Doctor of Philosophy

December 2010
 UMI Number: 3575901

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The dissertation of Jian Ding was reviewed and approved* by the following:

Frank M. Ahern
Senior Research Associate in Biobehavioral Health
Dissertation Adviser
Chair of Committee

Debra A. Heller
Senior Health Care Consultant in Magellan Health Services/The PACE Program
Adjunct Associate Professor of Biobehavioral Health

Jan S. Ulbrecht
Professor of Biobehavioral Health and Medicine

Linda A. Wray
Associate Professor of Biobehavioral Health

William L. Harkness
Professor of Statistics

Byron C. Jones
Professor of Biobehavioral Health
Professor-in-Charge of the Graduate Program of Biobehavioral Health

*Signatures are on file in the Graduate School.

ii
 ABSTRACT

Adherence to a medication regimen is generally defined as the extent to which patients take

medications as prescribed by their health care providers. Not only does medication non-

adherence waste health care resources, but it often reduces the effectiveness of prescribed

therapeutic regimens, substantially contributing to the worsening of disease, additional

comorbidity, and death. Older adults are at higher risk of medication non-adherence than

younger adults due to the likelihood of multiple chronic conditions for which medications are

available and prescribed, such as hypertension, coronary artery disease, diabetes, and

osteoporosis. Ample research has identified a number of predictors of medication non-

adherence and demonstrated associated adverse health outcomes. However, nearly all studies

have focused on examining a single therapeutic class; only few studies have examined

medication adherence across multiple therapeutic classes. In order to gain a better

understanding of the extent of non-adherence and its sequelae, it is important to evaluate

adherence to multiple therapeutic classes and associated outcomes in elderly populations in

natural settings which reflect real world scenarios.

The main purposes of the studies included in this dissertation are: 1) to describe medication

use status and the prevalence of medication adherence/non-adherence for multiple popular

chronic therapeutic classes in an elderly population; 2) to evaluate the association between

predictors and medication non-adherence for the elderly across multiple therapeutic classes;

and 3) to evaluate the relationship between medication non-adherence and health outcomes

for the elderly in a multiple therapeutic class setting.

iii
Two studies were conducted to fulfill the research objectives. In the first study, Descriptions

of Medication Use and Factors Related to Medication Non-Adherence, medication use

statuses, medication adherence levels and medication taking patterns were described for 15

popular chronic therapeutic classes; the medication adherence levels were compared based on

demographic factors, therapeutic classes, medication use patterns, medication use histories,

and several measurement methods. The effects of potential predictors on medication non-

adherence across multiple therapeutic classes were assessed. In the second study, Health

Outcomes of Medication Non-Adherence, a cross-sectional study and a cohort study were

conducted, respectively, to investigate the effects of medication non-adherence on

hospitalization and mortality in a multiple therapeutic class setting. The study subjects in both

studies were cardholders of Pennsylvanias Pharmaceutical Assistance Contract for the

Elderly (PACE) program, a state-funded program that offers prescription coverage to over

300,000 income-eligible Pennsylvania state residents.

The results from Study 1 showed that adherence rates (i.e., the proportion of users with

adherence scores greater than 0.8) for the 15 therapeutic classes ranged from 68% to 88% and

persistence rates (i.e., the proportion of users who continue refilling medications) ranged from

75% to 95%. The adherence rates for users of thyroid agents, calcium-channel blockers, and

ARB/ACE medications were higher than for those using other therapeutic classes. The

adherence rates for users of oral antidiabetic drugs and other cardiovascular drugs fell into a

second lower tier, followed by statins, Alzheimers treatments, antidepressants, and proton

pump inhibitors. The adherence rates were lowest for osteoporosis medications, overactive

bladder medications, and diuretics.

iv
Study 1 also revealed that race, medication use history, medication use pattern and therapeutic

class were significant predictors of medication non-adherence and non-persistence. For

example, African Americans were more likely to be non-adherent and non-persistent than

Whites and other race, adherence and persistence were positively associated with longer

medication use histories, and females and married persons generally had higher persistence

rates.

The results from Study 2 suggested an interaction effect between persistence and adherence

level (measured by proportion of days covered, PDC). For therapeutic classes with significant

interaction effects, lower PDC levels were positively associated with hospitalization and

hospitalization days for persistent users. On the other hand, for non-persistent users, lower

PDC levels were either unrelated to hospitalization and hospitalization days or associated with

non-hospitalization and less hospitalization days.

Study 2 also suggested a significant relationship between non-persistence and all-cause

mortality for ARB/ACE medications (HR = 1.39; P < 0.0001), -blockers (HR = 1.23; P =

0.002), calcium-channel blockers (HR = 1.15; P = 0.03), statins (HR = 1.29; P = 0.001),

overactive bladder drugs (HR = 1.49; P = 0.002) and thyroid agents (HR = 1.56; P = 0.0004).

The results also indicated a significant relationship between low PDC levels and mortality for

-blockers and cardiac glycosides, and barely significant relationships for oral antidiabetic

drugs and osteoporosis medications.

v
In summary, this project provides important information regarding medication use patterns, as

well as the prevalence and predictors of medication non-adherence and its associated health

outcomes in a multiple therapeutic class setting. In particular, this study identified several

predictors for general medication non-adherence and demonstrated independent effects of

medication non-adherence for each therapeutic class on health outcomes. These results can

inform the design of interventions to improve medication adherence in older adults.

vi
 TABLE OF CONTENTS

LIST OF TABLES.....................................................................................................................xii

LIST OF FIGURES.................................................................................................................. xiv

ACKNOWLEDGEMENTS ...................................................................................................... xv

CHAPTER 1: INTRODUCTION ............................................................................................... 1

1.1 Background and Significance ........................................................................................... 1

1.2 Descriptions and Objectives ............................................................................................. 4

1.3 Organization of the Dissertation ....................................................................................... 6

CHAPTER 2: LITERATURE REVIEW..................................................................................... 7

2.1 Research History of Medication Adherence ..................................................................... 7

2.2 Factors Related to Medication Adherence ...................................................................... 12

2.2.1 Individual Level Factors .......................................................................................... 13

2.2.2 Interpersonal Level Factors ...................................................................................... 15

2.2.3 Community/Organization Level Factors .................................................................. 17

2.2.4 Policy/Governmental Level Factors......................................................................... 18

2.2.5 Disease and Regimen Characteristics ...................................................................... 18

2.3 Theoretical Approaches for Understanding Medication Adherence ............................... 19

2.4 Measurement Methods for Medication Adherence ........................................................ 24

vii
 2.4.1 Introduction .............................................................................................................. 24

2.4.2 Claims-Based Measurement .................................................................................... 26

Medication Availability .................................................................................................. 28

Persistence ...................................................................................................................... 31

2.5 Health Outcomes of Medication Non-Adherence .......................................................... 32

2.6 Hypotheses...................................................................................................................... 34

CHAPTER 3: DATA AND VARIABLES ................................................................................. 37

3.1 Data ................................................................................................................................. 37

3.1.1 PACE Program and PACE Population ..................................................................... 37

3.1.2 Data Sources ............................................................................................................ 39

PACE Prescription Claims Data ..................................................................................... 39

PACE Eligibility Data..................................................................................................... 40

PACE Cardholder Data ................................................................................................... 40

Mortality Data................................................................................................................. 40

Medicare Data................................................................................................................. 41

3.1.3 Data Manipulation.................................................................................................... 42

3.2 Variables ......................................................................................................................... 43

Demographic Variables ..................................................................................................... 43

Therapeutic Class .............................................................................................................. 44

viii
 Medication Taking Pattern ................................................................................................ 44

Medication Adherence ...................................................................................................... 48

User Status ........................................................................................................................ 50

Mortality Status ................................................................................................................. 50

Hospitalization Days ......................................................................................................... 51

Comorbidity Index ............................................................................................................ 51

Variable Summary ............................................................................................................. 52

CHAPTER 4: STUDY 1: DESCRIPTIONS OF MEDICATION USE AND FACTORS

RELATED TO MEDICATION NON-ADHERENCE .............................................................. 54

4.1 Purpose ........................................................................................................................... 54

4.2 Methods .......................................................................................................................... 54

4.2.1 Study Design and Study Subjects............................................................................. 54

4.2.2 Statistical Analysis ................................................................................................... 55

4.3 Results ............................................................................................................................ 58

4.3.1 Demographic Characteristics of Study Subjects ...................................................... 58

4.3.2 Description of Therapeutic Classes .......................................................................... 59

4.3.3 Description of Medication Taking Behaviors .......................................................... 61

4.3.4 Description of Medication Adherence ..................................................................... 63

4.3.5 Predictors of Medication Non-Adherence ............................................................... 74

ix
 4.4 Discussion ....................................................................................................................... 77

4.4.1 Prevalence of Medication Adherence....................................................................... 77

4.4.2 Measurements of Medication Adherence ................................................................. 78

4.4.3 Predictors of Medication Non-Adherence ............................................................... 79

4.4.4 Strengths and Limitations ........................................................................................ 82

4.5 Chapter Summary ........................................................................................................... 84

CHAPTER 5: STUDY 2: HEALTH OUTCOMES OF MEDICATION

NON-ADHERENCE ................................................................................................................ 86

5.1 Purpose ........................................................................................................................... 86

5.2 Methods .......................................................................................................................... 86

5.2.1 Study Design and Study Subjects............................................................................. 86

5.2.2 Statistical Analysis ................................................................................................... 87

5.3 Results ............................................................................................................................ 89

5.3.1 Demographic Characteristics of Study Subjects ...................................................... 89

5.3.2 Relationship Between Medication Non-Adherence and Hospitalization................. 90

The Relationship Between Medication Non-Adherence and Hospitalization Within

Each Therapeutic Class................................................................................................... 91

The Relationship Between Medication Non-Adherence and Hospitalization Across

Multiple Therapeutic Classes ......................................................................................... 95

x
 The Relationship Between Medication Non-Adherence and Hospitalization Days

Across Multiple Therapeutic Classes ........................................................................... 101

5.3.3 Relationship Between Medication Non-Adherence and Mortality ........................ 107

The Relationship Between Medication Non-Adherence and Mortality Within Each

Therapeutic Class ......................................................................................................... 107

The Relationship Between Medication Non-Adherence and Mortality Across Multiple

Therapeutic Classes ...................................................................................................... 109

5.4 Discussion ..................................................................................................................... 113

5.4.1 Relationship between Medication Non-Adherence and Hospitalization ............... 113

5.4.2 Relationship between Medication Non-Adherence and Mortality......................... 115

5.4.3 Strengths and Limitations ...................................................................................... 117

5.5 Chapter Summary ......................................................................................................... 120

APPENDIX: MEDICATIONS STUDIED IN EACH THERAPEUTIC CLASS ................... 124

REFERENCES........................................................................................................................ 129

xi
 LIST OF TABLES

Table 3.1 Comparison of Demographic Distributions Across Older Adults in PACE,

Pennsylvania and the U.S. in 2005 .......................................................................................... 38

Table 3.2 Definitions and Coding Algorithms for Medication Taking Patterns....................... 47

Table 3.3 Variable Summary .................................................................................................... 53

Table 4.1 Layout of Data Used in Logistic Regression for Study 1......................................... 57

Table 4.2 Demographic Characteristics of Study Subjects in Study 1 ..................................... 58

Table 4.3 Therapeutic Class Characteristics ............................................................................ 60

Table 4.4 Frequency of Medication Taking Behaviors ............................................................ 61

Table 4.5 Medication Taking Behaviors for Each Therapeutic Class ...................................... 62

Table 4.6 Medication Adherence Scores and Persistence Rates, by Therapeutic Class........... 66

Table 4.7 Ranks of Non-Adherence Rates and Non-Persistence Rates of Therapeutic

Classes ...................................................................................................................................... 68

Table 4.8 Medication Adherence Scores and Persistence Rates, by Demographic Factors ..... 70

Table 4.9 Results of Odds Ratios from Logistic Regressions Predicting Non-adherence and

Non-Persistence........................................................................................................................ 75

Table 5.1 Demographic Characteristics of Study Subjects in Study 2 ..................................... 90

Table 5.2 Description of Hospitalization Days ....................................................................... 91

Table 5.3 Result of Zero-Inflated Negative Binomial Regression Predicting Hospitalization

Days among Persistent Users of Each Class ............................................................................ 92

Table 5.4 Result of Zero-Inflated Negative Binomial Regression Predicting Hospitalization

Days among Non-persistent Users of Each Class .................................................................... 93

xii
Table 5.5 Results of Logistic Regression Predicting Hospitalization (Main Effects) .............. 96

Table 5.6 Results of Logistic Regression Predicting Hospitalization

(Interaction Effects: PDC)........................................................................................................ 97

Table 5.7 Results of Logistic Regression Predicting Hospitalization

(Interaction Effects: Persistence) ............................................................................................. 98

Table 5.8 Results of Negative Binomial Regression Predicting Length of Hospitalization Stay

(Main Effects) ........................................................................................................................ 102

Table 5.9 Results of Negative Binomial Regression Predicting Length of Hospitalization Stay

(Interaction Effects: PDC)...................................................................................................... 103

Table 5.10 Results of Negative Binomial Regression Predicting Length of Hospitalization

Stay (Interaction Effects: Persistence) ................................................................................... 104

Table 5.11 Cox-Regression Model Results for Each Therapeutic Class ............................... 108

Table 5.12 Results of Cox-Regression Predicting Mortality (PDC and Persistence) ............ 110

Table 5.13 Results of Cox-Regression Predicting Mortality

(Demographic Variables and User Status) .............................................................................. 111

xiii
 LIST OF FIGURES

Figure 4.1 Distribution of the Number of Therapeutic Classes ............................................... 59

Figure 4.2. Distribution of MPR Scores .................................................................................. 63

Figure 4.3 Distribution of PDC Scores .................................................................................... 64

Figure 4.4 Non-Persistence Rate, by Grace Period .................................................................. 65

Figure 4.5 Medication Adherence Scores (PDC), by Therapeutic Class ................................. 67

Figure 4.6 Medication Adherence Scores (MPR), by Therapeutic Class ................................ 67

Figure 4.7 Percentages of Non-Adherent and Non-Persistent Users, by Therapeutic Class ... 69

Figure 4.8 Comparison of PDC, Adherence Rate and Persistence Rate, by Sex ..................... 71

Figure 4.9 Comparison of PDC, Adherence Rate and Persistence Rate, by Race ................... 71

Figure 4.10 Comparison of PDC, Adherence Rates and Persistence Rates, by Age................ 72

Figure 4.11 Comparison of PDC, Adherence Rate and Persistence Rate, by Marital Status ... 72

Figure 4.12 Comparison of PDC, Adherence Rate and Persistence Rate, by Income ............. 73

Figure 4.13 Comparison of PDC, Adherence Rate and Persistence Rate, by User Status ....... 73

Figure 4.14 Comparison of Medication Adherence Scores, Adherence Rates and Persistence

Rates, by Medication Use Pattern ............................................................................................ 74

Figure 5.1 Distribution of Length of Hospitalization Stay ...................................................... 91

xiv
 ACKNOWLEDGEMENTS

I would like to express my deepest gratitude to my advisor, Dr. Frank Ahern. I am greatly

indebted to Dr. Ahern for all of the guidance, assistance and encouragement he has provided

throughout my doctoral studies. He has always been supportive and willing to help. He

offered me great opportunities to enrich my studies and research experiences and helped me

to build my future career path.

I would also like to thank my committee members. I am truly grateful to Dr. Debra Heller for

her help and encouragement. She provided invaluable support, guidance, insights and

assistance in this work, especially regarding SAS programming and data management. I also

thank Dr. Linda Wray, Dr. Jan Ulbrecht and Dr. William Harkness for their invaluable support,

insights and encouragement on my work. I have benefited tremendously from stimulating and

fruitful discussions with them. Their expertise helped me think more critically,

comprehensively and deeply. I am privileged to have had them as committee members.

I also wish to thank staff members in our department, Shannon Anthony, Kathy Gilham, Lisa

Grove, Jodi Heaton, and Carol Brytzcuk, who have become my Penn State family. Their

kindness, warmth and caring have made me feel at home. I would also like to thank all of my

classmates and friends at Penn State. They made my time here a wonderful life experience.

Finally, I would like to thank my parents for their everlasting love, support and

encouragement. Special thanks also to my husband, Bin Zheng, for all of his love, sacrifices

and everything.

xv
 CHAPTER 1: INTRODUCTION

1.1 Background and Significance

Adherence to a medication regimen is generally defined as the extent to which patients

take medications as prescribed by their health care providers (Osterverg and Blaschke,

2005). It is a key link or mediator between medical practices and patient outcomes

(Vermeire et al., 2001; Kripalani et al., 2007). There is strong evidence that many

patients, especially elderly patients with chronic illnesses such as hypertension,

diabetes, and hyperlipidemia, have difficulty adhering to their recommended regimens

(WHO, 2003). The problem of medication adherence is formidable. Not only does

medication non-adherence waste health care resources, but it often reduces the

effectiveness of prescribed therapeutic regimens, substantially contributing to the

worsening of disease, additional comorbidity, and death (Kane et al., 2003; Ho et al.,

2006a; Ho et al., 2006b). A recent report (WHO, 2003) indicates that in the United

States, only 51% of the patients treated for hypertension adhere to their prescribed

treatments; and for patients with depression, only 40% to 70% adhere to

antidepressant therapies. Of all medication-related hospital admissions in the United

States, 33% to 69% are due to poor medication adherence, with a resultant cost of

approximately $100 billion a year (Osterberg and Blaschke, 2005). The World Health

Organization (WHO) has listed medication non-adherence as a leading cause of

preventable morbidity, mortality, and health care costs (Yeaw et al., 2008).

1
Older adults are at higher risk of medication non-adherence than younger adults due to

the greater likelihood of multiple chronic conditions, such as hypertension, coronary

artery disease, diabetes, and osteoporosis, for which medications are available and

prescribed. Ample research has identified many predictors of medication non-

adherence and has demonstrated associated adverse health outcomes. However, nearly

all studies have focused on a single therapeutic class; few studies have examined

medication adherence across multiple therapeutic classes. Based on the literature

review I conducted, only three published studies have examined medication adherence

across multiple classes.

In the first study, Briesacher and colleagues (2008) assessed adherence levels for

76,032 individuals aged 18 years or older who suffered from at least one of seven

chronic medical conditions (gout, hypercholesterolemia, hypertension, hypothyroidism,

osteoporosis, seizure disorders, and type II diabetes) and had started new drug

therapies. The authors compared the adherence levels (measured by Medication

Possession Ratios, MPR) among the medical conditions.

In the second study, Yeaw and colleagues (2009) evaluated adherence (measured by

Proportion of Days Covered, PDC) and persistence for 167,907 new users of any of

six drug classes (prostaglandin analogs, statins, bisphosphonates, oral antidiabetics,

angiotensin II receptor blockers (ARBs) and overactive bladder (OAB) medications)

during a 12-month period. The authors classified each patient into only one

2
medication class even though the patients may have been taking drugs from multiple

classes.

In the last study, Blackburn and colleagues (2005) reported the adherence rates for

patients (mean age = 58) taking statins, ACE inhibitors and -blockers who had

recently experienced cardiovascular events and were new statin users. They used

linear regression analyses to model the relationship between statin adherence and

potential predictors while treating adherence levels for ACE inhibitors and -blockers

as covariates.

In order to gain a better understanding of the extent of non-adherence and its sequelae,

it is important to evaluate adherence to multiple therapeutic classes and associated

outcomes in older adults in natural real world settings. Failure to examine real-world

medication use wherein patients, especially elderly patients, often take multiple

classes of medications, may lead to biased results on non-adherence and its outcomes.

For example, when evaluating the effects of medication adherence in one therapeutic

class on a specific health outcome, adherence levels for concurrent medications in

other therapeutic classes could also impact the health outcome being examined.

Neglecting these important confounding factors by not considering the context of

multiple medication use, could cause inaccurate estimates of the studied effects.

3
1.2 Descriptions and Objectives

The main purposes of this research were: 1) to describe medication use status and the

prevalence of medication adherence/non-adherence for multiple popular chronic

therapeutic classes in an elderly population; 2) to evaluate the association between

predictors and medication adherence for the elderly across multiple therapeutic classes;

and 3) to evaluate the relationship between medication adherence and health outcomes

for the elderly in a multiple therapeutic class setting.

Two sequent studies were conducted to fulfill the research objectives. In the first study,

Descriptions of Medication Use and Factors Related to Medication Non-Adherence,

medication use statuses, medication adherence levels and medication taking patterns

were comprehensively described; the relationships between potential predictors and

medication adherence across multiple therapeutic classes were examined. In the

second study, Health Outcomes of Medication Non-Adherence, a cross-sectional study

and a cohort study were conducted, respectively, to investigate the effects of

medication non-adherence on hospitalization and mortality in a multiple therapeutic

class setting. The specific aims of each study are described below.

4
 Study 1: Descriptions of Medication Use and Factors Related to Medication Non-

Adherence

1. Describe the status of medication use, including the number of therapeutic classes

taken during the study period, commonly used therapeutic classes and class

combinations.

2. Examine patterns of medication taking behaviors within therapeutic classes.

3. Compare medication adherence levels using several measurement methods.

4. Describe the prevalence of medication adherence/non-adherence based on

demographic variables (sex, age, race, income and marital status) and medication-

related factors (therapeutic class, user status and medication taking pattern).

5. Identify associations between potential predictors and medication adherence across

multiple therapeutic classes.

Study 2: Health Outcomes of Medication Non-Adherence

1. Evaluate the relationship of medication adherence with concurrent hospitalization

and hospitalization days across multiple therapeutic classes.

2. Evaluate the association between medication adherence and subsequent mortality

in a multiple therapeutic class setting.

3. Compare the impacts of non-adherence on health outcomes among therapeutic

classes.

5
1.3 Organization of the Dissertation

This rest of this dissertation is organized as follows. Chapter 2 reviews the literature

in the field of medication adherence. Chapter 3 introduces the data and variables used

in the study. Chapter 4 describes Study 1, Descriptions of Medication Use and Factors

Related to Medication Non-Adherence, and Chapter 5 presents Study 2, Health

Outcomes of Medication Non-adherence. Chapters 4 and 5 are each organized into five

sections: purpose, methods, results, discussion and chapter summary.

6
 CHAPTER 2: LITERATURE REVIEW

2.1 Research History of Medication Adherence

The problem of medication adherence was realized as early as the fourth century B.C.

when Hippocrates remarked that [the physician] should keep aware of the fact that

patients often lie when they state that they have taken certain medicines.(Haynes et

al., 1979). However, Hippocrates admonition about adherence received little attention

until the early 1900s when tuberculosis raised special concerns in the U.S. public

health community (Haynes et al., 1979; Lerner, 1997; Vermeire et al., 2001).

Alcoholic transient men with tuberculosis who resided in the rundown sections of

many cities were often unwilling to stay in hospitals and follow precautionary

instructions. The behaviors of these men raised great concerns about the transmission

of disease throughout their communities. However, relatively little was done about

this problem until the mid-1940s, when World War II veterans with tuberculosis raised

even more concerns. Those veterans showed a high rate (> 50%) of discharge from

hospital against medical advice. Quickly, the attention given to veterans spread to the

general population. In addition to tuberculosis, physicians and researchers also began

to focus on other diseases because of the widespread introduction, prescription and

use of antibiotics following World War II (Lerner, 1997). The growing number of

effective medications spotlighted the problem of non-compliance (Vermeire et al.,

2001).

7
In medical journals dating from the late 1940s and early 1950s, many articles were

published on this topic with titles such as "Why They Leave Against Advice" and

"How We Can Reduce 'Sign Outs'." From the 1950s through the 1960s, those

uncooperative patients were often described as "recalcitrant" and "unattached,

transient, male alcoholics." By the end of the 1960s, many researchers realized that

patients from different cultures had different "clinical realities," and that social factors

could influence the degree to which patients adhered to medical advice; it was

therefore deemed unreasonable to expect patients to always follow medical

instructions (Lerner, 1997).

Patterns of morbidity and mortality changed dramatically during the 20th century. In

the second half of the 20th century, primary health concerns in developed countries

shifted from infectious diseases to chronic diseases (DiMatteo and DiNicola, 1982).

Researchers noticed that although adherence to short-term treatment is relatively easy

to achieve, there are major adherence problems associated with long-term therapies.

With this trend, research on patient adherence grew rapidly (DiMatteo, 2004; Vermeire

et al., 2001).

In the 1970s, the medication adherence research discipline was established, with the

research team of Sackett and Haynes leading the way. David L. Sackett was a

physician and epidemiologist, who became interested in adherence issues while

practicing as a clinician in the early 1970s. He found that unpredictable and often

8
disappointing responses to hypertension therapies were not due to resistant disease

or inadequate drugs, but rather low compliance. The Newsletter on Compliance with

Therapeutic Regimens was started by this research team in 1973 and it quickly

attracted attention from the academic community and concerned clinicians. The

McMaster Workshop/Symposium on Compliance with Therapeutic Regimens was held

in May 1974. Following the symposium, two books were published in 1976 and 1979.

Before 1974, there were only 245 published scientific articles related to compliance.

Since then, thousands of studies have been conducted to identify the causes of non-

adherence and frame intervention designs to improve adherence (Haynes et al., 1976,

1979; Lerner, 1997).

At the end of the symposium, compliance became an accepted term defining patient

medication taking behaviors (Haynes et al., 1976, 1979). Sackett and Haynes proposed

a definition of compliance as: "the extent to which a person's behavior (in terms of

taking medications, following diets, or executing lifestyle changes) coincides with

medical or health advice" (Haynes et al., 1979). This term was very popular from the

1970s to early 1990s (Lerner, 1997).

At that time, a lack of compliance (not taking medication as prescribed) was thought

to result from ignorance and forgetfulness. Thus, a large number of studies focused on

using physical interventions to inform patients and help them remember to take

medications, such as providing more drug information, increasing convenience of care,

9
using reminder pill packages, and so forth. However, those interventions had only

modest effects (Wroe, 2002).

With the trend of patient autonomy in medical decision-making that has been growing

since the 1970s, the term compliance has received extensive criticism in recent

years. Its definition is based on the physician control model in which the patient

should obey or comply with what the doctor says with the underlying assumption that

medical advice is always good for patients, reflecting an overly authoritative approach

to patient care (Lerner, 1997).

In research work conducted between the 1960s and the 1980s, considerable attention

was given to conceptualizing patient non-adherence as a health-related decision-

making problem (Vermeire et al., 2001). Medication non-adherence has been

characterized not only as a vexing clinical concern, but also as a scientific problem

that researchers could study and correct (Lerner, 1997).

By the end of the 1970s, it was already clear that medication adherence is determined

by complex factors. Although many relevant research studies were conducted in the

1980s and 1990s, few new insights were added. A few ideas that did emerge in the

1990s were the importance of doctor-patient relationships and the influence of patient

perspectives on health beliefs. During this time period, a paternalistic approach to the

patient was abandoned and an approach considering the patient as a partner, sharing

10
decisions after being appropriately informed was accepted (Vermeire et al., 2001).

With this shift in thinking, the term adherence began to be widely used as an

alternative to compliance. This subtle shift in terminology effectively reduces a

doctors power in the doctor-patient relationship. It suggests that patient participation

in and engagement with treatment regimens is beneficial (Wroe, 2002; Vermeire et al.,

2001; Bosworth et al., 2006).

In the last decade, another wave of medication adherence research was published due

to the prevalence of HIV/AIDS, the impending transition to an aging society, and the

growing burden of chronic diseases in developed countries (Ingersoll and Cohen, 2008;

Bosworth et al., 2006). Medication management is a significant problem for the

elderly, since they are more likely to have multiple diseases and, therefore, are often

prescribed more medications (Banning, 2008). It has been reported that older adults

take an average of five to eight drugs daily (Chia et al., 2006).

In addition to significant changes in the diseases and patients studied in medication

adherence research in the last decade, theoretical progress has led to a further

distinction between two unique dimensions of adherence, intentional non-adherence

and unintentional non-adherence (Kim et al., 2007). Intentional non-adherence is

defined as deliberate behavior following an active decision-making process based on

specific reasons (e.g., side effects, necessity of taking the medication, financial

reasons) (Kim et al., 2007; Lowry et al., 2005; Wroe, 2002; Lehane and McCarthy,

11
2007). In contrast, unintentional non-adherence is considered to be a passive process,

and is more strongly associated with factors such as carelessness, forgetfulness,

disruptions in daily routines, or misunderstanding medication regimens. Such factors

include individual demographics (e.g., older age, less education, language barriers)

and clinical characteristics (e.g., anxiety, depression), as well as the complexity, type

and knowledge of medication regimens (Kim et al., 2007; Lowry et al., 2005; Wroe,

2002; Lehane and McCarthy, 2007). These two categories may overlap in some

patients (Clifford et al., 2008).

Here, a brief picture of medication adherence research history has been presented,

along with insights into how the concept of medication adherence changed over time.

In the following sections, several important research topics related to medication

adherence are discussed.

2.2 Factors Related to Medication Adherence

More than 200 factors have been identified as being related to medication adherence.

These factors can affect a patients ability and willingness to take medications. Those

factors are related to patients, diseases, regimens, and society, as well as the doctor-

patient relationship and the health care system. These factors can be further classified

into five categories: individual level, interpersonal level, community/organization

level, policy/government level, and disease or regimen characteristics.

12
2.2.1 Individual Level Factors

Although many associations have been found between various factors and medication

adherence, most of the results are inconsistent across studies (Vermeire et al., 2001).

One result that has been generally consistent is the negative relationship between age

and medication adherence. Compared to younger populations, older adults have more

age-related risks of medication adherence (Chia et al., 2006) such as poor vision,

hearing problems, declines in cognitive ability, the presence of psychological

problems, complex prescribed medication regimens, and physical disabilities

(Schectman, 2002; Russel, 2006). With poor vision, older patients may have

difficulties in reading instructions and discriminating between tablets with different

shapes or shades of the same color. Cognitive impairments affect a patients ability to

remember and planning of medication-taking routines may be reduced. When patients

have multiple chronic diseases, they may experience very complex treatment regimens

including multiple medications with dietary and fluid restrictions (Anderson et al.,

2000). Physical disabilities create difficulties for older patients who must manipulate

medication containers and swallow large medication tablets. Additionally, older age is

also related to lower income and lower health literacy. Collectively, these age-related

barriers affect the ability and willingness of older adults to take their medications.

However, there are still some research studies showing a positive relationship between

older age and adherence because older age may also be associated with more social

and safety recommendations (e.g., wearing a medic-alert bracelet), more support from

family members (e.g., being accompanied to doctor visits and being reminded to take

13
medications), and more cooperation with health providers (Anderson et al., 2000).

Health literacy is another factor that is consistently reported as being related to

medication non-adherence (Cartmel et al., 2000; Krueger et al., 2005; Kalichman et al.,

1999). Poor health literacy is often associated with less education or language barriers.

Some patients may have difficulties related to understanding instructions, medication

labels and warnings because of their poor health literacy levels (Kidd et al., 2000).

The shame or embarrassment associated with low literacy may also be a barrier to

communication with health care providers. It has been demonstrated that patients with

limited English proficiency have decreased access to health care services and perceive

a lower quality in the care they do receive. A lack of access to quality health care can

lead to non-adherence (Krueger et al., 2005).

The evidence supporting the impact of sex, race, and marital status on adherence is

mixed (Krueger et al., 2005). In general, women are often poorer and less educated

than men, therefore they are often assumed to have poor adherence. However, women

often have more knowledge about health-related issues and are more likely to engage

in good health behaviors than are men (Umberson, 1992; Alwin and Wray, 2005). In

terms of race, minorities are likely to have less education, greater language barriers

and more health problems requiring complex regimens (Alwin and Wray, 2005).

Married persons often receive support from spouses and may also receive support

from children (Williams and Umberson, 2004). In general, the bulk of research

14
suggests that minority status reduces the likelihood of adherence and marital status

increases the likelihood of adherence (Rand et al., 1995; Kalichman et al., 1999;

Cartmel et al., 2000; Kane et al,. 2001).

Beyond demographic factors, psychosocial and behavioral factors also play important

roles in medication adherence. These factors include ignorance about illnesses,

disbelief in the potential benefits of treatments, missed appointments, and a disregard

for medication advice provided by health care practitioners (Schectman, 2002;

Krueger et al., 2005). Patient beliefs regarding their abilities to take medications (self-

efficacy) can also affect adherence. Self-efficacy is the key to managing chronic

diseases independently (Williams et al., 2008). Patient perceptions about taking

medications (medication efficacy) can also affect medication taking behaviors. For

example, if a patient does not believe in the benefits or necessity of treatment or is

sensitive to medication side effects, that person may be unwilling to take the

recommended medication. Patient perceptions may result from limited knowledge

about a medication or the quality of communications and relationships with their

physicians (Schectman, 2002; Russel, 2006; Krueger et al., 2005).

2.2.2 Interpersonal Level Factors

At the interpersonal level, influences from a patients health care providers (e.g.,

physicians and pharmacists) and family members or other companions can influence

medication adherence behaviors.

15
Physicians play an important role in medication taking behavior. If physicians

prescribe complex regimens, fail to explain medication benefits and side effects

adequately, provide vague or incomplete documentation, ignore drug interactions, or

do not give consideration to a patients lifestyle or the cost of medications, patients

may be unwilling to take the prescribed medications (Osterberg and Blaschke, 2005).

The relationships between physicians and patients and the quality of their

communications also contribute to medication adherence. It has been reported that a

trusting and supportive relationship increases adherence (Krueger et al., 2005).

Conversely, if a patient is dissatisfied with the quality of communication during a

consultation, many patients may fail to follow the advice given to them (Vermeire et

al., 2001).

It has been increasingly recognized that the way a pharmacy provides its products may

also improve medication adherence. Pharmacists can provide medication education to

patients, monitor medication use, communicate with other health care providers about

favorable and adverse drug experiences, and predict and prevent drug problems

(Murray, 2004). Some research studies show that pharmacist monitoring has a positive

effect on patient satisfaction and adherence (Krueger et al., 2005).

Family members or other companions (e.g., live-in assistants) can help remind

patients to take medications, monitor their behaviors, and accompany them to doctor

16
visits. It has been reported that family cohesion and a stable home life can predict

medication adherence (Krueger et al., 2005).

2.2.3 Community/Organization Level Factors

Patient non-adherence is due partly to organizational constraints within pharmacies.

For example, there is a conflict between the need to provide more medication

instructions and the profit advantages of hiring fewer pharmacists; there is also no

monetary benefit for pharmacists who provide additional explanations to patients.

Thus, pharmacy practice has not been able to adequately respond to the unique needs

of elderly patients (Murray, 2004). In addition, some patients also have complaints

about health care or social support systems, such as limited access to health care, lack

of safe and secure mobility, changes in drug formulas, and so forth. These factors can

all reduce medication adherence (Murray, 2004; Larson and Lubkin, 2009).

Packaging and labeling for dispensed medications can also influence adherence. Older

patients may not be able to read labels with medication directions; and the colored

auxiliary labels with tiny print further challenge elderly patients visual and

discrimination ability (Murray, 2004). Furthermore, patients may be unable to open

medication container lids and be confused by overly complex information sheets

(Murray, 2004).

17
2.2.4 Policy/Governmental Level Factors

Limited financial support is one of the primary barriers to medication adherence

(Larson and Lubkin, 2009). Government has the power to address this issue by

providing more financial support to poor elderly and limiting drug prices (Osterberg

and Blaschke, 2005). Another way government can influence medication adherence is

to finance disease prevention efforts. Medication non-adherence often results in

wasting not only health care resources, but also other social resources. Governments

can save tremendous amounts of time and money by funding interventions (Osterberg

and Blaschke, 2005).

In addition, policies related to poverty, lack of insurance coverage, migration and

homelessness have all been considered as factors affecting adherence (Ingersoll and

Cohen, 2008). The older age population has increased dramatically over the last

decade, and this trend will continue (Larson and Lubkin, 2009). With an aging

population, it is reasonable to assume that the role of the government may need to

increase over time.

2.2.5 Disease and Regimen Characteristics

In addition to the factors described above, disease and regimen characteristics are also

important to medication adherence. Disease characteristics include chronicity,

symptom prominence, and response to treatment. Treatment regimen characteristics

include dose frequency, regimen complexity (multiple medications, multiple doses,

18
and specific dietary or time requirements), side effects and treatment duration

(Ingersoll and Cohen, 2008; Vermeire et al., 2001). Studies have shown that simple

and short regimens lead to improved adherence for a variety of medications (Ingersoll

and Cohen, 2008; Williams et al., 2008).

2.3 Theoretical Approaches for Understanding Medication Adherence

More than 200 factors have been identified as being related to medication adherence.

Many theoretical models have been used to systematically understand the concept of

medication adherence and specific related constructs, as well as the relationships

among factors. Among the numerous factors, some studies have shown that patient

beliefs are the most influential, explaining 7% to 19% of the variance in patient

medication adherence behavior. Patient belief factors include perceptions regarding

need, effectiveness, and safety of medications (Veazie and Cai, 2006). Since the 1970s,

several models incorporating patient beliefs have been used to explain patient

medication adherence behavior and to provide the basis for intervention designs aimed

at modifying patient behaviors.

The Health Belief Model is the most frequently used model for medication adherence

(Bosworth et al., 2006). This model focuses on a patient's belief system and decision-

making process. It proposes that adherence behavior is based on the trade-off between

perceived benefits and barriers to medication adherence, the perceived susceptibility

to and severity of a health condition, and the treatment options considered (Lerner,

19
1997; Bosworth et al., 2006). However, the Health Belief Mode1 is an individual level

model and neglects interpersonal, environmental, economic, and social factors. A

similar model is the Health Decision Model, which combines elements from the

Health Belief Model and patient preferences (DiClemente et al., 2002). The Health

Decision Model includes feedback loops, which suggests that adherence behavior can

also change beliefs. Other models or theories have been applied to medication

adherence, including the Theory of Planned Behavior, the Protection Motivation

Theory, the Self-Regulatory Model, the Stages of Change Model, the Social Cognitive

Theory, the Ecological Model, and the Information-Motivation-Behavioral Skills

Model (DiClemente et al., 2002).

The Theory of Planned Behavior (or Theory of Reasoned Action) proposes that patient

behavior is based on intention, which is determined by attitudes toward a behavior (a

persons overall evaluation of performing the behavior), subject norms (a persons

perception of how others feel about the behavior) and perceived behavioral control

(the extent of belief in personal control over performing the behavior) (Bosworth et al.,

2006). The level of perceived behavioral control can also directly predict behavior.

The theory also states that the behavior is repeatable (Bosworth et al., 2006; Krueger

et al., 2005). The limitations of this theory are that it does not take into account

discrepancies between intentions and actual adherence, and it does not address

potential changes in patient beliefs and attitudes over time (Bosworth et al., 2006).

20
The Stages of Change Model attempts to explain the adoption of a health behavior as a

dynamic process which includes six temporally ordered, discrete stages

(precontemplation, contemplation, preparation, action, maintenance and termination)

(Bosworth et al., 2006; Glanz et al., 2002). This model does not concern as much with

identifying the causes of a patient behavior change as with describing the stages of it

(Bosworth et al., 2006). A main strength of the Stages of Change Model is that it

provides a dynamic view of behavior. It can also be used in conjunction with a variety

of other theories and models that are relevant to different levels of influence at the

intrapersonal, interpersonal, environment or community levels (Glanz et al., 2002).

Social Learning/Cognitive Theory suggests that behavior is a response to external

stimuli and is shaped by rewards and punishment (Bosworth et al., 2006; Horne and

Weinman, 1999; Lehane and McCarthy, 2007). Similar to the Health Belief Model and

the Theory of Planned Behavior, this model also assumes that outcome expectancies

(i.e., a persons belief that a certain outcome can be expected as a result of a specific

behavior) or response efficacy (i.e., the effectiveness of a response to prevent or

eliminate a threat) influence behavior. Two important concepts emerged from Social

Cognitive Theory; health locus of control and self-efficacy. Locus of control indicates

whether patients believe what is happening to them (e.g., the outcome of treatment) is

contingent on their behaviors (internal locus of control) or is contingent on outside

forces such as luck, fate, chance or powerful others such as health providers that are

beyond their control (external locus of control). It has been assumed that a patient

21
with a high internal locus of control is more likely to adhere to medication regimens.

Self-efficacy is the confidence to carry out a specific behavior and achieve the

expected outcome. Self-efficacy has been shown to predict the extent to which people

are likely to engage in a behavior. Feelings of higher self-efficacy can also increase an

internal locus of control (Krueger et al., 2005; Veazie and Cai, 2006; Reach, 2008).

This model provides a comprehensive understanding of both why and how people

change their behavior. It also defines important concepts such as self-efficacy.

However, it has been criticized that this theory does not have one unifying principle or

structure (Glanz et al., 2002).

Similar to the Social Cognition Theory Model, the Self-Regulatory Model emphasizes

the role that feelings of self-efficacy and cognitive illness representations play, such as

beliefs about the cause, consequence, nature, duration, and control of disease, as well

as experience with an illness. This model breaks self-regulation into three stages:

representation of an illness, development and implementation of a plan to cope with

an illness, and evaluation of the coping mechanism. These stages also facilitate

feedback situations (Bosworth et al., 2006).

The ecological model is also used in medication adherence research. In this model,

attentions are not only directed at individual behavior, but also at multiple levels of

environmental factors (e.g., interpersonal, community, society, policy) (Kidd et al.,

2000).

22
Although many models have been developed in attempts to explain patient adherence,

there is no single model that can successfully provide an adequate description of

medication adherence behavior. Some review papers have suggested that, to date,

interventions have had little effect on improving medication adherence and have

limited predictive value (Lehane and McCarthy, 2007; Bosworth et al., 2006).

Researchers have also noticed that many models or theories share similar components,

such as self-efficacy, behavioral control, and behavioral intention. Some scholars have

suggested integrating models into interventions (Bosworth et al., 2006). Clearly,

further understanding non-adherence is necessary to developing effective interventions.

In the last decade, medication adherence has been further classified as being either

intentional or unintentional. This classification shapes the understanding of

medication taking behaviors and corresponding intervention strategies. Models based

on self-belief and self-efficacy in particular can be used to investigate intentional

medication non-adherence since those models do not include the unintentional

dimensions. Some intervention strategies such as creating reminders, forming habits,

minimizing routine disruptions, and simplifying treatment regimens may address

unintentional non-adherence (Lehane and McCarthy, 2007). Other strategies such as

improving doctor-patient relationships may be relevant to both intentional and

unintentional non-adherence.

23
After realizing the flaws associated with unilateral examination of either the

intentional or unintentional aspects of non-adherence, researchers started to develop

new models to address both dimensions simultaneously. For example, Johnson (2002)

proposed the Medication Adherence Model (MAM), which depicts a dynamic process

of initiating and maintaining medication adherence. It contains three key components:

purposeful action (a patients initial decision to take medication is based on perceived

need, effectiveness and safety), patterned behavior (patients establish medication

taking habits or patterns through access, routines, and remembering), and feedback

(patients use information, facts, prompts, or events to influence the first two

components and then influence adherence) (Johnson, 2002; Lehane and McCarthy,

2007). The simultaneous assessment of intentional and unintentional non-adherence

can provide a relatively complete understanding of this behavior. However, the

effectiveness of this model has not been well tested.

2.4 Measurement Methods for Medication Adherence

2.4.1 Introduction

Measurement methods are very important in research related to medication adherence.

Many methods are available, but there is no unequivocal consensus as to which

method is best (Murray et al., 2004). Methods available for measuring adherence are

either direct or indirect, and each method has its advantages and disadvantages

(Murray et al., 2004; Osterverg and Blaschke, 2005).

24
Direct methods include measuring concentrations of a drug or its metabolite in blood

or urine and detecting biomarkers (Osterverg and Blaschke, 2005). Direct

measurements have high validity, but are expensive, invasive, inconvenient, and not

available for all medications (Osterverg and Blaschke, 2005). These methods may not

be able to account for pharmacokinetic variability. Direct measurement is practical

only for single-dose therapies, intermittent administration, and hospital patients

(Vermeire et al., 2001).

Indirect methods include patient self-reports, interviews, pill counts, medication

diaries, electronic medication monitors or MEMS (medication event monitoring

systems), and prescription claims-based methods. Indirect measurements are generally

cheaper and more convenient, but also less valid. None of these methods can verify

whether patients actually take the medications (Osterverg and Blaschke, 2005). Self-

reports, interviews and pill counts often over-estimate medication adherence. The self-

report and interview methods are also vulnerable to recall and interviewer bias

(Murray et al., 2004; Osterverg and Blaschke, 2005). The self-report method is

insensitive but has good specificity (i.e., when patients report that they are not taking

medications, it can be assumed to be true). Pill counts can only give an overall

estimate of medication consumption over time, but cannot provide information about

does timing. MEMS can record the dates and times whenever medication containers

are opened or closed (Murray et al., 2004). However, pill counts and MEMS can lead

to subject coping strategies such as pill dumping (Murray et al., 2004)s.

25
Since the implementation of computerized administrative systems for prescription

drugs in health care organizations, pharmacies, and insurance programs, claims data

are increasingly used to measure prescription drug adherence. Claims-based methods

are particularly suitable for evaluating long-term therapies (Lau et al., 1997; Vik et al.,

2004; Andrade et al., 2006). In this dissertation, the claims-based methods are used to

measure medication adherence.

2.4.2 Claims-Based Measurement

Claims-based methods measure adherence behavior by examining medication refill

patterns. The assumption of these methods is that refill patterns reflect medication

adherence, because the rates at which patients obtain prescription refills are usually

consistent with the rates at which they consume them (Grymonpre et al., 2006).

Relative to other measurements such as self-reports and pill counts, claims-based

methods are relatively easy, inexpensive, quick, and are not affected by self-report,

interviewer or recall bias (Van Wijk et al., 2006). They are also more likely to reflect

medication use in a real-world setting (Andrade et al., 2006). Claims data are

generally complete and can be kept forever, so claims-based methods are especially

suitable for longitudinal analysis of prescription drug use over time (Lau et al., 1997;

Crystal et al., 2007). Additionally, claims-based methods can provide a large

population-based sample, which is especially important in behavior sciences, where

effect sizes are usually small (Strom, 1995).

26
However, the validity of claims-based measurement faces many challenges. One

important assumption of using claims-based measurement is that the patients use all

medications as prescribed. In fact, this measurement only reflects the drug availability

to the patient, but not the actual medication taking behavior. It can either over-

estimate or under-estimate actual adherence. Patients may provide medications to

others, dump medications before refilling, or save medications for future use (Sikka et

al., 2005; Martin et al., 2009; Grymonpre et al., 1998). On the other hand, some

patients may obtain drugs from sources that cannot be reflected in claims. For

example, patients may receive drug samples from physician offices and drug

assistance programs, or while hospitalized. Also, claims data do not reflect the use of

over-the-counter drugs and non-formulary drugs purchased out of pocket, thereby

underestimating actual medication adherence (Hess et al., 2006; Curtis et al., 2006).

Additionally, claims records may not be precise enough to detect small irregularities

in medication taking behavior; irregularities in claims records may not necessarily

mean that patients do not adhere to medication regimens (Van Wijk et al., 2006).

Claims data are generally reliable (Lau et al., 1997). However, the accuracy of claims-

based measurement relies greatly on the accuracy of the variable days supply,

which is entered by the dispensing pharmacist. In everyday practice, a pharmacist

calculates the days supply by comparing quantity supplied with the amount consumed

per day from the directions. It is possible for pharmacists to make erroneous estimates

in everyday practice (Christensen et al., 1997; Grymonpre et al., 1998). Data entry

27
errors, outdated labels, and incomplete data are all potential threats to data reliability

(Lau et al., 1997; Grymonpre et al., 2006).

Another disadvantage of claims data is population instability due to changes in health

plans and changes in coverage for specific enrollees and their family members (Strom,

1995). In addition, claims-based measurements cannot reflect psychological factors

underlying behaviors (Szeinbach et al., 2008).

Two sets of methods are commonly employed by claims-based measurements. One,

which is most commonly used, focuses on medication availability. The other focuses

on the duration or continuation of drug refills, often called persistence.

Medication Availability

Medication availability is often measured by medication adherence scores such as

Medication Possession Ratio (MPR) and Proportion of Days Covered (PDC). MPR is

defined as the proportion (or percentage) of days supply obtained during a period of

time (Andrade et al., 2006); and PDC is defined as the proportion of days when a

medication is available during a period of time (Martin et al., 2009).

There are several variations in MPR and PDC calculations. The main source of

variation lies in the definition of the period of time. Period of time is often defined as:

(1) the interval between the first and the last medication dispensing dates in a study

28
period; (2) the interval between the first dispensing date and study end date; or (3) the

interval between the first and the last dates of the study period. Intervals (1) and (2)

are unique to each study participant, while interval (3) is the same for all study

participants (Martin et al., 2009; Choudhry et al., 2009). When using interval (1),

further variation may stem from how the last refill is treated. Some researchers

include the last refill in the count of the days supply and add the days supply of the

last refill to the denominator, whereas others do not. For a small portion of studies,

hospitalization or residence in a long-term care facility are also considered in the

calculation. Some studies exclude patients who were hospitalized, some subtract the

number of hospitalization days from the denominator (Lau and Nau, 2004), and others

add the number of hospitalization days to the numerator (Andrade et al., 2006; Martin

et al., 2009). PDC values always range from 0 to 1. The MPR values can be greater

than 1. Some investigators truncate MPR to1 when the value is greater than 1, and the

truncated MPR is often called MPRt (Martin et al., 2009). However, by truncating,

medication overuse cannot be detected.

When studying medication adherence to an individual medication, the calculation is

straightforward. But if researchers want to measure the adherence level to a class of

medications, the calculation becomes complicated, because patients can exhibit

complex patterns when they take multiple related medications. To treat a condition,

patients may discontinue one or more drugs and switch to other drug(s), take several

drugs simultaneously, or start taking one or more drugs and add one or more drugs

29
later to their existing regimens (Choudhry et al., 2009). According to the definitions of

MPR and PDC, when calculating adherence level to one class of medications, the

numerator of MPR is the sum of days supply for all medications belonging to a

therapeutic class, and the numerator of PDC is the number of days when one or more

drugs of that class are available. It is clear that the presence of multiple drugs on the

same day would not lead to an increase in drug count in the PDC calculation, and that

PDC is less sensitive to complex behaviors such as switching, adding or discontinuing

medication (Martin et al., 2009). In general, when measuring adherence for a

therapeutic class, the PDC based method is more conservative than the MPR based

method.

In addition to calculating medication adherence to a therapeutic class directly from the

days supply of each individual drug (Briesacher et al., 2008; Choudhry et al., 2009;

Yeaw et al., 2009), some investigators calculate the adherence score of a therapeutic

class in two steps. They first calculate the adherence score (either MPR or PDC) for

each individual medication within one sub-class (e.g. generic class), and then use the

mean of the sub-class level adherence scores as the therapeutic class level adherence

score (Choudhry et al., 2009). There are also some researchers who consider patients

to be adherent to a therapeutic class if they have at least an 80% adherence level to all

sub-classes (Benner et al., 2009). They then use the proportion of patients who are

adherent as the adherence level for that therapeutic class (Choudhry et al., 2009).

30
Persistence

PDC and MPR related measurements evaluate the cumulative exposure to medication

over time in order to estimate medication availability. However, such measurements

do not provide information on the timeliness and consistency of refills, which is

another dimension of medication adherence called persistence. To reflect persistence

or discontinuation, a different type of method is needed (Vink et al., 2009; Sikka et al.,

2005; Martin et al., 2009).

Some researchers measure persistence as a function of gaps between refills, using a

defined grace period for gaps. A patient is classified as persistent if the person refills a

prescription by the end of the predetermined grace period; otherwise, that patient is

defined as non-persistent at that point in time. Some researchers have used grace

periods ranging from one-half to three-times the days supply of the preceding

prescription, while others have defined grace periods that are completely unrelated to

the days supply of the previous refill (Sikka et al., 2005).

The disadvantage of gap based methods is that they do not consider all refilling

behaviors during an observation period. Once a patient is classified as non-persistent,

refill behaviors occurring after the designation are neglected. However, a unique

advantage of this method is that it is naturally suitable for survival analysis. The

survival time can be defined as the time interval between the start of an observation

and the time when the first gap occurs (Sikka et al., 2005).

31
Although many methods are available to measure medication adherence, no method is

considered as the gold standard. The lack of consensus on a measurement method is a

major barrier to medication adherence research. Furthermore, some studies have

demonstrated that the adherence levels measured by different methods exhibit poor

agreement (Gunette, 2005). Adherence measurement techniques may directly affect

study results, therefore, measurement methods should be clearly explained when

presenting or interpreting adherence data.

2.5 Health Outcomes of Medication Non-Adherence

In comparison to the quantity of research on predictors of medication adherence, there

is a paucity of studies on the health outcomes (Vik et al., 2004). Medication non-

adherence can influence treatment efficacy by preventing patients from receiving the

full benefits of their prescribed medicines, lead to increased mortality and recurrent

hospitalization, and contribute to an undesirable disease prognosis (Chia et al., 2006).

Some studies have examined health outcomes of medication non-adherence in patients

with conditions such as heart disease, diabetes, and schizophrenia.

In a retrospective cohort study, Ho and colleagues (2008) reported that in patients with

coronary artery disease (CAD), non-adherence to -blockers, ACE inhibitors, and

statins was significantly associated with increased all-cause mortality risk and

cardiovascular mortality. In patients who had experienced myocardial infarction (MI)

in the past, medication non-adherence was associated with a higher mortality rate (Ho

32
et al., 2006a; Jackevicius et al., 2008). It has been estimated that medication non-

adherence is a contributing factor in 20% to 64% of rehospitalizations for heart failure

(Albert, 2008). In patients with heart failure, an association between medication non-

adherence and mortality has also been detected (Granger et al., 2005).

In patients with diabetes, it has been reported that medication non-adherence is

associated with increased risk for all-cause hospitalization, all-cause mortality (Ho et

al., 2006a; Kuo et al., 2003) and diabetes-related deaths (Kuo et al., 2003). It has also

been reported that in patients with diabetes, non-adherence was significantly

associated with outcomes such as higher HbA1c and LDL cholesterol levels (Pladeval

et al., 2004).

For schizophrenia patients, non-adherence to antipsychotic medication is considered

to be a significant barrier to achieving optimal outcomes. It has been reported that

patients may be at significantly increased risk for hospitalization as early as the first

ten days following a missed medication refill (Law et al., 2008). Good compliance

with atypical antipsychotic medications was associated with substantial reductions in

the risk for all-cause and psychosis-related hospitalizations (Ward et al., 2006).

On the whole, most studies have shown medication adherence to be generally

associated with better health outcomes, even if patients are assigned to placebo groups

in clinical trials (Vermeire et al., 2001; Simpson et al., 2006). However, some studies

33
have still shown that increased medication non-adherence was not associated with

increased risk of mortality or hospital admission (Holland et al., 2008; Vik et al.,

2004). Almost all of the authors in these studies pointed out that patients who were

non-adherent may have had other traits (e.g., unhealthy behavior and depression)

contributing to poorer health outcomes, but the effects of those confounding factors

were not clear.

Additionally, most researchers chose 80% as the cut-off point for adherence and non-

adherence in health outcome studies. This arbitrary categorization of adherence may

also impact study results.

2.6 Hypotheses

Based on the prior literature review, several hypotheses were proposed for the current

studies.

Study 1
More than 200 factors have been shown to be related to medication adherence. The

factors available for examination in the current study included demographic factors

(e.g., sex, race, age, income and marital status) and medication-related factors (e.g.,

therapeutic class, medication taking pattern and medication use history). Study

subjects were cardholders of Pennsylvanias Pharmaceutical Assistance Contract for

the Elderly (PACE) program. The study subjects used in this study was an elderly

34
population with low to moderate income; as a consequence, age and income levels did

not vary greatly in study subjects. As indicated by most previous studies, in general,

low socioeconomic status (SES) and a low health literacy levels are associated with

medication non-adherence (Cartmel et al., 2000; Krueger et al., 2005; Kalichman et al.,

1999). Minorities often have lower SES and lower health literacy levels because they

are likely to be less educated and have more language barriers (Alwin and Wray,

2005). Women are often poorer and less educated than men, but they are often more

likely to be engaged in healthy behaviors and have more health related knowledge

(Umberson, 1992; Alwin and Wray, 2005); therefore, it is more difficult to

hypothesize the relationship between sex and adherence. Married persons generally

have higher SES levels because they receive support from spouses and children

(Williams and Umberson, 2004), so it is likely that they would more able to be

adherent. Medication adherence is also related to the complexity of therapeutic

regimens, which can be reflected by therapeutic class and medication taking behavior.

Based on this summary of the literature review, the following hypotheses are proposed:

1. Elderly minorities are more likely to be medication non-adherent than are Whites.

2. Married elderly are more likely to be medication adherent than Non-married

elderly.

3. Medication taking behavior (pattern) is associated with medication adherence level.

4. Therapeutic class is associated with medication adherence level.

35
Study 2
Medication non-adherence reduces the effectiveness of prescribed therapeutic

regimens, and contributes substantially to the worsening of disease and, eventually,

mortality (Chia et al., 2006). Most prior studies have demonstrated that medication

non-adherence is associated with hospitalization and mortality in patients with heart

disease and diabetes, but the results have not always been consistent (Vermeire et al.,

2001; Vik et al., 2004; Simpson et al., 2006; Holland et al., 2008). The inconsistency

in results may be related to use of different measurements, different samples, different

sets of covariates, and interaction effects. I propose the following hypotheses for

Study 2:

1. Non-adherent patients are more likely to experience hospitalization and have more

hospitalization days than adherent patients.

2. Non-adherent patients are more likely to die than adherent patients.

3. Interaction effects may exist in the relationship between medication adherence and

health outcomes.

36
 CHAPTER 3: DATA AND VARIABLES

3.1 Data

3.1.1 PACE Program and PACE Population

The subjects were older adults who were enrolled in Pennsylvanias Pharmaceutical

Assistance Contract for the Elderly (PACE) or the PACE Needs Enhancement Tier

(PACENET) programs. The PACE and PACENET are state-funded programs

administered by the Pennsylvania Department of Aging that offers prescription

coverage to over 300,000 income-eligible Pennsylvania state residents who are 65

years of age or older. The PACE program was implemented on July 1, 1984, and

PACENET was created in 1996. The income eligibility for enrollment in PACE were

expanded in 1985, 1991, 1996 and 2003. The yearly income limits for enrollment

eligibility in 2003 were $14,500 for single people and $17,700 for married couples for

PACE, and $14,500-$23,500 for single people and $17,700-$31,500 for married

couples for PACENET. Only prescription medications are covered by PACE and

PACENET; the only exceptions are insulin, insulin syringes and insulin needles. Over-

the-counter medications are not covered, even if prescribed by physicians. The

program provides a maximum 30-day supply, or 100 tablets or capsules, whichever is

less (PACE Annual Report to the Pennsylvania General Assembly, January 1

December 31, 2005). In this dissertation, the term PACE is used to represent both the

PACE and the PACENET programs.

37
PACE cardholders are adults age 65 and older with low to moderate incomes;

therefore, their demographic characteristics differ from the general U.S. elderly

population. In general, PACE cardholders are older and disproportionally female,

compared to the Pennsylvania or U.S. population. In table 3.1, 2005 data are used as

an example to compare age, sex and race distributions across PACE, Pennsylvania,

and U.S. elderly.

Table 3.1 Comparison of Demographic Distributions Across Older Adults in

PACE, Pennsylvania and the U.S. in 2005

Variable Level PACE a (%) Pennsylvaniab (%) U.S.b (%)

Age 65-69 15 25 28
70-74 18 22 23
75-79 23 21 20
80-84 22 17 15
85+ 21 15 14

Sex Female 75 59 58
Male 25 41 42

Race White 90 92 88
African American 7 7 9
Other 3 1 4
a
PACE Annual Report to the Pennsylvania General Assembly, January 1 December
31, 2005
b
National Center for Health Statistics (NCHS) Bridged-Race Estimates. CDC Wonder.
http://wonder.cdc.gov/population.html

The 2005 data indicated that the PACE population had a higher proportion of older

adults who were aged 80 and above compared to the other two populations.

Additionally, 75% of PACE cardholders were female, which was also higher than the

other two populations. In terms of race, 90% of PACE cardholders were White, similar

38
to the other two populations. In addition, about 70% of PACE cardholders were single

or widowed, and approximately 5% resided in nursing homes or personal care

facilities.

In summary, the PACE data provide an opportunity to study medication use and,

further linked with other data, to study a variety of health outcomes and other health-

related issues. However, some demographic differences existed between the PACE

elderly and the elderly in the overall U.S. population; therefore, external validity must

be considered when generalizing the research results. The research results based on

use of the PACE population data would be more generalizable to elderly populations

with similar demographic characteristics.

3.1.2 Data Sources

For the current study, PACE prescription claims data, PACE membership eligibility

data, mortality data from Pennsylvania Department of Health, and Medicare data for

PACE elderly were used.

PACE Prescription Claims Data

The raw yearly PACE prescription claims data file is formatted into the refill history for

each PACE cardholder, with information including medication name, national drug code

(NDC), date of service, days supply, dosage, cost, provider, and etc. One observation in

the claims data represents one medication fill event. Therefore, one cardholder can

39
create multiple observations in the claims data file. The prescription claims data provide

medication use and medication adherence information for these studies.

PACE Eligibility Data

The yearly PACE membership eligibility data contain cardholder enrollment histories,

(e.g., start date and end date). The raw eligibility data files also contain multiple

observations per cardholder.

PACE Cardholder Data

The cardholder data set is a person-level file (i.e., one record per cardholder). These data

contain demographic information on PACE cardholders, such as date of birth, sex, race,

income, and marital status.

Mortality Data

Mortality data files were obtained from the Pennsylvania Department of Health. These

data contain mortality-related information on PACE cardholders, including date of death,

underlying cause of death and multiple causes of death. The cause of death is coded

using the International Classification of Disease 9th Revision (ICD-9) system.

40
Medicare Data

Medicare is a federal health insurance program for American citizens aged 65 years and

over. About 98% of PACE elderly are Medicare enrollees. Medicare Part A (Hospital

Insurance) covers hospital care, skilled nursing facility care, home health care, and

hospice care. Medicare Part B (supplemental medical insurance) covers general

physician visits, outpatient hospital visits and durable medical equipment. Medicare Part

C (Medicare Advantage Plan or Medicare Plus Choice) allows enrollees to receive

health care benefits from private insurance companies. Medicare Part D (effective

January 1, 2006) helps enrollees obtain prescription drug coverage. To exclude the

influence of Part D on medication use in the studies, the data from 2003 were used to

determine patient medication adherence, and the data for 2004 and 2005 constituted the

follow-up period.

Medicare data files obtained from the Centers for Medicare & Medicaid Services (CMS)

include the denominator files, inpatient files, outpatient files and carrier files. The

denominator file contains demographic and enrollment information for each Medicare

enrollee during a calendar year. The inpatient file contains information about inpatient

hospital services, including admission dates, discharge dates, diagnoses (ICD-9 code),

procedures, and so on. One of the health outcomes in Study 2--hospitalization days--was

calculated based on inpatient data. The comorbidity index, one of the covariates in Study

2, was calculated based on diagnosis information identified in the inpatient, outpatient

and carrier files.

41
3.1.3 Data Manipulation

The event-level PACE yearly membership eligibility file was converted into a person-

level file; and 12 new variables were created to represent the number of days in each of

the 12 months in a given year when cardholders were enrolled in the PACE or PACENET

programs. The demographic information from the PACE cardholder file, date and cause of

death from the mortality file, and Medicare enrollment status from the Medicare

denominator file, were added to the person-level PACE eligibility file. This new dataset

contained information on demographics, PACE enrollment status, Medicare enrollment

status and mortality status.

For the prescription claims data, the National Drug Code (NDC) was used to identify

and select medications belonging to the therapeutic classes of interest in this study so

therapeutic class variable could be added to each claim. Claims data were converted to

person-level and therapeutic-class level datasets. Medication use and medication

adherence indicator variables were then created for each therapeutic class used by a

cardholder.

The claims-level Medicare datasets (inpatient files, outpatient files and carrier files)

were converted into person-level data. The diagnosis information from the three sources

was combined and the comorbidity index was calculated for each patient. The value of

hospitalization days was calculated for each patient based on the admission date and

discharge date in their inpatient file.

42
After the above data manipulation procedures, the three newly generated datasets were

combined to create the necessary analytical datasets for the studies.

3.2 Variables

The variables used in this dissertation are introduced in this section. They include

demographic variables, therapeutic class, medication taking pattern, medication

adherence, user status, hospitalization days, mortality status, and comorbidity index.

Demographic Variables

The demographic variables used in this dissertation included sex, race, age, marital

status and income. These variables were extracted from the PACE cardholder files.

Among PACE cardholders, over 90% were White and about 5% were African

American, therefore race was classified into three categories: White, African American

and Other Race. Age was treated as a categorical variable with five categories: 65-69,

70-74, 75-79, 80-84, and 85 and above. For marital status, four categories were used:

married, married but living separately, single or widowed, and divorced. Annual

income was treated as a categorical variable with four categories: <$5,000, $5,000 to

$9,999, $10,000 to $14,999, and $15,999 and above.

43
Therapeutic Class

Based on the NDC, medications were classified into 15 classes according to the

American Hospital Formulary Service (AHFS) classification system, including

antidepressants, proton pump inhibitors, thyroid agents, Alzheimers treatments,

overactive bladder drugs, oral antidiabetic drugs, osteoporosis medications, and eight

cardiovascular classes, including angiotensin-converting enzyme inhibitors

/Angiotensin II receptor antagonists (ACE/ARB), calcium-channel blockers, -

blockers, statins, cardiac glycosides, vasodilators, diuretics, and antiplatelet therapies.

Only medications used orally were included in the study. Only study subjects who had

at least two claim records of a therapeutic class in one year were considered to be

chronic users of a class. These therapeutic classes were chosen because they are

widely used by the elderly population and they account for approximately 70% of all

medication claims of the study subjects in 2003. The specific mediations included in

each therapeutic class are listed in the Appendix.

Medication Taking Pattern

If patients only take one medication (based on specific chemical entity) in one class,

their medication taking pattern is straightforward. For patients taking multiple

medications in one class, medication taking behaviors become more complicated. Here,

taking multiple medications in one class indicated the use of drugs with different

chemical entities. Medications with different brand names but with the same chemical

entity were treated as being the same.

44
Medication taking behavior for multiple drugs can be classified into three basic

categories: medication switch, medication add-on, and poly-therapy (Choudhry et al.,

2009). Medication switch means patients change their regimens completely,

medication add-on indicates that patients add medication(s) to their existing regimens,

and poly-therapy refers to the existence of multiple medications in patient regimens

with no new medications introduced during the observation period. For patients using

two medications in one class, these three patterns are mutually exclusive. Medication

switch means switching from one medication to another (i.e., one-by-one switch), and

medication add-on indicates that one medication is added while another medication is

continued (i.e., add one medication at a time).

However, for patients taking three or more medications, in addition to the three basic

patterns patients may exhibit more complex medication taking behaviors constituting a

mix of two or three of the basic patterns. For example, some patients may use poly-

therapy for a while and then add one or more medications; others may switch from a

regimen with multiple medications to another poly-therapy regimen; still others may

follow a poly-therapy regimen and after a period of time, change a few of their

medication(s). There are so many possible pattern combinations that it is very difficult

to define them all. Because exploratory data analyses showed that only a small

proportion (less than 0.8%) of the study subjects exhibited those mixed patterns, I

determined that it was not necessary to further classify them into extremely detailed

45
categories. Thus, mixed patterns were classified into just two categories. If the

regimen was completely switched to a new regimen, this pattern was called mixed

switch, since the switch was the main characteristic of the pattern. For other mixed

patterns, the initial regimen did not completely change, and new medication(s) could

be added to the initial regimen while some old medications were discontinued; these

patterns were defined as other mixed.

The definitions and the coding algorithms of the medication taking patterns are

summarized in Table 3.2.

46
 Table 3.2 Definitions and Coding Algorithms for Medication Taking Patterns

Pattern Definition Coding Algorithm

One-by- Patient switches from one After a patient refills a medication for
one medication to another the last time, the person begins to fill
switch medication. another medication (i.e., the first
dispensing date of the new medication is
later than the last dispensing date of the
old medication).

Poly- Patient receives two or more Patient receives multiple medications on

therapy medications concurrently the same day or at any point before
refilling any of the multiple
medications, and no new medications
appear in the observation period.

One-by- Patient receives one medication After patient refills one medication at
one add- and follows it for a while and least one time, the patient begins a new
on then adds a new medication to medication that is taken in addition to
the existing regimen. the first one.

Mixed Pattern is a combination of two The first dispensing date of a new

switch or more of the basic patterns, and medication is later than any of the last
patient switches from one dispensing dates of the old medications,
regimen to another regimen. and this pattern is not one-by-one
switch.

Other Pattern is a combination of two There are new medication(s) added to

mixed or more of the basic patterns and the initial regimen, and this pattern does
the patients initial regimen is not not belong to any of the other patterns.
completely changed.

47
Medication Adherence
As mentioned in the literature review, two sets of claims-based methods are commonly

used to measure medication adherence. One set of methods focuses on medication

availability, such as PDC and MPR, while the other set of methods focuses on

continuation of medication refills (i.e., persistence). In the current studies, medication

adherence was measured using all three methods: PDC, MPR and persistence.

PDC and MPR were calculated based on refill dates and days supply. PDC was

calculated by therapeutic class for each patient as the proportion of days covered by at

least one medication in that class during the observation period. The denominator of

PDC was the number of days between the first and the last claim date of a therapeutic

class plus the days supply obtained at the last claim date. The formula for calculating

PDC is as follows:

PDC =
+

When calculating PDC, if a patient refills medications before exhausting previous fills,

the dispensing date of this refill should be moved to the date when the patient runs out

of medications in that therapeutic class completely. PDC values range from 0 to 1.

MPR was calculated by dividing the total days supply obtained during the observation

period by the number of days in the observation period. Patients may have been taking

multiple medications (based on chemical entity) concurrently in one class; therefore,

the days supply of all medications in one class could not be directly added up,

48
because it would have falsely inflated the MPR value. To obtain the MPR of a

therapeutic class for each patient, the MPR for each individual medication within a

therapeutic class was calculated first, and then the mean of the medication-level MPR

was used as the class-level MPR. The medication-level MPR was computed as the

total days supply of each medication divided by the number of days between the first

and the last claim dates of that medication plus the last days supply. The assumption

here was that patients treat different brand name medications in the same chemical

class equally, and patients take all of their medications whether or not there are

overlaps in prescription dispensing days. The formula for MPR is as follows:

+
=

where n is the number of medications in a therapeutic class. The value of MPR can be

greater than 1.

PDC and MPR estimate medication availability, however such variables cannot

provide insight into refilling consistency. Therefore, persistence was also measured in

order to assess this aspect of medication adherence. A patient was classified as

persistent in a therapeutic class if the patient refilled any of the medications belonging

to that class in during a predetermined grace period; otherwise, that patient was

considered to be non-persistent. The grace period in this study was defined as 90 days

after medications obtained on the last claim date should have run out.

49
User Status

The user status variable was defined based on the number of years a patient had used a

therapeutic class before the study began. According to the refill history of a three-year

pre-observation period, users of each therapeutic class were grouped into four

categories: new user, less-than-one-year user, one-to-two-year user, and two-or-more-

year user. If a user of a therapeutic class did not have any claim records in the pre-

observation period (i.e., the patient began using that therapeutic class in 2003), the

person was defined as a new user of that class; if a user did not have any claim records

for a therapeutic class in the years 2000 and 2001 and that user had at least two refill

records for that class in 2002 (i.e., the patient started using that therapeutic class in

2002), then that user was a less-than-one-year user; similarly, if a user started using a

therapeutic class in 2001, the patient was defined as a one-to-two year user; or if a

user had at least two refill records in every year of the three-year pre-observation

period, the patient was considered to be a two-or-more-year user. Other study subjects

who did not fall into the above categories were not considered to be chronic users of a

therapeutic class.

Mortality Status
The mortality status and date of death information was extracted from the mortality

data files obtained from the Pennsylvania Department of Health and PACE eligibility

files. This variable was also used as one of the dependent variables in Study 2.

50
Hospitalization Days

The length of hospitalization stay was generated from the Medicare inpatient data file

by summing the total hospitalization days for each patient in the study period. If a

patient was enrolled in the Medicare program (i.e., present in the denominator file, but

did not have any record in the inpatient file), the number of hospitalization days for

that patient was zero. This variable was treated as one of the dependent variables in

Study 2.

Comorbidity Index
A comorbidity index was created to evaluate the extent to which a patient was

suffering from concurrent illnesses, and was used as an indicator of disease burden.

There are two commonly used and well-validated comorbidity indices: the Charlson

comorbidity index and the Elixhauser comorbidity index. The Charlson comorbidity

index was originally developed based on medical record abstraction (Charlson et al.,

1987) and later adapted for administrative databases that use ICD-9-CM by Deyo et al.

(1992), Romano et al. (1993) and Quan et al. (2005). It represents the sum of the

weighted scores that are assigned to 17 medical conditions. The Elixhauser

comorbidity index (Elixhauser et al., 1998) is a newer index measuring up to 30

comorbidity conditions. An Elixhauser score represents the sum of a patients

comorbidity conditions. There is a demonstrated association between these two

indices and both mortality and length of hospital stay (Tang et al., 2008).

51
Exploratory analyses were conducted to compare the predictive performance of the

two indices. The Charlson and Elixhauser indices were included in separate regression

models to predict one year mortality and length of hospitalization stay while

controlling for demographic variables. Model fit statistics and c-statistics indicated

that these two indices performed similarly. In this study, an adapted Charlson index

was used. The Medicare inpatient, outpatient and carrier files were searched for

adapted Charlson index related diagnoses.

Variable Summary
The variables that were used in this dissertation are summarized in Table 3.3.

52
 Table 3.3 Variable Summary

Variable Type Levels

Female
Sex Binary
Male
White
Race Categorical African American
Other
65-69
70-74
Age Categorical 75-79
80-84
Demographic 85 and above
Variables Income Categorical < $5,000
$5,000-$9,999
$10,000-$14,999
$15,000 and above
Single/Widowed
Married
Marital Status Categorical Divorced
Married, living separately

Therapeutic Class Categorical 15 therapeutic classes

Continuous -
Adherence (PDC/MPR 80%)
Binary
Non-adherence (PDC/MPR < 80%)
PDC/MPR < 40%
Medication
40-59%
Adherence Categorical
60-79%
80% and above
Persistence
Persistence Binary
Medication Non-persistence
Related One medication
Variables One-by-one switch
Medication Taking One-by-one add-on
Categorical
Behavior Poly therapy
Mixed switch
Other mixed
New user
Less-than-one-year user
User Status Categorical One-to-two-year user
Two-or-more-year user

Hospitalization days Continuous -

Health Mortality status Binary Dead
Related Alive
Variables Time to death Continuous -
Comorbidity index Continuous -

53
 CHAPTER 4: STUDY 1: DESCRIPTIONS OF MEDICATION USE

AND FACTORS RELATED TO MEDICATION NON-ADHERENCE

4.1 Purpose

The purpose of Study 1 was to describe the status of medication use and the

prevalence of medication adherence/non-adherence for multiple popular chronic

therapeutic classes. Additionally, predictors of medication adherence were evaluated

across multiple therapeutic classes.

4.2 Methods

4.2.1 Study Design and Study Subjects

In Study 1, medication taking behaviors and medication adherence (PDC and MPR)

were evaluated for 2003, and a 90-day grace period was used to determine persistence

status. User status (i.e., number of years on a medication) was defined by data from

the pre-observation period (2000-2002).

PACE cardholders were selected for Study 1 if: 1) they were chronic users of at least

one of the 15 therapeutic classes and the first refill date of a class was between

January 1, 2003, and April 30, 2003; and 2) they were continuously enrolled in the

PACE program between January 1, 2000, and May 31, 2004. This period encompassed

the pre-observation period, the main study period, and the longest persistence grace

54
period (120 days) so that the length of medication use and persistence statuses could

be appropriately identified. Continuous enrollment was defined as cardholders having

PACE eligibility for at least 28 days of each month in the main study period (from

January 1, 2000, to May 31, 2004). Individuals were excluded if they died during the

study period or resided in nursing homes or personal care facilities. Oral antidiabetic

drug users who were also insulin users were excluded (n = 2331), because prescription

claims data do not provide sufficient information on insulin regimens. If these users

were included, the adherence level for oral antidiabetic drug users can be

underestimated. Because patients may switch their regimen from oral antidiabetic

drugs to insulin and insulin is not counted as an oral antidiabetic drug.

4.2.2 Statistical Analysis

First, descriptive analyses of medication use and medication adherence were

conducted. Then, models were constructed to examine the relationships between

potential predictors and medication adherence. The dependent variables in Study 1

were PDC and persistence. Independent variables included demographic factors (i.e.,

age, sex, race, marital status, and income), therapeutic class, medication taking pattern,

and user status.

PDC is a continuous variable ranging from 0 to 1. However, exploratory analysis

revealed that the distribution of PDC was not normal, but J-shaped. Although the

literature suggests that a beta distribution may be appropriate for J-shaped data, there

55
some difficulties with statistical software to fit a beta distribution. Therefore, PDC

was treated as a binary variable with two categories: under 80% (non-adherence), and

80% and above (adherence). Thus, binary logistic regression was used to predict non-

adherence and non-persistence. The cut-off point was chosen to be 80%, the same as

most of the previous studies. It has been demonstrated that this cut-off point is

reasonable when defining adherence and non-adherence based on predicting

hospitalization and it keeps a good balance between sensitivity and specificity

(Hansen et al., 2009; Karve et al., 2009).

To evaluate the predictors of medication adherence in a setting with multiple

therapeutic classes, adherence levels for all therapeutic classes used by individual

patients were included in the model, creating a repeated measure structure (i.e., the

dependent variable, medication adherence, was repeatedly measured in different

therapeutic classes, the within-subject factor). By using repeated measures, the

correlation among outcomes (i.e., the adherence levels within different classes) could

be captured and the adherence level among therapeutic classes could be compared,

thus avoiding the multiple comparisons problem. Table 4.1 illustrates an example

analytical data file. All statistical analyses were performed using SAS for windows,

version 9.2.

56
 Table 4.1 Layout of Data Used in Logistic Regression for Study 1

ID Sex 1 Race 2 Age Income MS3 CI 4 Class User Pattern A5 P6

1 M W 75-79 <5,000 M 5 ARB/ACE 1-year One med 1 1

2 or more
1 M W 75-79 <5,000 M 5 Beta Blocker One med 1 1
year
2 or more
1 M W 75-79 <5,000 M 5 Statin One med 0 1
year
2 F W 80-84 15,000 W 4 ARB/ACE 1-2 year One med 1 1
2 or more
2 F W 80-84 15,000 W 4 Oral Diabetic Poly 0 0
year
One-by-
2 F W 80-84 15,000 W 4 Thyroid Agent New 1 0
one switch
2 or more
2 F W 80-84 15,000 W 4 Statin One med 1 1
year

1
M=Male; F=Female
2
W=White
3
MS=Marital Status; M=Married; W=Widow
4
CI=Comorbidity Index
5
A=Adherence
6
P=Persistence

57
4.3 Results

4.3.1 Demographic Characteristics of Study Subjects

The demographic characteristics of the 74,299 study subjects who met the eligibility

criteria for Study 1 are displayed in Table 4.2. Most of the study subjects were white

female widows. About half of the study subjects were more than 80-years-old at the

beginning of 2003.

Table 4.2 Demographic Characteristics of Study Subjects in Study 1

Number of
Variable Level Percentage (%)
Subjects
Total - 74,299

Sex Female 63,347 85.3

Male 10,952 14.7

Race White 70,270 94.6

African American 3,514 4.7
Other 515 0.7

Age 65-69 2,615 3.5

70-74 12,963 17.4
75-79 20,358 27.4
80-84 20,641 27.8
85 and above 17,722 23.9
(Mean Age =806.2, ranges from 67-105)

Marital Status Single or Widowed 59,407 80.0

Married 10,269 13.8
Divorced 3,870 5.2
Married, Living Separately 757 1.0

Income $0 5,000 1,603 2.2

$5,000 10,000 21,012 28.3
$10,000 15,000 42,291 56.9
$15,000 and above 9,393 12.6
(Mean Income =$11,535$3,090, ranges from $0-$20,628)

58
4.3.2 Description of Therapeutic Classes

Figure 4.1 shows the distribution of the number of therapeutic classes taken by the

study subjects during 2003. The number of therapeutic classes ranged from 1 to 12,

with a mean of 3.2 and a standard deviation of 1.7.

Figure 4.1 Distribution of the Number of Therapeutic Classes

Table 4.3 shows both the number of users and percentage of subjects taking each

therapeutic class. It is evident that cardiovascular medications are widely used in the

study subjects. About 91% of the study subjects used at least one cardiovascular

59
 mediation class. ARB/ACE was the most often used cardiovascular medication class,

and about 44% of the study subjects were ARB/ACE users. The second most popular

class was -blockers, followed by statins, calcium-channel blockers, and diuretics.

Alzheimers disease medications were used the least. Less than 3% of the study

subjects were Alzheimers disease medication users. For each therapeutic class, more

than half of the subjects had been taking related medications for at least two years,

except for those taking antiplatelet therapies and Alzheimers medications. About 80%

of the subjects who took calcium-channel blockers, thyroid agents, and oral

antidiabetic drugs were long-term users (over two years), and 16% of Alzheimers

treatment patients were new users.

Table 4.3 Therapeutic Class Characteristics

Therapeutic Class All User New Less- 1-to-2- 2-and-

Number Percent User than-1- years more-
(%) (%) year user user years
(%) (%) user
(%)
ARB/ACE 32,994 44.4 3.9 10.9 11.5 73.7
-blockers 27,557 37.1 4.5 11.2 11.2 73.0
Statins 26,196 35.3 3.4 10.1 10.5 76.1
Calcium-channel blockers 25,219 33.9 3.0 8.2 8.7 80.1
Diuretics 24,349 32.8 5.6 12.6 11.3 70.6
Proton pump inhibitors 20,379 27.4 5.4 12.2 11.8 70.6
Thyroid agents 15,067 20.3 2.5 7.3 8.6 81.6
Osteoporosis medications 12,107 16.3 6.2 17.5 18.8 57.5
Antidepressants 11,459 15.4 7.0 14.7 13.1 65.2
Oral antidiabetic drugs 11,209 15.1 2.6 7.6 8.1 81.7
Vasodilators 10,504 14.1 4.0 9.7 9.5 76.8
Cardiac glycosides 7,241 9.7 4.8 12.6 13.4 69.2
Antiplatelet therapies 6,624 8.9 10.5 25.6 21.3 42.6
Overactive bladder drugs 3,816 5.1 9.3 20.7 17.9 52.1
Alzheimers treatments 1,685 2.3 16.0 33.2 23.4 27.4
Total 74,299 - - - - -

60
4.3.3 Description of Medication Taking Behaviors

Table 4.4 displays the number and percentage of users for each medication taking

pattern. Among all users (here the term user is invoked instead of study subject,

because one study subject may play the role of a user in more than one therapeutic

class), 87.5% took one medication within a therapeutic class. Among users who took

two medications in one class, approximately 50% exhibited a one-by-one switch

pattern, 25% a poly-therapy pattern, and 25% a one-by-one add-on pattern. For users

of three or more medications within one class, the most prevalent pattern was switch

(~45%), including mixed switch (24%) and one-by-one switch (21%). One third of the

users using three or more medications within a class had other-mixed pattern.

Table 4.4 Frequency of Medication Taking Behaviors

Pattern All Users Two Medications in Three or More

One Class Medications in
One Class
Frequency % Frequency % Frequency %
One medication 208,901 87.5 - - - -
One-by-one switch 13,315 5.6 12,544 47.9 771 21.2
Poly-therapy 7,430 3.1 6,862 26.2 646 17.7
One-by-one add-on 7,031 3.0 6,784 25.9 169 4.6
Other mixed 1,186 0.5 - - 1,186 32.5
Mixed switch 874 0.4 - - 874 24.0
Total 238,737 100 26,190 100 3,646 100

Table 4.5 presents user medication taking behaviors for each therapeutic class. For each

therapeutic class, most study subjects used just one medication, especially those using

thyroid agents and cardiac glycosides. For users taking two or more ARB/ACE

medications, -blockers, statins, calcium-channel blockers, proton pump inhibitors,

61
 antidepressants, osteoporosis medications, overactive bladder drugs and Alzheimers

treatments, one-by-one switch was the most prevalent pattern. One-by-one add-on was

the most prevalent pattern among users taking multiple vasodilators. For oral

antidiabetic drug users, only 56% used a single medication; approximately 25% took

multiple antidiabetic drugs concurrently.

The mean number of medications used in each therapeutic class is also included in Table

4.5. The data show that oral diabetic medication users were more likely to use multiple

oral diabetic medications, and almost all thyroid agents and cardiac glycoside users used

only one medication within each class.

Table 4.5 Medication Taking Behaviors for Each Therapeutic Class

Number Pattern (%)

of Drugs One One- Poly- One- Other Mixed
within Medic by-One therapy by-One Mixed Switch
Class ation Switch Add-on
ARB/ACE 1.13 87.7 8.1 1.6 2.0 0.2 0.3
-blockers 1.06 94.1 4.6 0.4 0.8 0.03 0.05
Statins 1.04 95.7 3.7 0.1 0.4 0 0.02
Calcium-channel blockers 1.10 90.3 7.4 0.5 1.5 0.1 0.1
Diuretics 1.18 83.9 4.6 4.6 5.5 0.7 0.7
Proton pump inhibitors 1.20 82.0 13.0 1.0 3.0 0.2 0.7
Thyroid agents 1.00 99.7 0.2 0.1 0.1 0 0
Oral antidiabetic drugs 1.58 56.1 3.8 25.1 8.1 5.1 1.8
Osteoporosis medications 1.10 90.1 4.2 3.2 2.2 0.2 0.1
Antidepressants 1.24 79.9 7.8 5.5 4.5 1.2 1.0
Vasodilators 1.27 73.7 3.4 7.0 15.5 0.2 0.2
Cardiac glycosides 1.00 99.8 0.1 0.01 0.03 0 0
Antiplatelet therapies 1.05 95.0 1.8 1.6 1.5 0.06 0.02
Overactive bladder drugs 1.10 90.7 6.7 0.6 1.9 0.05 0.03
Alzheimers treatments 1.06 94.1 4.8 0.2 0.8 0 0

62
4.3.4 Description of Medication Adherence

The MPR and PDC distributions for all users are presented in Figures 4.2 and 4.3,

respectively. These two figures show a J-shaped distribution of medication adherence

scores, indicating that most of the users had reasonable adherence levels. Since a J-

shaped distribution cannot be easily transformed into a normal distribution, some

commonly used descriptive statistics like mean and standard deviation may not be

appropriate. Therefore, median, 25% quartile and 75% quartile are used to describe

the data. Among all therapeutic class users, the 25% quartile, median, and 75%

quartile of PDC were 0.85, 0.94, and 0.97, respectively; for MPR, the values were

0.87, 0.97, and 0.997 , respectively.

22.5

20.0

17.5

15.0

12.5
Percent

10.0

7.5

5.0

2.5

0
0.01 0.07 0.13 0.19 0.25 0.31 0.37 0.43 0.49 0.55 0.61 0.67 0.73 0.79 0.85 0.91 0.97 1.03 1.09 1.15 1.21 1.27 1.33 1.39 1.45 1.51 1.57 1.63 1.69 1.75 1.81 1.87 1.93 1.99 2.05 2.11 2.17 2.23 2.29 2.35 2.41 2.47 2.53 2.59

mprmean

Figure 4.2. Distribution of MPR Scores

63
 25

20

15
Percent

10

0
0.01 0.05 0.09 0.13 0.17 0.21 0.25 0.29 0.33 0.37 0.41 0.45 0.49 0.53 0.57 0.61 0.65 0.69 0.73 0.77 0.81 0.85 0.89 0.93 0.97 1.01

pdcclass

Figure 4.3 Distribution of PDC Scores

The persistence rate by grace period for all users was 68.6% for 30 days, 84.9% for 60

days, 87.2% for 90 days, and 88.3% for 120 days. When using shorter grace period,

more people who refill their medications after that grace period will be classified as

non-persistence. On the other hand, since the study subjects need to be continuously

enrolled in the PACE program until the end of the grace period, using longer grace

period will reduce the number of study subjects. Figure 4.4 demonstrated that the

proportion of study subjects who were non-persistent when using 90 days as grace

period was very close to that when using 120 days as grace period. Thus, a 90-day

grace period was chosen for this study.

64
 Figure 4.4 Non-Persistence Rate, by Grace Period

Adherent users were defined as users with adherence scores greater than 0.8. The

overall adherence rate was 80% when using PDC as the adherence score and 82%

when using MPR. The overall persistence rate was 87%. Table 4.6 presents the 25%

quartile, median, and 75% quartile for MPR and PDC scores, as well as adherent user

and persistent user percentages for each therapeutic class.

The order of therapeutic classes in Table 4.6 is based on the adherence rate according

to PDC. According to all measures, thyroid agent users had the highest adherence and

persistence rates. Users of calcium-channel blockers and ARB/ACE medications had

the second- and third-highest adherence rates. Users of diuretics, overactive bladder

drugs, and osteoporosis medications had lower adherence rates compared to users in

other therapeutic classes. Oral antidiabetic drug users had the second-highest

persistence rate; users of overactive bladder drugs and cardiac glycosides had the

lowest persistence rates. This table also shows that using the MPR method can result

65
 in higher adherence rates than the PDC method, except in the oral antidiabetic drug

and vasodilator classes.

Table 4.6 Medication Adherence Scores and Persistence Rates, by Therapeutic

Class
PDC MPR
Pe (%)
A a(%) Q1 b Mc Q3 d A a(%) Q1 b Mc Q3 d
Thyroid agents 88.5 0.892 0.948 0.970 90.3 0.922 0.984 1.003 95.0
Calcium-channel blockers 87.7 0.894 0.952 0.973 89.5 0.922 0.984 1.000 87.6
ARB/ACE 85.7 0.883 0.948 0.972 88.4 0.914 0.981 1.000 89.2
Oral antidiabetic drugs 85.0 0.884 0.955 0.980 83.3 0.868 0.963 0.996 92.4
Antiplatelet therapies 84.7 0.873 0.943 0.969 86.0 0.892 0.970 0.997 85.1
Cardiac glycosides 83.0 0.869 0.945 0.970 84.8 0.893 0.978 1.000 76.5
-blockers 82.1 0.863 0.945 0.970 84.2 0.892 0.976 1.000 90.6
Vasodilators 81.3 0.860 0.944 0.970 78.3 0.842 0.970 0.997 87.3
Statins 79.3 0.833 0.930 0.965 82.0 0.857 0.957 0.992 88.7
Alzheimers treatments 77.2 0.814 0.922 0.961 81.2 0.848 0.955 0.994 85.6
Antidepressants 76.1 0.809 0.927 0.966 80.0 0.844 0.957 0.997 83.9
Proton pump inhibitors 74.8 0.798 0.922 0.963 79.2 0.838 0.955 0.994 84.5
Osteoporosis medications 70.4 0.763 0.900 0.956 72.7 0.780 0.923 0.984 83.1
Overactive bladder drugs 68.4 0.743 0.895 0.956 72.7 0.783 0.928 0.989 75.1
Diuretics 68.1 0.735 0.905 0.964 70.5 0.755 0.929 0.992 82.1
a
A=Adherence Rate; b Q1=25% quartile; c M=Median; d Q3=75% quartile;
e
P=Persistence Rate

To compare medication adherence scores among therapeutic classes, the median, 25%

quartile, and 75% quartile PDC and MPR values for each therapeutic class are

displayed in Figures 4.5 and 4.6, respectively. The orders of therapeutic classes for

each figure are based on the median values. Although the MPR value for each class

was always greater than the PDC value, the relative trend for both values among

classes was approximately consistent. However, the relative adherence level for oral

antidiabetic medication users was much higher when measured by PDC (ranked first)

than by MPR (ranked eighth).

66
Figure 4.5 Medication Adherence Scores (PDC), by Therapeutic Class

Figure 4.6 Medication Adherence Scores (MPR), by Therapeutic Class

67
The percentage of non-adherent users based on PDC and MPR, and the percentage of

non-persistent users for each therapeutic class are presented in Figure 4.7. The number

of non-adherent users for each therapeutic class based on PDC was higher than those

based on MPR, except for the vasodilator class and the antidiabetic medication class.

The ranks of non-adherence rate (based on PDC) and non-persistence rate of each

therapeutic class are illustrated in Table 4.7. Users of diuretics, osteoporosis

medications and overactive bladder medications were more non-adherent than those in

other classes. Users of overactive bladder drugs had the highest non-persistence rate.

The non-persistence rate among cardiac glycoside users was high (rank second), while

the non-adherence rate was relatively low. The non-adherence and non-persistence

rates for users of thyroid agents, calcium-channel blockers, and ARB/ACE

medications were always lower than those of other therapeutic classes.

Table 4.7 Ranks of Non-Adherence Rates and Non-Persistence Rates of

Therapeutic Classes

Non-Adherence Rate Non-Adherence Rate Non-Persistence

(Based on PDC) (Based on MPR) Rate
Diuretics 1 1 3
Overactive bladder drugs 2 2 1
Osteoporosis medications 3 3 4
Proton pump inhibitors 4 5 6
Antidepressants 5 6 5
Alzheimers treatments 6 7 8
Statins 7 8 11
Vasodilators 8 4 9
-blockers 9 10 13
Cardiac glycosides 10 11 2
Antiplatelet therapies 11 12 7
Oral antidiabetic drugs 12 9 14
ARB/ACE 13 13 12
Calcium-channel blockers 14 14 10
Thyroid agents 15 15 15

68
 Figure 4.7 Percentages of Non-Adherent and Non-Persistent Users, by
Therapeutic Class

The medication adherence scores and persistence rates for different demographic

factors, usage patterns, and user statuses are presented in Table 4.8. The median, 25%

quartile, and 75% quartile of PDC scores, adherence rates (based on PDC) and

persistence rates are compared in Figures 4.8 to 4.14.

69
 Table 4.8 Medication Adherence Scores and Persistence Rates, by Demographic
Factors

PDC MPR
Pe (%)
A a(%) Q1 b Mc Q3 d A a(%) Q1 b Mc Q3 d
Sex Female 80.3 0.845 0.938 0.968 82.4 0.868 0968 0.997 87.4
Male 80.5 0.851 0.944 0.972 82.4 0.871 0.970 0.997 85.5

Race White 80.8 0.850 0.940 0.969 82.9 0.873 0.970 0.997 87.3
African
70.4 0.760 0.903 0.959 72.9 0.781 0.926 0.986 84.2
American
Other 75.8 0.809 0.930 0.967 78.6 0.836 0.953 0.995 85.8

Age 65-69 80.3 0.849 0.943 0.971 82.1 0.870 0.973 0.997 87.3
70-74 80.8 0.851 0.943 0.970 82.8 0.875 0.971 0.997 88.0
75-79 80.6 0.847 0.940 0.969 82.6 0.870 0.968 0.997 87.4
80-84 80.5 0.846 0.939 0.969 82.7 0.871 0.968 0.997 87.2
85 + 79.5 0.838 0.935 0.967 81.6 0.861 0.965 0.997 86.2

Marital Single or
80.4 0.846 0.939 0.969 82.5 0.870 0.968 0.997 87.3
Status Widowed
Married 80.4 0.847 0.942 0.970 82.4 0.870 0.970 0.997 86.8
Divorced 79.7 0.840 0.937 0.968 81.7 0.864 0.966 0.997 86.9
Married,
Living 78.3 0.826 0.932 0.967 80.3 0.845 0.956 0.994 85.3
Separately

Income $0 5,000 80.2 0.843 0.934 0.967 82.9 0.868 0.965 1.000 88.9
$5,000
80.2 0.846 0.939 0.969 82.4 0.868 0.968 0.997 87.1
10,000
$10,000
80.5 0.846 0.939 0.969 82.5 0.870 0.968 0.997 87.4
15,000
$15,000+ 80.1 0.844 0.940 0.970 82.1 0.867 0.968 0.997 85.8

User New user 70.6 0.765 0.916 0.967 76.4 0.813 0.955 1.003 68.8
Less-than-1-
75.5 0.804 0.927 0.965 78.8 0.835 0.957 0.997 80.2
year user
1-to-2-year
80.0 0.825 0.932 0.966 80.5 0.852 0.962 0.995 85.2
user
2-or-more-
82.1 0.860 0.943 0.970 93.7 0.880 0.971 0.997 89.8
year user

One
Pattern 80.9 0.850 0.940 0.968 82.4 0.871 0.970 0.997 87.0
medication
One-by-one
81.5 0.846 0.933 0.970 74.2 0.795 0.925 0.988 91.8
add-on
One-by-one
66.0 0.725 0.883 0.953 90.7 0.912 0.979 1.004 82.4
switch
Poly-therapy 89.3 0.922 0.972 0.992 75.8 0.807 0.936 0.989 93.5
Mixed
73.9 0.794 0.900 0.966 86.6 0.868 0.953 0.998 88.4
switch
Other mixed 90.6 0.907 0.970 0.992 80.6 0.838 0.926 0.984 94.1
a b c d
A=Adherence Rate; Q1=25% quartile; M=Median; Q3=75% quartile;
e
P=Persistence Rate

70
Figure 4.8 suggests that no clear sex differences existed for PDC scores and adherence

rates; however, females had better persistence rates than males.

Figure 4.8 Comparison of PDC, Adherence Rate and Persistence Rate, by Sex

Figure 4.9 indicates that white users had the best adherence levels and persistence

rates, and other races had better adherence levels and persistence rates than African

Americans.

Figure 4.9 Comparison of PDC, Adherence Rate and Persistence Rate, by Race
71
As shown in Figure 4.10, users 85-years-old and older had the lowest adherence level

and persistence rate among all age groups.

Figure 4.10 Comparison of PDC, Adherence Rates and Persistence Rates, by Age

Figure 4.11 shows that users who were married but living separately had lower

adherence and persistence rates than people with other marital statuses.

Figure 4.11 Comparison of PDC, Adherence Rate and Persistence Rate, by

Marital Status
72
For income, there was no clear difference in terms of adherence; however, there was a

negative relationship between income and persistence level, as shown in Figure 4.12.

Figure 4.12 Comparison of PDC, Adherence Rate and Persistence Rate, by

Income

Figure 4.13 illustrates how the length of time using a therapeutic class was positively

associated with adherence and persistence levels.

Figure 4.13 Comparison of PDC, Adherence Rate and Persistence Rate, by User
Status
73
Medication adherence scores and persistence rates for each medication use pattern are

shown in Figure 4.14. Patients with switching patterns (one-by-one switch or mixed

switch) had lower PDC levels and persistence rates, but higher MPR levels than other

patterns. PDC values were higher than MPR values in subjects using poly-therapy,

one-by-one add-on and other mixed patterns. For other patterns, MPR values were

higher than PDC values, indicating that adherence levels for different medication

taking patterns were sensitive to measurement methods. The figure also shows how

PDC results were consistent with persistence rate results.

Figure 4.14 Comparison of Medication Adherence Scores, Adherence Rates and

Persistence Rates, by Medication Use Pattern

4.3.5 Predictors of Medication Non-Adherence

Two logistic regression models were built to predict non-adherence (PDC < 80%) and

non-persistence respectively. The results presented in Table 4.9 suggest that race, user

status, medication use pattern and therapeutic class were each significant predictors of

non-adherence (PDC < 80%). The effect of income was barely significant.

74
 Table 4.9 Results of Odds Ratios from Logistic Regressions Predicting Non-
adherence and Non-Persistence

Non-Adherence Non-Persistence
Odds P- Odds P-
95% CI 95% CI
Ratio Value Ratio Value
Sex Male vs. Female 0.98 0.94-1.02 0.45 1.16 1.11-1.22 <0.0001
Race (Ref=White)
African American 1.86 1.75-1.97 <0.0001 1.30 1.22-1.39 <0.0001
Other Race 1.42 1.21-1.65 <0.0001 1.17 0.98-1.41 0.09
Age (Ref=65-69)
70-74 0.98 0.90-1.55 0.54 0.95 0.87-1.04 0.27
75-79 1.00 0.93-1.08 0.97 1.00 0.91-1.08 0.91
80-84 1.01 0.93-1.09 0.84 1.01 0.93-1.10 0.74
85 + 1.07 0.99-1.16 0.07 1.09 1.00-1.18 0.06
Marital
(Ref= Married)
Status
Single or Widowed 0.99 0.94-1.05 0.84 1.14 1.07-1.22 <0.0001
Divorced 1.04 0.96-1.13 0.30 1.20 1.10-1.30 <0.0001
Married, Living Separately 1.10 0.96-1.26 0.18 1.29 1.10-1.52 0.002
Income (Ref=$15,000+)
$0 5,000 0.93 0.83-1.03 0.15 0.66 0.58-0.75 <0.0001
$5,000 10,000 0.94 0.88-1.00 0.04 0.80 0.75-0.85 <0.0001
$10,000 15,000 0.95 0.90-1.00 0.05 0.79 0.74-0.84 <0.0001
User (Ref=2-or-more-year user)
New user 1.64 1.57-1.72 <0.0001 3.54 3.38-3.71 <0.0001
Less-than-1-year user 1.35 1.31-1.39 <0.0001 1.98 1.91-2.05 <0.0001
1-to-2-year user 1.22 1.18-1.26 <0.0001 1.44 1.38-1.49 <0.0001
Pattern (Ref=One medication)
One-by-one add-on 0.84 0.79-0.90 <0.0001 0.56 0.51-0.62 <0.0001
One-by-one switch 2.09 2.01-2.18 <0.0001 1.26 1.20-1.33 <0.0001
Poly-therapy 0.48 0.44-0.52 <0.0001 0.53 0.48-0.58 <0.0001
Mixed switch 1.31 1.12-1.54 0.0008 0.82 0.66-1.03 0.09
Other mixed 0.41 0.33-0.50 <0.0001 0.51 0.39-0.65 <0.0001
(Ref=calcium-channel
Class
blockers)
Alzheimers treatments 1.89 1.68-2.13 <0.0001 0.77 0.67-0.89 0.0004
ARB/ACE 1.19 1.14-1.25 <0.0001 0.82 0.78-0.86 <0.0001
-blockers 1.63 1.55-1.71 <0.0001 0.69 0.66-0.73 <0.0001
Cardiac glycosides 1.60 1.49-1.72 <0.0001 2.08 1.95-2.22 <0.0001
Antidepressants 2.36 2.23-2.50 <0.0001 1.26 1.16-1.34 <0.0001
Diuretics 3.67 3.50-3.54 <0.0001 1.53 1.46-1.61 <0.0001
Proton pump inhibitors 2.35 2.24-2.46 <0.0001 1.21 1.15-1.27 <0.0001
Overactive bladder drugs 3.29 3.05-3.55 <0.0001 1.96 1.81-2.13 <0.0001
Oral antidiabetic drugs 1.66 1.56-1.76 <0.0001 0.71 0.66-0.76 <0.0001
Osteoporosis medications 3.14 2.97-3.31 <0.0001 1.32 1.24-1.40 <0.0001
Antiplatelet therapies 1.30 1.21-1.40 <0.0001 0.95 0.88-1.03 0.22
Statins 2.02 1.93-2.12 <0.0001 0.90 0.85-0.95 <0.0001
Thyroid agents 1.05 0.98-1.11 0.13 0.39 0.36-0.42 <0.0001
Vasodilators 1.96 1.84-2.08 <0.0001 1.10 1.03-1.18 0.005

75
African Americans and Other Races were respectively 1.86 (95% CI = 1.75-1.97, P <

0.0001) and 1.42 (95% CI = 1.21-1.65, P < 0.0001) times more likely to be non-

adherent than Whites. Additionally, new users, less-than-one-year users and one-to-

two year users were respectively 1.64 (95% CI = 1.57 - 1.72, P < 0.0001), 1.35 (95%

CI = 1.31 - 1.39, P < 0.0001) and 1.22 (95% CI = 1.28 - 1.26, P < 0.0001) times more

likely to be non-adherent than long-term users. In terms of medication taking patterns,

elderly using switch patterns (either one-by-one switch or mixed switch) were more

associated with non-adherence than those using a one-medication pattern, and elderly

with other patterns were less likely to be non-adherent. Comparing therapeutic classes,

when calcium-channel blockers were used as the reference group, users in all other

classes except for thyroid agents were more likely to be non-adherent.

Sex, marital status, and income were significant predictors of non-persistence along

with the significant predictors identified for non-adherence. Males were 1.16 (P <

0.0001) times more likely to be non-persistent. Compared to married people, elderly

with other marital statuses (single or widowed, divorced, or married but living

separately) were more likely to be non-persistent. Compared to the highest income

group (> $15,000), elderly in other income groups were less likely to be non-persistent.

76
4.4 Discussion

This study described medication use and medication adherence in a group of elderly

people. Medication adherence levels of 15 therapeutic classes were compared using

several measurement methods, and potential predictors of medication adherence were

assessed in a multiple therapeutic classes setting.

4.4.1 Prevalence of Medication Adherence

The adherence rates (PDC 0.8) for the 15 therapeutic classes ranged from 68% to

88% and the persistence rates ranged from 75% to 95%. The study subjects presented

a reasonable adherence level. The adherence rates for users of thyroid agents, calcium-

channel blockers, and ARB/ACE medications were higher than those for other

therapeutic classes. The adherence rates for users of oral antidiabetic drugs and other

cardiovascular drugs fell into a second lower tier, followed by statins, Alzheimers

treatments, antidepressants, and proton pump inhibitors. The adherence rates were the

lowest for osteoporosis medications, overactive bladder medications, and diuretics.

These results were similar to previous findings in other studies. Briesacher et al. (2008)

reported that the order of adherence rates in an adult population was, from high to low,

hypertension therapies, hypothyroidism medications, oral antidiabetic drugs,

hypercholesterolemia medications, and osteoporosis medications. The order reported

by Yeaw et al. (2009) for new users was oral antidiabetics, ARBs, statins, and

overactive bladder medications.

77
4.4.2 Measurements of Medication Adherence

The results of this study confirmed the discrepancies between PDC-based and MPR-

based adherence scores which have been illustrated in several previous works (Martin

et al., 2009; Choudhry et al., 2009). This study also confirmed that the discrepancies

between these two measurements stemmed mainly from complex medication taking

patterns. The PDC and MPR adherence rates for the one-medication use pattern did

not differ much (only 1.5%). However, the differences were pronounced for other

patterns, most substantially one-by-one switch. The PDC adherence rate for this

pattern was 66%, contrasted with an MPR adherence rate of 90.7%. The differences

for other complex prescription patterns ranged from 7.3% to 13.5%. This trend was

similar to the results reported by Choudhry et al. (2009) for oral antidiabetic drug

users. In their study, the difference for a one-drug switcher was 23%, whereas the

differences for other patterns ranged from 8% to 14%. The adherence levels for users

who exhibited poly-therapy, one-by-one add-on or other mixed patterns were higher

when measured by PDC than those when measured by MPR. This can also explain that

the ranks of non-adherence rates of oral antidiabetic drugs and vasodilators based on

PDC were lower than the ranks of those based on MPR.

Martin et al. (2009) suggested that PDC should be considered when measuring

adherence to a medication class, because overlapping prescriptions would not result in

overestimating adherence, and the PDC method is less sensitive to complex temporal

changes in therapy. PDC provides a more conservative estimate and a more accurate

78
picture of medication adherence within a class than the MPR method, which may

overestimate the true adherence for people who switch therapies. In addition to these

considerations, our results also suggests that when comparing adherence among

different medication use patterns, persistence rate trends more closely resembled

PDC-based adherence. Although persistence and medication availability are two

dimensions of general adherence (Sikka et al., 2005), there are still some shared

components between them. It seems reasonable that the persistence and adherence

rates for the same study subjects exhibited a similar pattern. Hence, the results for

PDC-based medication adherence were preferred and reported here. However for

therapeutic classes where polypharmacy is needed, PDC may not reflect the adherence

level of each medication. Thus other measurements need to be considered for these

classes.

4.4.3 Predictors of Medication Non-Adherence

In addition to the significant effects of therapeutic class and medication taking pattern

on medication adherence, race, sex, marital status, user status and income also proved

to be influential.

The results supported our hypothesis that minorities would be more likely to have low

medication adherence rates. Our results showed that African Americans were 1.86 and

1.30 times more likely to be non-adherent and non-persistent than Whites; their non-

adherence and non-persistence rates were also higher than those of other races. The

79
low adherence level in minorities may be due to low education levels, low health

literacy levels, language barriers, or other factors.

The oldest group ( 85 years old) were more likely to be non-adherent and non-

persistent than younger elderly, although the effects were not statistically significant

(P = 0.07 and 0.06, respectively). The oldest elderly in the study subjects may have

more age-related risks of medication adherence such as poor vision, hearing problems,

decline in cognitive abilities, psychological problems, complexities of prescribed

medication regimens and physical disabilities which can impact medication taking

abilities (Chia et al., 2006; Schectman, 2002; Russel, 2006). The oldest of the elderly

may also be associated with lower education levels and lower health literacy, which

are also barriers to medication adherence.

Females and married people generally had higher persistence rates in this study.

Women are more likely to be engaged in healthy behavior than men (Umberson, 1992;

Alwin and Wray, 2005) and married people generally receive more social support

(William and Umberson, 2004), so it is likely that they may be able to be more

persistent. However, these effects were not significant for adherence. An unexpected

result was the relationship between income and non-persistence; the highest income

group had the highest non-persistence rate, which is a phenomenon that remains

unexplained in these analyses. One possible explanation might be the difference

between the PACE and PACENET programs. The subjects in this study were either

80
PACE or PACENET cardholders. The yearly income limits of enrollment eligibility

for PACE are $14,500 for single people and $17,700 for married couples; for

PACENET, the limits are $14,500-$23,500 for single people and $17,700-$31,500 for

married couples. Thus, most of the people in the highest income group ( $15,000)

were PACENET cardholders. The difference in prescription benefits offered by these

two programs might have had some effects on persistence behavior. Further study is

needed to investigate this relationship.

Medication use history (user status) was demonstrated to be a significant predictor of

medication adherence. To our knowledge, this study is among the first to

quantitatively evaluate and test the effect of medication use history on medication

adherence. Our results indicated that the longer an older adult uses a medication, the

more adherent or persistent the person is. This trend is consistent with other studies

(Blackburn et al., 2005). Relative to long-term users who had been using the

medications for at least two years at the beginning of the study, the odds ratios of non-

adherence for new users, less-than-one-year users, and one-to-two-year users were

1.64, 1.35, and 1.22, respectively; the odds ratios for non-persistence were 3.54, 1.98,

and 1.44, respectively. These results suggest that the first year of therapy is a critical

time period for developing medication adherence behavior.

In summary, the results indicate that minorities, especially African Americans, the

oldest members of the population, and new users, should be targeted with

81
interventions designed to improve medication adherence in an elderly population

similar to the study subjects.

4.4.4 Strengths and Limitations

To our knowledge, this study is among the few to investigate medication adherence

among several therapeutic classes and evaluate the effects of potential predictors of

medication adherence across them. To our knowledge this study is the first to examine

medication adherence across as many therapeutic classes as were included in this

study. To fulfill the study purpose, adherence levels for multiple therapeutic classes

were treated as multiple outcomes in one model by using a repeated measure

technique. This strategy took into account the correlation among medication adherence

levels for multiple therapeutic classes. Results obtained from this model integrated the

results from separate models for each individual class. Thus, results from this study

can be applied not only to medication adherence for a particular therapeutic class, but

also to general medication adherence. This is very useful for designing intervention

strategies that improve medication adherence in the elderly population at large. From a

statistical point of view, one model with multiple dependent variables can avoid the

high family-wise type I error which is caused by doing a separate analysis for each

dependent variable. If the type I error is high, it is possible that the significance of the

results are caused by repeated use of the data. Another advantage of this analysis

strategy is that adherence level differences may be compared and tested among

multiple therapeutic classes.

82
Administrative claims data were used in the study to measure medication adherence.

Some advantages of claims-based data are that the data are generally complete and

accurate, with no recall or interviewer biases, and are likely to reflect medication

usage in a real-world setting (Andrade et al., 2006). However the claims-based method

of measuring adherence behavior is based on the assumption that medication refill

patterns reflect medication adherence. Although this assumption has been supported

by research (Grymonpre et al., 2006), there are still some risks. It is possible that the

claims-based method can either overestimate or underestimate actual adherence for

various reasons, such as dumping medications, giving medications to others, and

obtaining medications from other sources.

Another limitation of using claims data is the lack of background information on why

patients either fail to refill their medications on time, or stop taking them altogether.

Additionally, there is no way of knowing whether such behaviors stem from patient

decisions or physician recommendations; this background knowledge has the potential

to influence the interpretation of results.

Finally, psychosocial and behavioral factors (e.g., patient perceptions or beliefs about

taking medication and self-efficacy) and interpersonal factors (e.g., doctor-patient

relationships, communications between pharmacists and patients, and family member

support) can also affect mediation adherence. Such factors were not considered in this

study.

83
4.5 Chapter Summary

In this chapter, medication use and medication adherence for 15 therapeutic classes

were described; the medication adherence levels were compared based on

demographic factors, therapeutic class, medication use pattern, and user status. The

effects of potential predictors were tested in logistic regression with repeated measure.

The adherence levels were also compared using different measurements.

This study show that the adherence rates for the 15 therapeutic classes ranged from

68% to 88% and the persistence rates ranged from 75% to 95%. The adherence rates

for users of thyroid agents, calcium-channel blockers, and ARB/ACE medications

were higher than those for other therapeutic classes. The adherence rates for users of

oral antidiabetic drugs and other cardiovascular drugs fell into a second lower tier,

followed by statins, Alzheimers treatments, antidepressants, and proton pump

inhibitors. The adherence rates were the lowest for osteoporosis medications,

overactive bladder medications, and diuretics.

This study revealed that race, user status, medication use pattern and therapeutic class

were significant predictors of medication non-adherence and non-persistence. African

American were most likely to be non-adherent and non-persistent. The longer an older

adult uses a medication, the more adherent or persistent the person is. Female sex and

married status were associated with persistence, while high income in this study was

related to non-persistence. The results in this study also indicated that adherence

84
levels of different medication taking patterns were sensitive to medication adherence

measurement methods.

85
 CHAPTER 5: STUDY 2: HEALTH OUTCOMES OF MEDICATION

NON-ADHERENCE

5.1 Purpose

The main purpose of Study 2 was to evaluate medication non-adherence and its

relationship with mortality and concurrent hospitalization in a multiple therapeutic

class setting.

5.2 Methods

5.2.1 Study Design and Study Subjects

Two health outcomes are of interest in this study: the number of hospitalization days

and mortality. A cross-sectional study and retrospective cohort study were conducted

for each of these two outcomes. The data from 2003 were used to determine patient

medication taking behaviors, medication adherence, and hospitalization days; data

from 2004-2005 (the follow-up period) were used to observe mortality status. These

study years were chosen because they satisfied a need for recent data while excluding

the influence of Medicare Part D (effective January 1, 2006) on medication use in the

study subjects.

The study subjects for Study 2 included the subjects from Study 1 who were eligible

Medicare enrollees in 2003 and not participating in Health Maintenance Organizations

86
(HMO). This is because Medicare claims for HMO enrollees may be incomplete.

Combining the PACE and Medicare data yielded 52,987 subjects. The mortality

observation period was from June 1, 2004, to December 31, 2005. Among the 52,987

study subjects, 47,599 (90%) were continuously enrolled in the PACE program until

the end of the follow-up period or until the month before they died. Data regarding

these 47,599 subjects were used to examine the relationship between medication

adherence and mortality. Among them, 5,523 (11.6%) people died during the follow-

up period. Those people who were not PACE-eligible in the follow-up period were

excluded because loss of PACE membership could have influenced medication taking

behaviors and adherence levels.

In examining the relationship between adherence and hospitalization, new users in

each therapeutic class were eliminated from the study subjects. This was done because

new users could have begun taking their new medications at any point during the year,

likely causing the relationship between adherence and hospitalization days in a

calendar year to be non-concurrent among new users. After excluding new users the

study subjects for analyses were 52,373 older adults.

5.2.2 Statistical Analysis

To examine the relationship between medication adherence and health outcomes

across multiple therapeutic classes, the statistical analyses were conducted in two

steps (Hosmer and Lemeshow, 2000). First, each therapeutic class was examined

87
independently; those therapeutic classes in which medication adherence (either PDC

or persistence) had significant effects on health outcomes were identified. Next, the

PDC and persistence variables of the identified therapeutic classes were combined into

one model in order to examine the independent effects of class-specific medication

adherence on health outcomes while controlling the adherence levels for other

therapeutic classes. The demographic variables, comorbidity index, and user statuses

were also included in the models as covariates. In the first step, a P-value of 0.25 was

used as the significance level; generally, if the P-value of a variable is greater than

0.25, it can be assumed that the variable does not have any effect on the outcome.

The exploratory analysis revealed that a large proportion of the study subjects had not

been hospitalized. For count data (such as the number of hospitalization days) which

are characterized by a high number of zero values and over-dispersion (variance >>

mean), zero-inflated negative binomial models are often considered. Zero-inflated

negative binomial models were used in this study to examine the relationship between

medication adherence and hospitalization days within each therapeutic class. A zero-

inflated negative binomial model is the combination of two components: a logit model

is used to predict the certain zero group, and a negative binomial model is used to

predict the counts for those not belonging to certain zero cases (Erdman et al, 2008).

The SAS COUNRREG procedure was used to analyze the zero-inflated negative

binomial models. The dependent variable was the number of hospitalization days. The

main independent variables were PDC level (categorical) and persistence; other

covariates included demographic variables, the comorbidity index, and user status.

88
When fitting the model to multiple therapeutic classes, logistic regression was used to

model hospitalizations within all study subjects, whereas negative binomial regression

was used to model hospitalization days within non-zero cases. This is due to the fact

that the COUNRREG procedure does not work when the number of variables is very

large. The SAS PROC GENMOD procedure was used to conduct logistic and negative

binomial regressions.

Cox regression (proportional hazards regression) was used to examine the relationship

between medication adherence and mortality. The dependent variable was the time

from the end of the study (May 31, 2004) to the date of death or the last observation

date (December 31, 2005). The independent variables were the same as those used to

predict hospitalization. The SAS PROC PHREG procedure was used to analyze the

Cox regression. All statistical analyses were performed using SAS for Windows,

version 9.2.

5.3 Results

5.3.1 Demographic Characteristics of Study Subjects

The demographic characteristics of the study subjects are presented in Table 5.1. The

demographic characteristics were similar to the study subjects in Study 1, however,

the study subjects in Study 2 were somewhat older and included more Whites.

89
 Table 5.1 Demographic Characteristics of Study Subjects in Study 2

Number of
Variable Level Percentage (%)
Study Subjects
Total - 52,987 -

Sex Female 45,347 85.6

Male 7,640 14.4

Race White 50,911 96.1

African American 1,756 3.3
Other 320 0.6

Age 65-69 1,676 3.2

70-74 8,569 16.2
75-79 14,034 26.5
80-84 13,641 28.4
85 above 17,722 25.7
(Mean Age =80.36.2, ranges from 67-105)

Marital Status Single or Widowed 43,087 81.3

Married 6,865 13.0
Divorced 2,567 4.8
Married, Living 468 0.9
Separately

Income $0 5,000 1,275 2.4

$5,000 10,000 14,674 27.7
$10,000 15,000 30,337 57.3
$15,000+ 6,701 12.6
(Mean Income =11,5423,106, ranges from 0-20,628)

5.3.2 Relationship Between Medication Non-Adherence and Hospitalization

The distribution of hospitalization days (ranging from 0 to 169) is presented in Figure

5.1. Among the 52,373 study subjects, 13,109 (25%) had been hospitalized at least

once, and 39,264 (75%) of them has not experienced any hospitalizations during 2003,

creating a large number of zeros in the data. Some descriptive statistics of

hospitalization days are presented in Table 5.2.

90
 140000

120000

100000

80000
Count

60000

40000

20000

0
1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 85 89 93 97 101 105 109 113 117 121 125 129 133 137 141 145 149 153 157 161 165 169
hosdays

Figure 5.1 Distribution of Length of Hospitalization Stay

Table 5.2 Description of Hospitalization Days

Study Subjects with
All Study Subjects
Hospitalization
Mean 3.47 12.07
Standard deviation 8.75 12.74
Q1 0 4
Median 0 8
Q3 3 15

The Relationship Between Medication Non-Adherence and Hospitalization Within

Each Therapeutic Class

The exploratory analysis revealed that the effect of PDC on hospitalization days was

different for persistent users and non-persistent users. Therefore, separate models were

built for persistent users and non-persistent users in each individual class. Among the

covariates, marital status and user status were not significant for any classes, so these

two variables were excluded from the models.

The exponential of the coefficients of each PDC level and the corresponding P-values

are presented in Tables 5.3 and 5.4 for persistent and non-persistent users, respectively.
91
 Table 5.3 Result of Zero-Inflated Negative Binomial Regression Predicting
Hospitalization Days among Persistent Users of Each Classa

PDC (ref=80-100%)
Therapeutic 0-39% 40-59% 60-79%
N
Class Model Exp Exp Exp
b P-value b P-value b P-value
(coef) (coef) (coef)
Alzheimers 887 count 0.89 0.79 1.03 0.93 1.68 0.0005
treatments zero 0.32 0.11 1.17 0.74 0.88 0.61
6,609 count 1.24 0.26 1.35 0.001 1.30 <.0001
Antidepressants
zero 1.14 0.65 0.94 0.66 0.61 <.0001
Proton pump 11,912 count 1.29 0.02 1.19 0.01 1.45 <.0001
inhibitors zero 0.75 0.09 0.93 0.47 0.66 <.0001
Overactive 1,868 count 0.71 0.28 1.24 0.15 1.30 0.004
bladder drugs zero 0.89 0.81 1.05 0.82 0.71 0.03
Oral antidiabetic 8,625 count 2.03 0.002 1.44 <.0001 1.45 <.0001
drugs zero 0.95 0.88 0.83 0.24 0.58 <.0001
Osteoporosis 6,979 count 1.45 0.003 1.25 0.005 1.42 <.0001
medications zero 0.54 0.002 0.76 0.02 0.65 <.0001
10,166 count 0.76 0.28 1.56 <.0001 1.40 <.0001
Thyroid agents
zero 0.61 0.21 0.59 0.001 0.55 <.0001
20,192 count 1.76 <.0001 1.33 <.0001 1.42 <.0001
ARB/ACE
zero 0.52 0.01 0.72 0.001 0.53 <.0001
-blockers 17,626 count 1.36 0.02 1.26 <.0001 1.49 <.0001
zero 0.44 0.0007 0.76 0.002 0.56 <.0001
Cardiac 3,959 count 1.27 0.36 1.17 0.16 1.50 <.0001
glycosides zero 0.91 0.83 0.97 0.89 0.54 <.0001
14,226 count 1.31 0.0009 1.28 <.0001 1.26 <.0001
Diuretics
zero 0.52 <.0001 0.73 <.0001 0.56 <.0001
Antiplatelet 3,724 count 2.32 0.02 1.33 0.03 1.50 <.0001
therapies zero 1.15 0.83 1.05 0.81 0.67 0.004
Calcium-channel 15,319 count 1.51 0.01 1.40 <.0001 1.52 <.0001
blockers zero 0.41 0.002 0.60 0.0001 0.62 <.0001
6,677 count 1.06 0.73 1.45 <.0001 1.48 <.0001
Vasodilators
zero 0.89 0.65 0.64 0.001 0.66 <.0001
15,709 count 1.38 0.01 1.39 <.0001 1.42 <.0001
Statins
zero 0.63 0.02 0.65 <.0001 0.71 <.0001

a
Demographic variables (age, race, sex and income) and the Charlson comorbidity
index were also included in each model, but the results are not shown in the table.
b
Exp(coef) = Exponential of Coefficient

92
 Table 5.4 Result of Zero-Inflated Negative Binomial Regression Predicting
Hospitalization Days among Non-persistent Users of Each Classa

PDC (ref=80-100%)
Therapeutic Class 0-39% 40-59% 60-79%
N Model
Exp Exp Exp
b P-value b P-value b P-value
(coef) (coef) (coef)
Alzheimers count 1.02 0.99 3.14 0.31 1.50 0.34
128
treatments zero n/a n/a n/a n/a n/a n/a
count 0.67 0.05 0.84 0.26 1.24 0.06
Antidepressants 1,032
zero 1.37 0.31 1.38 0.18 0.96 0.83
Proton pump count 1.07 0.59 1.17 0.13 0.98 0.85
1,824
inhibitors zero 1.44 0.06 1.71 0.001 1.08 0.60
Overactive bladder count 0.69 0.13 0.98 0.92 1.19 0.28
543
drugs zero 0.88 0.73 1.45 0.22 0.98 0.93
Oral antidiabetic count 0.58 0.04 1.11 0.57 1.11 0.43
661
drugs zero 3.71 0.01 2.68 0.003 1.12 0.71
Osteoporosis count 1.14 0.34 1.03 0.83 1.16 0.15
1,272
medications zero 1.12 0.64 1.50 0.04 1.10 0.58
count 0.74 0.60 0.88 0.63 1.04 0.81
Thyroid agents 502
zero 4.05 0.08 1.11 0.80 0.69 0.19
count 0.82 0.28 0.84 0.12 1.07 0.33
ARB/ACE 2,261
zero 2.77 0.001 1.75 0.004 1.18 0.25
count 1.09 0.65 0.98 0.89 0.93 0.41
-blockers 1,525
zero 1.51 0.19 1.68 0.01 0.91 0.59
count 1.19 0.50 1.40 0.01 1.31 0.01
Cardiac glycosides 1,167
zero 1.56 0.34 0.75 0.30 1.49 0.06
count 0.87 0.16 1.03 0.73 1.08 0.24
Diuretics 2,657
zero 1.75 0.0005 1.78 <.0001 0.95 0.66
Antiplatelet count 0.62 0.15 0.86 0.52 1.48 0.01
534
therapies zero 2.58 0.10 2.65 0.03 1.86 0.06
Calcium-channel count 0.97 0.90 1.08 0.53 1.02 0.77
2,010
blockers zero 1.85 0.11 1.38 0.19 1.28 0.12
count 0.96 0.78 0.80 0.10 1.09 0.42
Vasodilators 800
zero 2.40 0.0003 1.89 0.02 1.04 0.89
count 0.75 0.17 0.92 0.52 0.96 0.63
Statins 1,832
zero 2.79 0.0006 1.39 0.08 1.09 0.58

a
Demographic variables (age, race, sex and income) and Charlson comorbidity index
were also included in each model, but the results are not shown in the table.
b
Exp(coef) = Exponential of Coefficient

93
Among persistent users of each class who did not belong to the "certain zero" group,

non-adherent (PDC < 80%) users experienced more hospitalization days than adherent

users. The coefficients of the model component predicting the "certain zero" group

showed that non-adherent users were more likely to be hospitalized. These effects

were significant for the 60-79% PDC level in all 15 therapeutic classes, and most also

showed significant effects for the 0-39% and 40-59% levels. For example, ARB/ACE

users with PDC levels of 0-39%, 40-59% and 60-79% experienced, respectively, 1.76

(P < 0.0001), 1.33 (P < 0.0001) and 1.42 (P < 0.0001) times more hospitalization days

than adherent ARB/ACE users, and they were 0.52 (P = 0.01), 0.72 (P = 0.001) and

0.53 (P = 0.001) times less likely to be in the no hospitalization group than the

adherent users.

For the non-persistent users of each class, most of the potential significant effects (P <

0.25) were in the opposite direction relative to the effects identified among the

persistent users. For example, among non-persistent ARB/ACE users, the number of

hospitalization days for the 40-59% PDC group were 0.84 (P = 0.12) times the number

of hospitalization days for adherent users; ARB/ACE non-persistent users in the 0-

39%, 40-59%, and 60-79% PDC groups were, respectively, 2.77 (P = 0.001), 1.75 (P =

0.004) and 1.18 (P = 0.25) times more likely to be in the zero hospitalization group.

94
These results suggest that there is an interaction effect between PDC and persistence

on hospitalization and the number of hospitalization days. Therefore, interaction terms

for PDC and persistence were included in the model built for multiple classes.

According to the selection criteria (P < 0.25), all therapeutic classes were included in

the model for multiple classes, described in the next section.

The Relationship Between Medication Non-Adherence and Hospitalization Across

Multiple Therapeutic Classes

The results obtained for each individual therapeutic class suggested that adherence

levels were associated with the probability of hospitalization; there also seemed to be

interaction effects between PDC and persistence that impacted hospitalization.

Therefore, the PDC and persistence variables for all classes were included in one

model along with their interaction terms in order to examine their effects while

controlling the demographic variables, comorbidity index, and user status. The results

suggested that the interaction terms for Alzheimers treatments, antidepressants,

overactive bladder drugs, antiplatelet therapy medications, and thyroid agents were

not statistically significant; thus, the interaction terms for these classes were removed

from the model. The results of the reduced model are shown in Tables 5.5, 5.6, and 5.7.

95
 Table 5.5 Results of Logistic Regression Predicting Hospitalization
(Main Effects)

Odds Ratio 95% CI P-Value

Sex Female vs. Male 1.34 1.25-1.44 <.0001
Race White vs. Non-White 1.36 1.20-1.53 <.0001
Age (ref=65-69 years)
70-74 1.08 0.93-1.25 0.33
75-79 1.16 1.01-1.34 0.04
80-84 1.18 1.02-1.36 0.03
above 85 1.42 1.23-1.65 <.0001
Income (ref=15000 and above)
$10,000-14,999 1.05 0.97-1.13 0.23
$5,000-9,999 0.99 0.91-1.07 0.82
$0-5,000 1.01 0.86-1.19 0.86
Charlson Comorbidity Index 1.81 1.78-1.84 <0.0001
PDC (ref=80-100%)
Alzheimers treatments
0-39% 1.61 0.50-5.13 0.42
40-59% 0.66 0.29-1.50 0.32
60-79% 0.91 0.60-1.39 0.66
Antidepressants
0-39% 0.78 0.51-1.19 0.25
40-59% 0.91 0.72-1.17 0.47
60-79% 1.37 1.17-1.60 0.00
Overactive bladder drugs
0-39% 1.00 0.58-1.73 0.99
40-59% 0.78 0.55-1.13 0.19
60-79% 1.20 0.92-1.56 0.17
Antiplatelet therapies
0-39% 0.66 0.28-1.55 0.34
40-59% 0.70 0.48-1.03 0.07
60-79% 1.01 0.78-1.30 0.95
Thyroid agents
0-39% 0.89 0.46-1.73 0.73
40-59% 1.40 1.03-1.90 0.03
60-79% 1.44 1.21-1.72 <.0001
Non-persistence vs. Persistence
Alzheimers treatments 1.79 1.14-2.80 0.01
Antidepressants 1.11 0.93-1.31 0.25
Overactive bladder drugs 1.38 1.09-1.76 0.01
Antiplatelet therapies 2.06 1.65-2.57 <.0001
Thyroid agents 0.94 0.75-1.19 0.61

96
 Table 5.6 Results of Logistic Regression Predicting Hospitalization
(Interaction Effects: PDC)

Persistent Group Non-Persistent Group

Odds Odds
95% CI P-Value 95% CI P-Value
Ratio Ratio
PDC (ref=80-100%)
ARB/ACE
0-39% 1.57 0.98-2.52 0.06 0.35 0.19-0.63 0.0005
40-59% 1.13 0.92-1.38 0.25 0.56 0.38-0.82 0.003
60-79% 1.51 1.33-1.71 <.0001 0.80 0.60-1.07 0.13
-blockers
0-39% 2.04 1.26-3.29 0.003 0.73 0.40-1.35 0.32
40-59% 1.17 0.97-1.40 0.10 0.65 0.43-0.98 0.04
60-79% 1.49 1.31-1.68 <.0001 0.97 0.69-1.35 0.84
Cardiac glycoside
0-39% 0.87 0.37-2.03 0.74 0.79 0.32-1.93 0.60
40-59% 0.86 0.59-1.26 0.44 1.26 0.72-2.21 0.42
60-79% 1.40 1.08-1.81 0.01 0.64 0.42-0.97 0.03
Calcium-channel blockers
0-39% 2.03 1.13-3.64 0.02 0.54 0.25-1.18 0.12
40-59% 1.38 1.07-1.78 0.01 0.71 0.44-1.14 0.16
60-79% 1.31 1.12-1.52 0.0005 0.73 0.54-0.99 0.04
Diuretics
0-39% 1.69 1.27-2.23 0.0003 0.64 0.46-0.87 0.01
40-59% 1.27 1.09-1.47 0.002 0.60 0.46-0.78 0.0001
60-79% 1.59 1.42-1.78 <.0001 1.07 0.84-1.36 0.57
Statins
0-39% 1.37 0.92-2.05 0.12 0.42 0.24-0.75 0.003
40-59% 1.35 1.11-1.64 0.002 0.80 0.55-1.15 0.23
60-79% 1.19 1.05-1.36 0.01 0.97 0.72-1.31 0.84
Vasodilators
0-39% 1.01 0.60-1.72 0.97 0.59 0.38-0.93 0.02
40-59% 1.42 1.06-1.89 0.02 0.64 0.38-1.08 0.10
60-79% 1.21 0.99-1.49 0.06 0.90 0.54-1.52 0.70
Oral antidiabetic drugs
0-39% 1.03 0.49-2.17 0.95 0.33 0.13-0.82 0.02
40-59% 1.05 0.78-1.43 0.73 0.43 0.23-0.83 0.01
60-79% 1.45 1.21-1.74 <.0001 0.84 0.47-1.47 0.54
Osteoporosis medications
0-39% 1.67 1.11-2.52 0.01 0.90 0.57-1.42 0.66
40-59% 1.13 0.88-1.44 0.34 0.68 0.46-0.99 0.04
60-79% 1.42 1.21-1.66 <.0001 0.95 0.67-1.34 0.77
Proton pump inhibitors
0-39% 1.18 0.84-1.66 0.33 0.83 0.57-1.21 0.34
40-59% 0.98 0.80-1.19 0.81 0.71 0.51-0.98 0.04
60-79% 1.32 1.16-1.51 <.0001 0.98 0.73-1.31 0.87

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 Table 5.7 Results of Logistic Regression Predicting Hospitalization
(Interaction Effects: Persistence)

Odds Ratio 95% CI P-Value

Non-persistence vs. Persistence
ARB/ACE
0-39% 0.45 0.21-0.94 0.03
40-59% 1.00 0.66-1.51 1.00
60-79% 1.07 0.80-1.42 0.66
80-100% 2.00 1.77-2.26 <.0001
-blockers
0-39% 0.59 0.28-1.26 0.18
40-59% 0.92 0.61-1.39 0.69
60-79% 1.07 0.77-1.48 0.68
80-100% 1.65 1.41-1.93 <.0001
Calcium-channel blockers
0-39% 0.72 0.28-1.89 0.51
40-59% 1.38 0.82-2.35 0.23
60-79% 1.50 1.09-2.07 0.01
80-100% 2.70 2.38-3.06 <.0001
Diuretics
0-39% 0.68 0.46-1.01 0.06
40-59% 0.85 0.65-1.11 0.23
60-79% 1.21 0.97-1.52 0.09
80-100% 1.80 1.56-2.07 <.0001
Cardiac glycoside
0-39% 1.28 0.38-4.35 0.69
40-59% 2.07 1.07-3.98 0.03
60-79% 0.64 0.41-1.01 0.06
80-100% 1.41 1.18-1.68 0.00
Proton pump inhibitors
0-39% 0.98 0.55-1.75 0.95
40-59% 1.09 0.73-1.64 0.67
60-79% 1.22 0.88-1.68 0.23
80-100% 1.82 1.49-2.22 <.0001
Statins
0-39% 0.41 0.21-0.82 0.01
40-59% 0.79 0.54-1.17 0.24
60-79% 1.09 0.82-1.46 0.54
80-100% 1.35 1.15-1.58 0.0002
Vasodilators
0-39% 1.42 0.73-2.74 0.30
40-59% 1.09 0.63-1.90 0.76
60-79% 1.80 1.08-3.00 0.02
80-100% 2.42 1.92-3.04 <.0001
Oral antidiabetic drugs
0-39% 0.59 0.19-1.90 0.38
40-59% 0.77 0.39-1.52 0.45
60-79% 1.08 0.62-1.86 0.79
80-100% 1.87 1.48-2.37 <.0001
Osteoporosis medications
0-39% 0.74 0.46-1.19 0.21
40-59% 0.76 0.54-1.08 0.13
60-79% 0.78 0.59-1.02 0.07
80-100% 1.05 0.89-1.24 0.57

98
The results in Table 5.5 indicate that females were 1.34 (95% CI = 1.25 - 1.44, P <

0.0001) times more likely to experience hospitalization than males. Whites were 1.36

(95% CI = 1.20 - 1.53, P < 0.0001) times more likely to be hospitalized than non-

Whites. Age was also a significant predictor of hospitalization, since the odds of

hospitalization increased with age. Income was not a significant predictor of

hospitalization. There were also significant effects between the Charlson comorbidity

index and hospitalization. When the index increased by one unit, the odds of

hospitalization increased by 81%.

The PDC variables for Alzheimers treatment, overactive bladder drugs and

antiplatelet therapy were not significant predictors of hospitalization. Antidepressant

users in the 60-79% PDC group and thyroid agent users in the 40-79% PDC group

were more likely to be hospitalized than the corresponding adherent users. Non-

persistent users of Alzheimers treatments, overactive bladder drugs and antiplatelet

therapy medications were, respectively, 1.79 (95% CI = 1.14 - 2.80, P = 0.01), 1.38

(95% CI = 1.09 - 1.76, P = 0.01), and 2.06 (95% CI = 1.65 - 2.57, P < 0.0001) times

more likely to be hospitalized than the corresponding persistent users.

Tables 5.6 and 5.7 present the results of the therapeutic classes in which the

interaction effects between PDC and persistence were significant. The results suggest

that PDC had opposite effects on hospitalization rates for persistent and non-persistent

users. In the persistent group, lower PDC levels indicated a significant increase in the

odds of hospitalization. However, in the non-persistent group people with low PDC

99
levels (especially those at the 0-59% PDC level) were less likely to experience

hospitalization than the corresponding adherent users. For example, persistent statin

users at the 40-59% and 60-79% PDC levels were, respectively, 1.35 (95% CI = 1.11 -

1.64, P = 0.002) and 1.19 (95% CI = 1.05 - 1.36, P = 0.01) times more likely to be

hospitalized than persistent statin users in the 80-100% PDC group. Non-persistent

statin users at the 0-40% PDC level were 0.42 (95% CI = 0.24 - 0.75, P = 0.003) times

less likely to be hospitalized than non-persistent statin users in 80-100% PDC group.

The results of the effects of persistence at different PDC levels (Table 5.7) suggest

that for those at the 80-100% PDC level for ARB/ACE medications, -blockers,

calcium-channel blockers, diuretics, cardiac glycosides, proton pump inhibitors,

statins, vasodilators, and oral antidiabetic drugs, non-persistent users were more likely

to experience hospitalization than persistent users. This relationship was also

significant for users at the 60-79% PDC level for calcium-channel blockers and

vasodilators, and the 40-59% PDC level for cardiac glycosides. For the ARB/ACE

medication and statin users at the 0-39% PDC level, non-persistent users were less

likely to be hospitalized than persistent users.

100
The Relationship Between Medication Non-Adherence and Hospitalization Days

Across Multiple Therapeutic Classes

The data for the 13,109 study subjects who experienced hospitalizations in 2003 were

used to examine the relationship between adherence levels for multiple medication

classes and the lengths of hospitalizations. Similar to the modeling procedure for

hospitalization occurrences, the PDC and persistence variables for all classes and their

interaction terms were included in one negative binomial model to predict the length

of hospitalization stays while controlling for demographic variables and the

comorbidity index. The results suggested that the interaction terms for PDC and

persistence of Alzheimers treatments, cardiac glycosides, antidepressants, overactive

bladder drugs, osteoporosis medications, antiplatelet therapies, and thyroid agents

were not significant, so they were excluded from the model. The results of the

reduced negative binomial model across multiple therapeutic classes are shown in

Tables 5.8, 5.9, and 5.10.

101
Table 5.8 Results of Negative Binomial Regression Predicting Length of
Hospitalization Stay (Main Effects)

Exponential of
95% CI P-Value
Coefficient
Sex Female vs. Male 1.17 1.13-1.22 <.0001
Race White vs. Non-White 1.01 0.94-1.08 0.85
Age (ref=65-69 years)
70-74 0.94 0.86-1.03 0.17
75-79 0.94 0.86-1.03 0.16
80-84 0.94 0.86-1.02 0.15
above 85 0.93 0.85-1.01 0.08
Income (ref=15,000 and above)
$10,000-14,999 1.04 1.00-1.09 0.05
$5,000-9,999 1.06 1.01-1.11 0.01
$0-5,000 1.01 0.91-1.11 0.90
Charlson Comorbidity Index 1.16 1.15-1.17 <.0001
PDC (ref=80-100%)
Alzheimers treatments
0-39% 0.78 0.41-1.47 0.45
40-59% 1.05 0.67-1.66 0.83
60-79% 1.44 1.15-1.79 0.001
Cardiac glycosides
0-39% 1.16 0.83-1.62 0.37
40-59% 1.05 0.90-1.23 0.52
60-79% 1.19 1.08-1.33 0.0008
Antidepressants
0-39% 0.86 0.68-1.07 0.18
40-59% 1.04 0.92-1.19 0.52
60-79% 1.13 1.04-1.22 0.003
Overactive bladder drugs
0-39% 0.65 0.48-0.89 0.01
40-59% 0.90 0.73-1.10 0.30
60-79% 1.12 0.98-1.29 0.10
Osteoporosis medications
0-39% 1.17 1.00-1.37 0.05
40-59% 1.04 0.93-1.17 0.48
60-79% 1.24 1.14-1.34 <.0001
Antiplatelet therapies
0-39% 1.07 0.70-1.62 0.76
40-59% 1.02 0.84-1.24 0.86
60-79% 1.14 1.01-1.29 0.03
Thyroid agents
0-39% 0.62 0.41-0.94 0.03
40-59% 1.29 1.10-1.52 0.002
60-79% 1.08 0.99-1.18 0.07
Non-Persistence vs. Persistence
Alzheimers treatments 1.14 0.92-1.40 0.22
Cardiac glycosides 1.05 0.97-1.13 0.27
Antidepressants 1.07 0.99-1.16 0.11
Overactive bladder drugs 1.09 0.96-1.23 0.20
Osteoporosis medications 1.10 1.02-1.19 0.02
Antiplatelet therapies 1.16 1.05-1.28 0.002
Thyroid agents 0.97 0.86-1.09 0.61

102
 Table 5.9 Results of Negative Binomial Regression Predicting Length of
Hospitalization Stay (Interaction Effects: PDC)

Persistent Group Non-Persistent Group

Exp Exp
a 95% CI P-Value a 95% CI P-Value
(coef) (coef)
PDC (ref=80-100%)
ARB/ACE
0-39% 1.39 1.09-1.78 0.01 0.82 0.60-1.14 0.24
40-59% 1.11 1.00-1.24 0.06 0.81 0.67-0.98 0.03
60-79% 1.18 1.10-1.26 <.0001 0.99 0.88-1.13 0.93
-blockers
0-39% 1.19 0.95-1.48 0.13 1.03 0.74-1.42 0.88
40-59% 1.09 0.98-1.20 0.10 0.95 0.78-1.17 0.66
60-79% 1.24 1.16-1.32 <.0001 0.90 0.78-1.05 0.19
Calcium-channel blockers
0-39% 1.26 0.94-1.68 0.12 0.88 0.58-1.32 0.53
40-59% 1.19 1.03-1.36 0.02 0.98 0.78-1.22 0.84
60-79% 1.27 1.17-1.38 <.0001 0.95 0.83-1.09 0.48
Diuretics
0-39% 1.13 0.98-1.30 0.10 0.90 0.75-1.07 0.21
40-59% 1.12 1.03-1.21 0.01 0.97 0.84-1.11 0.65
60-79% 1.11 1.04-1.17 0.0007 1.06 0.94-1.18 0.33
Proton pump inhibitors
0-39% 1.10 0.91-1.32 0.32 1.13 0.91-1.39 0.27
40-59% 1.00 0.89-1.12 0.96 1.12 0.94-1.34 0.21
60-79% 1.22 1.14-1.30 <.0001 0.96 0.82-1.12 0.59
Statins
0-39% 1.12 0.90-1.39 0.31 0.69 0.49-0.97 0.03
40-59% 1.15 1.03-1.28 0.01 0.90 0.74-1.11 0.34
60-79% 1.21 1.13-1.30 <.0001 0.98 0.84-1.14 0.79
Vasodilators
0-39% 0.99 0.75-1.30 0.93 1.07 0.86-1.33 0.54
40-59% 1.20 1.04-1.38 0.01 0.77 0.60-0.98 0.03
60-79% 1.20 1.09-1.33 0.0003 0.98 0.81-1.19 0.83
Oral antidiabetic drugs
0-39% 1.62 1.07-2.46 0.02 0.57 0.35-0.93 0.02
40-59% 1.17 0.99-1.37 0.07 1.07 0.78-1.47 0.66
60-79% 1.23 1.12-1.35 <.0001 1.07 0.85-1.35 0.55

a
Exp(coef) = Exponential of Coefficient

103
 Table 5.10 Results of Negative Binomial Regression Predicting Length of
Hospitalization Stay (Interaction Effects: Persistence)

Exponential of
95% CI P-Value
Coefficient
Non-Persistence vs. Persistence
ARB/ACE
0-39% 0.78 0.52-1.16 0.22
40-59% 0.95 0.77-1.18 0.65
60-79% 1.11 0.97-1.26 0.13
80-100% 1.31 1.24-1.39 <.0001
-blockers
0-39% 1.05 0.72-1.55 0.80
40-59% 1.07 0.86-1.33 0.54
60-79% 0.89 0.77-1.03 0.11
80-100% 1.22 1.13-1.31 <.0001
Calcium-channel blockers
0-39% 0.93 0.56-1.53 0.77
40-59% 1.10 0.85-1.42 0.48
60-79% 1.00 0.86-1.16 0.98
80-100% 1.33 1.26-1.41 <.0001
Diuretics
0-39% 0.89 0.72-1.11 0.30
40-59% 0.97 0.84-1.12 0.69
60-79% 1.07 0.97-1.19 0.19
80-100% 1.12 1.05-1.21 0.001
Proton pump inhibitors
0-39% 1.06 0.81-1.38 0.67
40-59% 1.16 0.96-1.41 0.13
60-79% 0.81 0.70-0.94 0.005
80-100% 1.03 0.95-1.12 0.45
Statins
0-39% 0.76 0.51-1.13 0.17
40-59% 0.97 0.78-1.21 0.78
60-79% 1.00 0.86-1.16 0.97
80-100% 1.23 1.14-1.33 <.0001
Vasodilators
0-39% 1.41 1.00-1.98 0.05
40-59% 0.83 0.64-1.08 0.17
60-79% 1.06 0.87-1.29 0.57
80-100% 1.30 1.18-1.43 <.0001
Oral antidiabetic drugs
0-39% 0.41 0.22-0.78 0.01
40-59% 1.08 0.77-1.52 0.66
60-79% 1.02 0.81-1.29 0.84
80-100% 1.17 1.06-1.30 0.002

104
Among study subjects who were hospitalized in 2003, the number of hospitalization

days for females was 1.17 (95% CI = 1.13 - 1.22, P < 0.0001) times the number of

hospitalization days for males. For every one-point increase in the Charlson

comorbidity index, the number of hospitalization days increased 16 percent. The

hospitalization days for people with incomes ranging from $5,000 to $9,999 per year

was 6% (95% CI = 1.01 - 1.11, P = 0.01) higher than the highest income group. The

difference between the group making $10,000 to $14,999 per year and the reference

group was barely significant. Age and race were not significant predictors of the

number of hospitalization days.

The 60-79% PDC level for Alzheimers treatments, cardiac glycosides, antidepressants,

osteoporosis medications, antiplatelet therapies, and thyroid agents was significantly

associated with longer hospitalization stays relative to the corresponding adherent

users (PDC 80%). For example, the number of hospitalization days for osteoporosis

medication users at the 60-79% PDC level were 1.24 (95% CI = 1.01 - 1.29, P <

0.0001) times higher than the number of hospitalization days for adherent osteoporosis

medications users. However users at the 0-39% PDC level for overactive bladder

drugs and thyroid agents experienced fewer hospitalization days relative to adherent

users.

Non-persistent osteoporosis medication and antiplatelet therapy users experienced

more hospitalization days than the corresponding persistent users. The persistence

105
variables for Alzheimers treatments, cardiac glycosides, antidepressants, overactive

bladder drugs, and thyroid agents were not significant predictors of the number of

hospitalization days.

The results indicated significant interaction effects between PDC and persistence for

ARB/ACE medications, -blockers, statins, calcium-channel blockers, diuretics,

proton pump inhibitors, oral antidiabetic drugs, vasodilators, cardiac glycosides, and

antiplatelet therapies. For persistent users of these classes, lower PDC levels were

associated with more hospitalization days. However this association did not exist in

the non-persistent users. In non-persistent users of ARB/ACE medications, statins,

oral antidiabetic drugs and vasodilators, low PDC levels (either 0-40% or 40-59%)

were associated with fewer hospitalization days. For example, among persistent statin

users, the number of hospitalization days for users at the 40-59% and 60-79% PDC

levels were, respectively, 1.15 (95% CI = 1.03 - 1.28, P = 0.01) and 1.21 (95% CI =

1.13 - 1.30, P < 0.0001) times higher than the number of hospitalization days for users

at the 80-100% PDC level. For non-persistent statin users, the number of

hospitalization days for those at the 0-40% PDC level were 0.69 (95% CI = 0.49 - 0.97,

P = 0.03) times lower than the reference group.

For the ARB/ACE medication, -blocker, statin, calcium-channel blocker, diuretic,

proton pump inhibitor, oral antidiabetic drug, vasodilator, cardiac glycoside, and

antiplatelet therapy classes, non-persistent users stayed in the hospital longer than

106
persistent users at the 80-100% PDC level. Among oral antidiabetic drugs users at the

0-40% PDC level, persistent users had more hospitalization days than non-persistent

users.

5.3.3 Relationship Between Medication Non-Adherence and Mortality

The Relationship Between Medication Non-Adherence and Mortality Within Each

Therapeutic Class

Cox-regression models were built for each of the 15 therapeutic classes. The results of

the exploratory analysis did not show any significant interaction effects between PDC

and persistence on mortality. Therefore, only the main effects of PDC and persistence

were included in the model. Unlike the hospitalization predictions, user status had

significant effects on mortality; this variable was included in the model along with

other demographic variables and the comorbidity index as covariates.

The hazard ratios and P-values of PDC, persistence, and user status obtained from the

Cox-regressions built for each individual class are summarized and presented in Table

5.11. The results required that all therapeutic classes be included in the Cox-

regression model for multiple classes based on the 0.25 significance level.

107
 Table 5.11 Cox-Regression Model Results for Each Therapeutic Class a
b User (ref=new user)
PDC (ref=80-100%) P
Therapeutic less 2 or
N Non-P 1-2
Class 0-39% 40-59% 60-79% than 1 more
vs. P years
year years
HR 1.48 0.51 0.98 1.15 0.87 0.97 1.15
Alzheimers 895
treatments P 0.39 0.11 0.89 0.49 0.51 0.90 0.53
HR 1.10 1.12 1.07 1.41 1.13 1.15 1.22
ARB/ACE 21,042
P 0.64 0.25 0.28 <.0001 0.32 0.25 0.06
HR 0.57 1.08 1.22 1.28 0.91 1.17 1.02
-blockers 18,043
P 0.03 0.39 0.002 0.0003 0.44 0.18 0.86
Cardiac HR 1.61 1.44 1.17 0.97 0.83 0.91 0.94
4,771
glycoside P 0.05 0.00 0.11 0.74 0.27 0.56 0.65
HR 0.66 0.89 0.99 0.82 1.16 1.30 0.93
Antidepressants 7,103
P 0.12 0.37 0.93 0.05 0.31 0.08 0.58
HR 0.86 1.05 1.09 0.88 1.12 1.11 1.21
Diuretics 15,823
P 0.22 0.43 0.09 0.04 0.33 0.37 0.06
Proton pump HR 0.70 0.85 1.07 0.95 0.99 0.98 0.89
12,903
inhibitors P 0.03 0.11 0.36 0.52 0.94 0.89 0.26
Overactive HR 0.98 0.91 0.92 1.54 1.08 1.02 1.17
2,276
bladder drugs P 0.95 0.63 0.58 0.00 0.74 0.93 0.48
Oral antidiabetic HR 1.38 1.16 1.27 1.23 1.37 1.70 1.56
8,494
drugs P 0.28 0.30 0.01 0.06 0.20 0.03 0.04
Osteoporosis HR 1.39 0.95 1.10 1.04 1.52 1.40 1.39
7,888
medications P 0.05 0.71 0.32 0.69 0.03 0.08 0.06
Antiplatelet HR 1.08 0.79 0.97 1.19 1.31 1.26 1.299
4,169
therapies P 0.83 0.26 0.83 0.10 0.07 0.13 0.06
HR 0.90 0.91 1.00 1.37 1.12 0.97 1.18
Statins 16,555
P 0.60 0.45 0.98 <.0001 0.50 0.83 0.25
HR 0.80 0.99 1.22 1.67 0.86 0.87 1.02
Thyroid agents 9,820
P 0.62 0.96 0.05 <.0001 0.46 0.47 0.90
HR 0.85 0.97 0.88 1.06 1.01 1.05 0.97
Vasodilators 6,912
P 0.37 0.79 0.22 0.55 0.95 0.76 0.85
Calcium-channel HR 0.97 1.10 1.16 1.23 1.46 1.55 1.58
16,139
blockers P 0.92 0.45 0.06 0.00 0.03 0.01 0.003

a
Demographic variables (age, race, sex and income) and the Charlson comorbidity
index were also included in each model, but the results are not included in the table.
b
P=Persistence; Non-P=Non-Persistence

108
The Relationship Between Medication Non-Adherence and Mortality Across Multiple

Therapeutic Classes

The adherence and persistence rates and user statuses for all 15 therapeutic classes

were included in the model at the beginning. The results indicated that the PDC and

persistence variables for Alzheimers treatments, antiplatelet therapies, proton pump

inhibitors and vasodilators were not significant; therefore, those classes were removed

from the model. The results from the reduced Cox-regression model for multiple

classes are shown in Tables 5.12 and 5.13.

109
Table 5.12 Results of Cox-Regression Predicting Mortality (PDC and Persistence)

Varaible Hazard Ratio 95% CI P-Value

PDC (ref=80-100%)
ARB/ACE
0-39% 1.13 0.75-1.72 0.56
40-59% 1.10 0.90-1.34 0.36
60-79% 1.03 0.90-1.17 0.71
-blockers
0-39% 0.58 0.35-0.97 0.04
40-59% 1.02 0.86-1.22 0.81
60-79% 1.17 1.03-1.33 0.01
Cardiac glycosides
0-39% 1.51 0.93-2.45 0.10
40-59% 1.29 1.01-1.64 0.04
60-79% 1.05 0.87-1.27 0.62
Calcium-channel blockers
0-39% 0.99 0.57-1.72 0.98
40-59% 1.04 0.81-1.35 0.74
60-79% 1.12 0.96-1.31 0.14
Antidepressants
0-39% 0.64 0.38-1.07 0.09
40-59% 0.85 0.65-1.11 0.24
60-79% 0.96 0.80-1.16 0.69
Diuretics
0-39% 0.86 0.68-1.09 0.21
40-59% 1.02 0.89-1.16 0.82
60-79% 1.04 0.94-1.15 0.45
Statins
0-39% 0.93 0.62-1.41 0.74
40-59% 0.91 0.71-1.15 0.42
60-79% 0.98 0.84-1.15 0.81
Overactive bladder drugs
0-39% 1.08 0.61-1.92 0.78
40-59% 0.91 0.61-1.36 0.65
60-79% 0.88 0.65-1.20 0.42
Oral antidiabetic drugs
0-39% 1.53 0.86-2.73 0.15
40-59% 1.16 0.87-1.55 0.32
60-79% 1.20 1.00-1.44 0.06
Osteoporosis medications
0-39% 1.40 1.00-1.94 0.05
40-59% 0.94 0.72-1.23 0.66
60-79% 1.09 0.91-1.31 0.36
Thyroid agents
0-39% 0.80 0.33-1.95 0.63
40-59% 1.02 0.69-1.49 0.93
60-79% 1.10 0.90-1.34 0.34
Non-persistence vs. Persistence
ARB/ACE 1.39 1.24-1.56 <0.0001
-blockers 1.23 1.08-1.41 0.002
Calcium-channel blockers 1.15 1.02-1.30 0.03
Statins 1.29 1.11-1.51 0.001
Cardiac glycosides 0.89 0.77-1.04 0.13
Diuretics 0.86 0.77-0.97 0.01
Antidepressants 0.77 0.63-0.94 0.01
Overactive bladder drugs 1.49 1.16-1.90 0.002
Oral antidiabetic drugs 1.06 0.86-1.31 0.58
Osteoporosis medications 0.99 0.82-1.21 0.94
Thyroid agents 1.56 1.22-1.99 0.0004

110
 Table 5.13 Results of Cox-Regression Predicting Mortality
(Demographic Variables and User Status)
Variable Hazard Ratio 95% CI P-Value
Sex Male vs. Female 1.72 1.60-1.84 <.0001
Race White vs. Non-White 1.22 1.06-1.42 0.01
Age 1.08 1.08-1.09 <.0001
Income (ref=15000 and above)
$10,000-14,999 0.99 0.91-1.08 0.84
$5,000-9,999 1.12 1.02-1.23 0.02
$0-4,999 0.78 0.62-0.99 0.04
Charlson Comorbidity Index 1.24 1.22-1.25 <0.0001
User Status (Ref=new user)
ARB/ACE less than 1-year 1.12 0.88-1.42 0.35
1-2 year user 1.10 0.87-1.39 0.42
2 and more year 1.15 0.94-1.42 0.18

-blockers less than 1-year 0.87 0.69-1.10 0.23

1-2 year user 1.13 0.90-1.41 0.30
2 and more year 0.98 0.81-1.20 0.86
Cardiac glycosides
less than 1-year 0.86 0.62-1.19 0.36
1-2 year user 0.94 0.68-1.29 0.70
2 and more year 0.97 0.73-1.28 0.83
Calcium-channel blockers
less than 1-year 1.53 1.09-2.15 0.01
1-2 year user 1.62 1.16-2.27 0.005
2 and more year 1.64 1.21-2.22 0.001
Antidepressants
less than 1-year 1.15 0.87-1.53 0.33
1-2 year user 1.25 0.94-1.67 0.12
2 and more year 0.92 0.72-1.19 0.54
Diuretics
less than 1-year 1.18 0.95-1.48 0.14
1-2 year user 1.12 0.90-1.41 0.32
2 and more year 1.23 1.01-1.49 0.04
Overactive bladder drugs
less than 1-year 1.14 0.72-1.82 0.57
1-2 year user 1.09 0.66-1.78 0.74
2 and more year 1.23 0.80-1.89 0.34
Oral antidiabetic drugs
less than 1-year 1.41 0.87-2.29 0.16
1-2 year user 1.79 1.12-2.87 0.02
2 and more year 1.58 1.03-2.42 0.04
Osteoporosis medications
less than 1-year 1.49 1.03-2.16 0.03
1-2 year user 1.41 0.97-2.04 0.07
2 and more year 1.36 0.96-1.91 0.08
Statins
less than 1-year 1.09 0.79-1.50 0.61
1-2 year user 0.89 0.64-1.24 0.49
2 and more year 1.10 0.83-1.47 0.50
Thyroid agents
less than 1-year 0.88 0.59-1.31 0.53
1-2 year user 0.85 0.57-1.25 0.40
2 and more year 1.01 0.72-1.42 0.95

111
The hazard of death for -blocker users at the 0-39% and 60-79% PDC levels were,

respectively, 0.58 (95% CI = 0.35 - 0.97, P = 0.04) and 1.17 (95% CI = 1.03 - 1.33, P

= 0.01) times the hazard of death for those who were in 80-100% PDC group. Chances

of death for cardiac glycoside users at the 40-59% PDC level were 1.29 (95%

CI=1.01-1.64, P=0.04) times higher than for those who were in 80-100% PDC group.

The effects of being at the 60-79% PDC level for the oral antidiabetic drug class and

the 0-39% PDC level for the osteoporosis medication class were barely significant.

The PDC variables for other classes were not significant after controlling for the

effects of persistence and other covariates.

Among the classes of ARB/ACE medications, -blockers, calcium-channel blockers,

overactive bladder drugs, statins and thyroid agents, non-persistent users were more

likely to die than persistent users, with hazard ratios for these classes ranging from

1.15 to 1.56. For antidepressants and diuretics, non-persistent users were less likely to

die than persistent users. The persistence variables for cardiac glycosides, oral

antidiabetic drugs, and osteoporosis medications were not significant.

The results of the covariates (Table 5.13) indicated that males were more likely to die

than females. Whites were more likely to die than non-Whites. For each one-year

increase in age and one-unit increase in the Charlson comorbidity index, hazard of

death increased by an estimated 8 percent and 24 percent, respectively. The chances of

death for study subjects in the $5,000-9,999 and $0-4,999 income groups were

112
respectively 1.12 (95% CI = 1.02 - 1.23, P = 0.02) and 0.78 (95% CI = 0.62 - 0.99, P =

0.04) times those who were in the highest income group. The results also suggested

that long-term users of calcium-channel blockers, diuretics, oral antidiabetic drugs,

and osteoporosis medications were more likely to die than new users.

5.4 Discussion

The health outcome study was designed to evaluate the independent effect of

medication adherence in a therapeutic class on health outcomes, and to compare the

effects among therapeutic classes. Health outcomes included a concurrent outcome

(hospitalization), and a subsequent health outcome (mortality).

5.4.1 Relationship between Medication Non-Adherence and Hospitalization

The interaction effects between PDC level and persistence discovered in this study are

noteworthy. Results suggest that for medication classes with significant interaction

effects, lower PDC levels were positively associated with hospitalization and

hospitalization days for persistent users. On the other hand, for non-persistent users of

those medication classes, lower PDC levels were either unrelated to hospitalization

and hospitalization days, or associated with non-hospitalization and less

hospitalization days. The relationship identified in the persistent group is consistent

with the hypothesis; however, the relationship shown in the non-persistent group was

unexpected. Two possible explanations are given below.

113
One is that some non-persistent users stopped taking medications because of improved

health conditions, thereby decreasing hospitalization. With improved health status,

patients may have begun taken fewer medications than prescribed, eventually stopping

their regimens because they were no longer necessary. This may also explain why

significant effects were most likely to exist at the 0-39% and 40-59% PDC levels

bordering on non-persistence.

The other possible reason stems from the exclusion of considering hospitalization

from medication adherence calculations. When staying in hospitals, patients may

receive medications and stop refilling their prescriptions. If those patients resume

their previous regimens after being discharged from the hospital (persistence), the

PDC for these patients may be underestimated. A relationship between low PDC levels

and hospitalization would then be observed among persistent users. If patients

discontinue their previous therapies after being discharged from the hospital (non-

persistence), either instructed by the physicians or for other reasons, their PDC levels

would not be underestimated. This could explain the relationship between high PDC

levels and hospitalization among non-persistent users. To clarify this association and

exclude the second possibility, hospitalization days should be incorporated into

adherence calculations, and the effects tested again using the adjusted adherence

values to see whether interaction effects still exist.

114
For the persistent users of each therapeutic class with interaction effects, medication

non-adherence was associated with hospitalization. Similar results were reported in

other studies. For example, Sokol et al. (2005) demonstrated that among diabetes and

hypertension patients, concurrent hospitalization rates decreased as medication

adherence increased. Some studies show that people who were non-adherent to oral

hyperglycemic drugs had a high risk of hospitalization during the follow-up period

(Lau and Nau, 2004; Ho et al., 2006)

Further studies are needed to find the reasons why people are non-persistent or non-

adherent and to investigate biological and clinical plausibility for this interaction

effect.

5.4.2 Relationship between Medication Non-Adherence and Mortality

This study suggested a significant relationship between non-persistence and all-cause

mortality for ARB/ACE medications (HR = 1.39), -blockers (HR = 1.23), calcium-

channel blockers (HR = 1.15), statins (HR = 1.29), overactive bladder drugs (HR =

1.49) and thyroid agents (HR = 1.56). There were not many significant relationships

between low adherence and all-cause mortality. The results only indicated a

significant relationship between low PDC levels and mortality for -blockers and

cardiac glycosides, and barely significant relationships for oral antidiabetic and

osteoporosis medications. These results may suggest that the consequences of non-

persistence were more severe than non-adherence in the study subjects, and

115
interventions designed to improve persistence may be more effective in reducing

mortality.

The relationship between non-adherence and all-cause mortality has been reported for

several cardiovascular and oral antidiabetic medications. For example, it was reported

that in those patients with coronary artery disease, the hazard ratios of non-adherence

on all-cause mortality were 1.74, 1.50, and 1.85 for ACE inhibitors, -blockers, and

statins, respectively (Ho et al., 2008). Among patients with diabetes, the odds ratio of

non-adherence for all-cause mortality was 1.81 (Ho et al., 2006a). For patients with

myocardial infarction, non-adherence or discontinuation of -blockers and statins was

associated with higher mortality (Ho et al., 2006b; Rasmussen et al, 2007). To the

best of our knowledge, this study is the first to have found significant relationships

between non-persistence and all-cause mortality for overactive bladder drugs and

thyroid agents. The magnitudes of the effects for these two classes were even higher

than ARB/ACE medications, -blockers, calcium-channel blockers, and statins. This

study also suggested a negative relationship between non-persistence and mortality for

diuretics and antidepressants. Further investigations are needed to better understand

these relationships.

116
5.4.3 Strengths and Limitations

To study the health outcomes of medication adherence among the elderly, the study

subjects included patients who took medications in more than one therapeutic class,

making the study subjects more representative of the general elderly population. This

study differs from previous studies that defined study subjects as users of just one

therapeutic class. Hence, the effects of medication adherence in a particular

therapeutic class were independent of adherence levels in other classes.

When compared, significant medication adherence effects in a one-class model

became insignificant or smaller in a multiple-class model. The calcium-channel

blockers class is a perfect example. When predicting hospitalization occurrences, the

odds ratios for the 0-39%, 40-59% and 60-79% PDC groups were, respectively, 2.43

(1/0.41) with a Pvalue of 0.002, 1.67 (1/0.6) with a P-value of 0.0001, and 1.61

(1/0.62) with a P-value 0.0001 in the one-class model. In the multiple-class model,

however, these values were 2.03 with a P-value of 0.02, 1.38 with a P-value of 0.01,

and 1.31 with a P-value of 0.0005, respectively. When predicting hospitalization days,

the coefficients for the same three low PDC levels were 1.51 (P = 0.01), 1.40 (P

< .0001) and 1.52 (P < .0001), respectively in the one-class model; in contrast, these

coefficients were 1.26 (P = 0.12), 1.19 (P = 0.02) and 1.27 (P < .0001), respectively in

the multiple-class model. For mortality, the hazard ratio of non-persistence was 1.24

(P = 0.0008) in the one-class model, and 1.15 (P = 0.03) in the multiple-class model.

These results suggest that the practice of taking multiple medications concurrently

117
must be considered during analysis, or the effects of medication adherence of a

therapeutic class can be overestimated.

As in Study 1, claims data were used. Claims-based data create large sample sizes,

granting studies more statistical power to identify potential predictors, confounding

factors, and interaction effects. In addition to the limitations associated with claims

data discussed in Chapter 4, others must be noted. First, all studies introduced in this

dissertation were observational studies, so they could not provide strong causal

evidence because of a lack of randomization. The study examining the relationship

between medication adherence and concurrent hospitalization was a cross-sectional

study. The cross-sectional nature of the design made it more difficult to draw causal

relationship conclusions, because it did not provide a clear time sequence of exposure

and outcomes. I evaluated the concurrent relationship between medication adherence

and hospitalization because no good hypothesis exists about the time-lag effect

between medication non-adherence and hospitalization. In future studies, the effects of

medication adherence on hospitalization in the following year should be evaluated.

The time-lag effect may also deserve further investigation.

Second, when defining users of antidiabetic drugs, patients who used insulin were

excluded from the study subjects to avoid the influence of insulin on the calculation of

medication adherence. Insulin is a very popular medication for treating patients with

diabetes, especially for treating those who are very sick with other illness that makes

118
oral andidiabetic drugs ineffective (Rubin, 2008). In the current studies, a group of

very sick diabetes patients was probably excluded by excluding insulin users, thus

results from this study may not be generalizable to insulin users. Further studies are

needed to understand the difference between insulin users and other oral antidiabetic

drug users.

The third limitation of this study concerns the applicability of the findings to the

general population. Since most of the study subjects were White widows, the external

validity of the study may be questionable when applying the results to other

populations. The selection criteria may also limit the generalizability of the results. In

Study 2, study subjects were both PACE and Medicare members and HMO members

were excluded due to a lack of data. Although almost all of the PACE cardholders

were also Medicare members, about a third of them were excluded in Study 2 due to

HMO status.

In addition, the health outcomes studied here are all-cause hospitalization and all-

cause mortality. In order to understand biological meaning of the relationship between

non-adherence / non-persistence and health outcomes, the next step of the study will

be to examine what the reasons for hospitalizations were and what the causes of death

were. As most of the previous studies, a cut-off point 80% was used in the current

study to define adherence and non-adherence. In future studies, sensitivity analyses

should be conducted to evaluate how different cut-off points may affect the results.

119
5.5 Chapter Summary

In this chapter, relationships between adherence and hospitalization occurrences,

number of hospitalization days, and mortality were examined across multiple

therapeutic classes of prescription medications. Results presented in this chapter

suggest that the effects of medication adherence in the particular therapeutic classes

examined in this study were independent of adherence levels in other therapeutic

classes.

The results in this study also suggested an interaction effect between persistence and

PDC level. For medication classes with significant interaction effects, lower PDC

levels were positively associated with hospitalization and hospitalization days for

persistent users; for non-persistent users, lower PDC levels were either unrelated to

hospitalization and hospitalization days or associated with non-hospitalization and less

hospitalization days. This study revealed significant relationships between non-

persistence and all-cause mortality for ARB/ACE medication, -blockers, calcium-

channel blockers, statins, overactive bladder drugs and thyroid agents. The results also

indicated a significant relationships between low PDC levels and mortality for -

blockers and cardiac glycosides, and barely significant relationships for oral

antidiabetic drugs and osteoporosis medications. The effects for each therapeutic class

are summarized below.

120
Non-persistent users of Alzheimers treatments and antiplatelet medications were more

likely to be hospitalized than persistent users; users at the 60-79% PDC level

experienced more hospitalization days than adherent users. No relationship was

identified between adherence and mortality in these two classes.

For the other seven cardiovascular medication classes (ARB/ACE medications, statins,

-blockers, calcium-channel blockers, diuretics, vasodilators and cardiac glycosides),

lower PDC levels were associated with a higher probability of experiencing

hospitalization in persistent users and a lower probability of hospitalization in non-

persistent users. Except for the cardiac glycoside class, lower PDC levels were

associated with more hospitalization days in persistent users. For users of ARB/ACE

medications, statins and vasodilators, lower PDC levels were associated with fewer

hospitalization days in non-persistent users. In the ARB/ACE, -blocker, calcium-

channel blocker, and statin classes, non-persistent users were more likely to die than

persistent users. For diuretics, however, non-persistence was associated with a lower

chance of death than persistence. For hospitalization occurrences and number of

hospitalization days, the association with non-persistence was strongest for users at

the 80-100% PDC.

For the antidepressant class, users at the 60-79% PDC level were more likely to be

hospitalized and had longer hospitalization stays than adherent users; non-persistent

users were less likely to die than persistent users.

121
For the overactive bladder drug class, non-persistent users were more likely to be

hospitalized and/or die than persistent users; users in 0-39% PDC group experienced

fewer hospitalization days than adherent users.

For the thyroid agent class, users at the 40-59% PDC level were more likely to be

hospitalized and had longer hospitalization stays than adherent users; users in the 60-

79% PDC group were more likely to be hospitalized, and users in 0-39% PDC group

experienced fewer hospitalization days than adherent users. Additionally, non-

persistent users were more likely to die than persistent users.

For the oral antidiabetic medication class, lower PDC levels were associated with a

higher probability of hospitalization and more hospitalization days for persistent users,

but a lower probability of hospitalization and fewer hospitalization days for non-

persistent users. Users at the 60-79% PDC level had a higher probability of death than

users at the 80-100% PDC level. Non-persistence was associated with a higher

probability of hospitalization and more hospitalization days for users at the 80-100%

PDC level; however, this relationship was the opposite for the 0-39% PDC level.

For osteoporosis medications, some lower PDC levels were associated with a higher

probability of hospitalization in persistent users, but a lower probability of

hospitalization in non-persistent users. Lower PDC levels and non-persistence were

also associated with more hospitalization days.

122
Compared to adherent users, persistent users of proton pump inhibitors at the 60-79%

PDC level were associated with a higher probability of hospitalization and

experienced more hospitalization days. Non-persistence in this class was associated

with a higher probability of hospitalization and more hospitalization days for users at

the 80-100% PDC level. Neither PDC nor persistence was associated with mortality

for proton pump inhibitors.

123
 APPENDIX

MEDICATIONS STUDIED IN EACH THERAPEUTIC CLASS

The generic names of medications studied in each therapeutic class are listed below.

The order of medications is based on the claims volume in the study period.

-blockers
Atenolol
Metoprolol Tartrate
Metoprolol Succinate
Propranolol Hydrochloride
Carvedilol
Bisoprolol Fumarate/Hydrochlorothiazide
Sotalol Hydrochloride
Nadolol
Atenolol/Chlorthalidone
Bisoprolol Fumarate
Acebutolol Hydrochloride
Pindolol
Hydrochlorothiazide/Metoprolol Tartrate
Timolol Maleate
Hydrochlorothiazide/Propranolol Hydrochloride
Betaxolol Hydrochloride
Bendroflumethiazide/Nadolol
Hydrochlorothiazide/Timolol Maleate
Penbutolol Sulfate

Statins
Atorvastatin Calcium
Simvastatin
Pravastatin Sodium
Lovastatin
Fluvastatin Sodium
Rosuvastatin Calcium
Lovastatin/Niacin
Ezetimibe/Simvastatin
Aspirin/Pravastatin Sodium

124
ARB/ACE
Lisinopril
Enalapril Maleate
Losartan Potassium
Valsartan
Quinapril Hydrochloride
Ramipril
Hydrochlorothiazide/Losartan Potassium
Hydrochlorothiazide/Valsartan
Hydrochlorothiazide/Lisinopril
Irbesartan
Benazepril Hydrochloride
Fosinopril Sodium
Captopril
Candesartan Cilexetil
Hydrochlorothiazide/Irbesartan
Olmesartan Medoxomil
Enalapril Maleate/Hydrochlorothiazide
Telmisartan
Benazepril Hydrochloride/Hydrochlorothiazide
Moexipril Hydrochloride
Candesartan Cilexetil/Hydrochlorothiazide
Trandolapril
Hydrochlorothiazide/Quinapril Hydrochloride
Perindopril Erbumine
Hydrochlorothiazide/Telmisartan
Hydrochlorothiazide/Olmesartan Medoxomil
Captopril/Hydrochlorothiazide
Trandolapril/Verapamil Hydrochloride
Fosinopril Sodium/Hydrochlorothiazide
Eprosartan Mesylate
Hydrochlorothiazide/Moexipril Hydrochloride
Enalapril Maleate/Felodipine
Eprosartan Mesylate/Hydrochlorothiazide
Eplerenone

Vasodilators
Isosorbide Mononitrate
Nitroglycerin
Isosorbide Dinitrate
Papaverine Hydrochloride
Isoxsuprine Hydrochloride
Bosentan

125
Calcium-channel blockers
Amlodipine Besylate
Diltiazem Hydrochloride
Verapamil Hydrochloride
Nifedipine
Amlodipine Besylate/Benazepril Hydrochloride
Felodipine
Isradipine
Nisoldipine
niCARdipine hydrochloride
Bepridil Hydrochloride
Nimodipine

Cardiac glycosides
Digoxin

Diuretics
Furosemide
Hydrochlorothiazide/Triamterene
Hydrochlorothiazide
Torsemide
Bumetanide
Spironolactone
Indapamide
Metolazone
Amiloride Hydrochloride/Hydrochlorothiazide
Hydrochlorothiazide/Spironolactone
Chlorthalidone
Acetazolamide
Methazolamide
Methyclothiazide
Chlorothiazide
Amiloride Hydrochloride
Bendroflumethiazide
Triamterene
Ethacrynic Acid
Trichlormethiazide

Antiplatelet therapies
Clopidogrel Hydrogen Sulfate
Cilostazol
Aspirin/Dipyridamole
Dipyridamole
Ticlopidine Hydrochloride
Anagrelide Hydrochloride
126
Oral antidiabetic drugs
Metformin Hydrochloride
Glipizide
Glyburide
Pioglitazone Hydrochloride
Rosiglitazone Maleate
Glimepiride
Glyburide/Metformin Hydrochloride
Repaglinide
glyBURIDE, micronized
Nateglinide
chlorproPAMIDE
Acarbose
Metformin Hydrochloride/Rosiglitazone Maleate
Miglitol
TOLAZamide
Glipizide/Metformin Hydrochloride
TOLBUTamide
acetoHEXAMIDE

Thyroid agents
Levothyroxine Sodium
Thyroid
Liothyronine Sodium
Levothyroxine Sodium/Liothyronine Sodium

Proton pump inhibitors

Omeprazole
Lansoprazole
Esomeprazole Magnesium
Pantoprazole Sodium
Ranitidine Hydrochloride
Famotidine
Rabeprazole Sodium
Nizatidine
Cimetidine
Cimetidine Hydrochloride
Omeprazole/Sodium Bicarbonate

Osteoporosis medications
Alendronate Sodium
Risedronate Sodium
Raloxifene Hydrochloride
Calcitonin (Salmon)
Etidronate Disodium
127
Antidepressants
Sertraline Hydrochloride
Paroxetine Hydrochloride
Citalopram Hydrobromide
Amitriptyline Hydrochloride
Fluoxetine Hydrochloride
Venlafaxine Hydrochloride
Trazodone Hydrochloride
Mirtazapine
Escitalopram Oxalate
Nortriptyline Hydrochloride
Doxepin Hydrochloride
buPROPion hydrochloride
Amitriptyline Hydrochloride/Perphenazine
Imipramine Hydrochloride
Nefazodone Hydrochloride
Desipramine Hydrochloride
Fluvoxamine Maleate
Amitriptyline Hydrochloride/Chlordiazepoxide
clomiPRAMINE hydrochloride
Maprotiline Hydrochloride
Amoxapine
Duloxetine Hydrochloride
Trimipramine Maleate
Tranylcypromine Sulfate
Imipramine Pamoate
Phenelzine Sulfate
Protriptyline Hydrochloride
Paroxetine Mesylate

Overactive bladder drugs

Tolterodine Tartrate
Oxybutynin Chloride
Oxybutynin
Flavoxate Hydrochloride
Trospium Chloride

Alzheimers treatments
Donepezil Hydrochloride
Rivastigmine Tartrate
Galantamine Hydrobromide
Tacrine Hydrochloride

128
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 VITA

Jian Ding

EDUCATION

2010 Ph.D Biobehavioral Health, The Pennsylvania State University,

University Park, PA
2006 M.S. Environmental Sciences, Peking University, Beijing, China
2003 B.Med. Preventive Medicine, Peking University, Beijing, China

PUBLICATIONS & PRESENTATIONS

Ding, J., Ahern, F.M., Heller, D.A., Hancock-Gold, C., Read, A.L. Intentional and
Unintentional Medication Under-Utilization and Mortality among the Elderly. Ready to
submit.

Ding, J., Ahern, F.M., Heller, D.A. A Longitudinal Study of Factors Related to
Medication Adherence to Multiple Medication Classes among the Elderly. Poster
presentation at Gerontological Society of Americas 62th Annual Scientific Meeting.
Atlanta, GA, U.S., Nov. 18-22, 2009.

Ding, J., Ahern, F.M., Heller, D.A., Gold, C.H, Read, A.L. (2008). Self-Reported
Medication Under-Utilization and Mortality among Elderly (Abstract). Gerontologist, 48,
756-757.

Ding, J., Zhang, J, Feng, J. (2008). Assessment of human exposure to pentachlorophenol

in Jintan, Jiangsu. Acta Scientiae Circumstantiae (China), 28 (7):1400-1405.

Ding, J., Zhang, J. (2006). Comparison of Toxicity between Coarse and Fine Particles.
Journal of Environmental Health (China), 23(5):466-467.

Ding, J., Peng, R., Yue W, Pan X. (2004). The Current Status and Influence Factors of
Indoor Air Pollution in Urban Area in Beijing. Journal of Environmental Health (China),
21(6): 361-363.

AWARDS & HONORS

2009-10, 2008-09, 2007-08 Hintz Graduate Education Enhancement Fellowship Award

Penn State University
2008 Emerging Scholars and Professional Organization Poster
Award at Gerontological Society of Americas 61th Annual
Scientific Meeting
2006-2007 Graduate Fellowship, Penn State University