ORIGINAL INVESTIGATION
`
`Predictors of Adherence With Antihypertensive
`and Lipid-Lowering Therapy
`
`Richard H. Chapman, PhD; Joshua S. Benner, PharmD, ScD; Allison A. Petrilla, BA; Jonothan C. Tierce, CPhil;
`S. Robert Collins, BS; David S. Battleman, MD; J. Sanford Schwartz, MD
`
`Background: Patients with comorbid hypertension and
`dyslipidemia are at high risk for cardiovascular disease,
`which can be considerably mitigated by treatment. Ad-
`herence with prescribed drug therapy is, therefore, es-
`pecially important in these patients. This study was un-
`dertaken to describe the patterns and predictors of
`adherence with concomitant antihypertensive (AH) and
`lipid-lowering (LL) therapy.
`
`Methods: This retrospective cohort study examined 8406
`enrollees in a US managed care plan who initiated treat-
`ment with AH and LL therapy within a 90-day period.
`Adherence was measured as the proportion of days cov-
`ered in each 3-month interval following initiation of con-
`comitant therapy (mean follow-up, 12.9 months). Pa-
`tients were considered adherent if they had filled
`prescriptions sufficient to cover at least 80% of days with
`both classes of medications. A multivariate regression
`model evaluated potential predictors of adherence.
`
`Results: The percentage of patients adherent with both
`AH and LL therapy declined sharply following treat-
`ment initiation, with 44.7%, 35.9%, and 35.8% of pa-
`tients adherent at 3, 6, and 12 months, respectively. Af-
`ter adjustment for age, sex, and other potential predictors,
`patients were more likely to be adherent if they initiated
`AH and LL therapy together, had a history of coronary
`heart disease or congestive heart failure, or took fewer
`other medications.
`
`Conclusions: Adherence with concomitant AH and LL
`therapy is poor, with only 1 in 3 patients adherent with
`both medications at 6 months. Physicians may be able
`to significantly improve adherence by initiating AH and
`LL therapy concomitantly and by reducing pill burden.
`
`Arch Intern Med. 2005;165:1147-1152
`
`Author Affiliations:
`ValueMedics Research, LLC,
`Arlington, Va (Drs Chapman
`and Benner, Ms Petrilla, and
`Mr Tierce); Waratah
`Corporation, Durham, NC
`(Mr Collins); Department of
`Outcomes Research, Pfizer Inc,
`New York, NY (Dr Battleman);
`Leonard Davis Institute of
`Health Economics
`(Drs Battleman and Schwartz)
`and Division of General
`Internal Medicine, Department
`of Medicine, School of Medicine
`and Health Care Systems
`Department, Wharton School
`(Dr Schwartz), University of
`Pennsylvania, Philadelphia.
`Financial Disclosure:
`ValueMedics Research, LLC, has
`received payments for research
`and consulting from Pfizer Inc;
`and Dr Schwartz has received
`research support from and does
`consulting for Pfizer Inc.
`
`C ARDIOVASCULAR DISEASE
`
`(CVD) accounts for in ex-
`cess of 930 000 deaths
`and $350 billion in di-
`rect medical costs and lost
`productivity in the United States each
`year.1 Numerous clinical trials and meta-
`analyses have concluded that antihyper-
`tensive (AH) and lipid-lowering (LL)
`medications substantially reduce the risk
`of coronary heart disease (CHD), stroke,
`and death in patients with CVD risk fac-
`tors,2-6 with long-term therapy yielding the
`greatest benefit.2,3,7,8
`In actual practice, however, long-term
`adherence and persistence with pre-
`scribed drug therapy are poor. Of all writ-
`ten prescriptions, 14% are never filled and
`another 13% are filled but never taken.9
`Among patients who actually initiate
`therapy with 3-hydroxy-3-methylglu-
`taryl coenzyme A reductase inhibitors
`(statins), observational studies10-12 have re-
`ported 1-year discontinuation rates of 15%
`to 60%, depending on the patient popu-
`
`lation, practice setting, and year of study.
`Among low-income elderly patients, only
`26% were still taking statins regularly 5
`years after initiating therapy.13 Similar
`trends have been observed with AH medi-
`cations. During the first year of AH treat-
`ment, the average elderly patient had filled
`AH prescriptions less than 50% of the
`time14 and only 1 patient in 5 exhibited
`compliance sufficient to obtain the thera-
`peutic benefits observed in clinical trials.14
`Many patients have both hyperten-
`sion and dyslipidemia.15 The presence of
`both of these cardiovascular risk factors
`places patients at substantially greater risk
`of CHD events than either condition
`alone.16 In these patients, adherence with
`concomitant AH and LL therapy is espe-
`cially important. However, adherence with
`concomitant therapy is not well under-
`stood, because previous studies have ex-
`amined persistence with single-drug
`classes.
`The objectives of this study were to (1)
`study the pattern of adherence with con-
`
`(REPRINTED) ARCH INTERN MED/ VOL 165, MAY 23, 2005
`1147
`
`WWW.ARCHINTERNMED.COM
`
`©2005 American Medical Association. All rights reserved.
`
`Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/intemed/12030/ by a Cambridge Hospital User on 04/04/2017
`
`Par Pharm., Inc.
`Exhibit 1050
`Page 001
`
`

`

`comitant AH and LL therapy in a US managed care popu-
`lation and (2) identify patient and regimen characteris-
`tics that predicted optimal adherence with concomitant
`therapy.
`
`METHODS
`
`PATIENTS
`
`This retrospective cohort study examined enrollees in a US man-
`aged care organization from January 1, 1996, until April 30,
`2001. Data were retrieved from a computerized database (the
`Protocare Sciences Managed Care Database) of filled prescrip-
`tion records and paid claims for medical services and proce-
`dures. All patient identifiers were removed before analysis to
`maintain patient confidentiality and to adhere to Health Infor-
`mation Portability and Accountability Act of 1996 standards
`and requirements.
`All enrollees who initiated AH or LL prescription drug
`therapy between January 1, 1997, and January 30, 2001, and
`were continuously eligible for pharmacy benefits throughout
`enrollment were identified. The analysis was restricted to new
`users by requiring that patients had no filled prescriptions for
`the relevant drug class during the prior 12 months. New users
`of AH medications were also required to be diagnosed as hav-
`ing hypertension before initiation of therapy, because many AH
`medications are used for other indications.
`To identify new starters of concomitant therapy, only those
`patients who initiated treatment with both AH and LL therapy
`within a 90-day window were analyzed. A 90-day window was
`selected to minimize the possibility that patients would have
`become nonadherent with the AH treatment before initiating
`LL therapy, and vice versa. Patients were retained in the analy-
`sis from the first date of concomitant therapy (the index date)
`until death, disenrollment from the health plan, or April 30,
`2001, whichever occurred first.
`
`OUTCOME MEASURES
`
`Adherence with AH alone, LL alone, and both AH and LL was
`measured in 91-day intervals from the index date. Adherence
`was defined as the proportion of days covered by a given drug
`class in each time interval, based on number of days supplied
`and quantity of medication dispensed for each filled prescrip-
`tion.12-14 An imputed value for days supplied was used if miss-
`ing or if the quantity dispensed divided by the days supplied
`yielded an implausible daily dosing frequency (0.5-2 for stat-
`ins, 0.5-6 for other LL drugs, or 0.5-4 for AH medications). The
`imputed value was based on the modal daily dosing frequency
`for each drug. This imputation algorithm affected less than 1%
`of the patient intervals in our files. A day was assumed to be
`covered if any AH or LL drug was available. Thus, estimates of
`adherence represented an upper bound on actual adherence with
`prescribed therapy. Patients were classified as adherent if they
`had an indication-specific proportion of days covered of 80%
`or more in a given 91-day interval, consistent with other stud-
`ies12-14 of drug adherence. Patients were considered adherent
`with concomitant therapy if at least 80% of days were covered
`by both AH and LL drugs.
`
`POTENTIAL PREDICTORS OF ADHERENCE WITH
`CONCOMITANT THERAPY
`
`To identify potential predictors of adherence with concomi-
`tant AH and LL therapy, we examined a set of demographic (eg,
`age and sex) and clinical (eg, outpatient diagnoses, medical pro-
`
`cedures, and prescriptions filled during the 365 days before the
`index date) characteristics that have been observed previously
`to affect adherence with prescribed medication use for chronic
`conditions.11-14,17 Patients who had evidence of pretreatment CHD
`were categorized into 3 groups: (1) angina or coronary angi-
`ography; (2) coronary artery bypass graft, percutaneous trans-
`luminal coronary angioplasty, or history of CHD; and (3) acute
`or prior myocardial infarction.13 Patients who met the criteria
`for more than one group were assigned to the highest category
`whose criteria they met. Other comorbid conditions assessed
`included history of stroke, congestive heart failure, diabetes
`mellitus, depression, and dementia.
`Health services use was also assessed based on the year be-
`fore initiating concomitant therapy, and included frequency of
`hospitalizations, frequency of outpatient physician visits, and
`number of medications prescribed. After examining the distri-
`butions of these measures, it was determined that hospitaliza-
`tion would be analyzed as a binary covariate, while the num-
`ber of physician visits would be analyzed in quartiles.
`
`STATISTICAL ANALYSIS
`
`The mean, median, and interquartile ranges for proportion of
`days covered were calculated for each drug indication (AH or
`LL) and for concomitant therapy (AH and LL). The propor-
`tion of patients classified as adherent in each 91-day interval
`was determined for concomitant therapy and for AH and LL
`drugs separately. Significant predictors of adherence with con-
`comitant therapy were identified using generalized linear mod-
`els for repeated measures18 to estimate the probability that a
`subject had at least 80% of days covered by both AH and LL
`therapy in each interval. The decline in persistence over time
`(in months) was assumed to be linear on the loge scale.
`Potential predictors of adherence were considered statisti-
`cally significant at P⬍.05. The final multivariate model was ad-
`justed for time since the index date and for all the characteris-
`tics previously listed. All summary statistics were performed using
`a commercially available software program (SPSS 11.5; SPSS Inc,
`Chicago, Ill), and the multivariate model was fitted using SAS
`statistical software, version 8.02 (SAS Institute Inc, Cary, NC).
`
`RESULTS
`
`POPULATION CHARACTERISTICS
`
`A total of 8406 concomitant AH and LL therapy users
`met study inclusion criteria. Patients were followed up
`for an average of 12.9 months (range, 3-36 months). Of
`the patients, 33.6% initiated concomitant therapy on the
`same date, while 36.7%, 16.9%, and 12.7% initiated AH
`and LL therapy within 1 to 30, 31 to 60, and 61 to 90
`days, respectively.
`Approximately half of patients were younger than 65
`on the date that they initiated concomitant therapy, and
`half were women (Table 1). In the year before their in-
`dex date, 2.5% of patients had evidence of angina or coro-
`nary angiography, 18.2% underwent prior percutane-
`ous transluminal coronary angioplasty, prior coronary
`artery bypass grafting, or treatment for chronic CHD, and
`11.0% experienced or had a history of an acute myocar-
`dial infarction. Most patients (68.3%) had none of these
`CHD-related diagnoses or procedures. Diabetes melli-
`tus was the most prevalent comorbid condition, fol-
`lowed by stroke (Table 1).
`
`(REPRINTED) ARCH INTERN MED/ VOL 165, MAY 23, 2005
`1148
`
`WWW.ARCHINTERNMED.COM
`
`©2005 American Medical Association. All rights reserved.
`
`Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/intemed/12030/ by a Cambridge Hospital User on 04/04/2017
`
`Par Pharm., Inc.
`Exhibit 1050
`Page 002
`
`

`

`PATTERNS OF USE OVER TIME
`
`The percentage of patients adherent with both AH and
`LL therapy (Figure) declined sharply following treat-
`ment initiation, with 44.7%, 35.9%, and 35.8% of the
`population adherent at 3, 6, and 12 months, respec-
`tively, after which adherence generally stabilized. In each
`time interval examined, an additional 25.3% to 29.6% of
`patients were adherent with either AH or LL therapy, but
`not both. Relatively few patients were adherent with LL
`therapy and nonadherent with AH therapy (Figure). The
`proportion of patients who were nonadherent with both
`AH and LL medications increased from 27.4% at 3 months
`to 35.0% at 6 months, and reached its maximum of 39.0%
`after 27 months.
`
`PREDICTORS OF ADHERENCE WITH
`CONCOMITANT AH AND LL MEDICATIONS
`
`After adjusting for age, sex, and other measured vari-
`ables, the strongest predictor of adherence with con-
`comitant therapy was the number of other prescription
`medications taken in the year before initiating concomi-
`tant therapy (Table 2). As the number of other pre-
`scribed medications decreased, the likelihood of adher-
`ence with concomitant AH and LL therapy increased. For
`example, patients taking no other medications were ap-
`proximately twice as likely to be adherent with concomi-
`tant therapy as those taking 6 or more other medica-
`tions.
`The second strongest predictor of adherence with con-
`comitant AH and LL therapy was age. Adherence was
`greatest among patients aged 55 to 64 years, followed by
`those aged 65 to 74 and 45 to 54 years. Sex also was a
`significant predictor of adherence, with women less likely
`to be adherent than men.
`Time between initiation of AH and LL therapy was the
`third strongest predictor of adherence. Patients who
`started these regimens on the same day or within 1 month
`of each other were 34% (95% confidence interval, 18%-
`52%) more likely to be adherent with both medications
`during the 3-year study period, compared with patients
`who initiated therapy 2 to 3 months apart. Time since
`initiation of concomitant therapy also was a strong pre-
`dictor of nonadherence. The adjusted odds of being ad-
`herent with concomitant therapy declined by 14% for ev-
`ery unit increase in months (on a natural log scale)
`following treatment initiation. For example, 14.3% fewer
`patients were adherent at 2.75 months than at 1 month
`(loge[2.75]=1).
`Patients with a higher CVD risk at baseline were gen-
`erally more adherent than those without CVD risk fac-
`tors (Table 2). For example, patients with a history of acute
`or prior myocardial infarction in the year preceding treat-
`ment initiation had 28% greater odds of adherence than
`those without any evidence of CHD. However, a history
`of diabetes mellitus, a diagnosis of angina, or a history of
`coronary angiography without revascularization or myo-
`cardial infarction was not associated with significantly im-
`proved adherence. Patients who had been hospitalized at
`least once for any cause in the pretreatment year were
`slightly less likely to be adherent over time.
`
`Table 1. Characteristics of 8406 Patients Who Initiated Both
`Lipid-Lowering and Antihypertensive Drug Therapy Within
`90 Days of Each Other
`
`Characteristic
`Demographics
`Age, y
`18-24
`25-34
`35-44
`45-54
`55-64
`65-74
`75-84
`ⱖ85
`Female sex
`Clinical history for the year before the index date
`Coronary artery disease
`Level 1 (angina or coronary angiography)
`Level 2 (CHD, CABG, or PTCA)
`Level 3 (acute MI)
`Stroke
`Congestive heart failure
`Depression
`Dementia
`Diabetes mellitus
`Charlson comorbidity index†
`Health services in the year before the index date
`No. of prescription medications†
`No. of outpatient physician visits†
`Hospitalized
`
`Value*
`
`0.7
`0.9
`6.5
`19.9
`23.8
`30.5
`15.9
`1.8
`46.9
`
`2.5
`18.2
`11.0
`9.5
`7.5
`5.0
`1.2
`20.8
`0.90 (1.26)
`
`3.96 (3.91)
`3.89 (4.17)
`24.8
`
`Abbreviations: CABG, coronary artery bypass graft; CHD, coronary heart
`disease; MI, myocardial infarction; PTCA, percutaneous transluminal
`coronary angioplasty.
`*Data are given as percentage of patients unless otherwise indicated.
`†Data are given as mean (SD).
`
`COMMENT
`
`This study, one of the first to empirically estimate pat-
`terns and predictors of joint long-term adherence with
`AH and LL medications, demonstrated that less than half
`of patients (44.7%) were adherent with both AH and LL
`therapies 3 months after medication initiation, a figure
`that decreased to 35.8% at 12 months. However, at each
`time point, an additional 25.3% to 29.6% of patients were
`adherent with either AH or LL therapy. Adherence with
`AH therapies was, on average, approximately 10% to 15%
`greater than with LL medications over time.
`Age was a strong predictor of adherence with con-
`comitant AH and LL therapy. Women were less adher-
`ent than men. After adjusting for age, sex, and other mea-
`sured variables, the initiation of AH and LL therapy
`together, a history of CHD or congestive heart failure,
`and taking few other medications also were demon-
`strated to predict adherence with concomitant AH and
`LL therapy.
`Of the patients in this concomitant therapy cohort,
`7574 (90.1%) were between the ages of 45 and 84 years.
`All descriptive analyses and the multivariate model were,
`therefore, repeated within this subset of patients. The re-
`sults of the descriptive analyses and the patterns of ad-
`herence mirrored those found in the entire cohort. These
`
`(REPRINTED) ARCH INTERN MED/ VOL 165, MAY 23, 2005
`1149
`
`WWW.ARCHINTERNMED.COM
`
`©2005 American Medical Association. All rights reserved.
`
`Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/intemed/12030/ by a Cambridge Hospital User on 04/04/2017
`
`Par Pharm., Inc.
`Exhibit 1050
`Page 003
`
`

`

`3
`
`6
`
`9
`
`12
`
`15
`18
`21
`24
`Time Since the Index Date, mo
`
`27
`
`30
`
`33
`
`36
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`% of Patients
`
`Nonadherent
`Adherent to LL Therapy and Nonadherent to AH Therapy
`Adherent to AH Therapy and Nonadherent to LL Therapy
`Adherent to LL and AH Therapy
`
`Total No. of Patients
`
`8406
`
`7439
`
`6655
`
`5759
`
`4997
`
`4204
`
`3358
`
`2495
`
`1501
`
`1200
`
`926
`
`691
`
`Nonadherent
`Adherent to LL Therapy and Nonadherent to AH Therapy
`Adherent to AH Therapy and Nonadherent to LL Therapy
`Adherent to LL and AH Therapy
`
`27.4
`8.5
`19.4
`44.7
`
`35.0
`7.2
`21.9
`35.9
`
`35.9
`6.5
`21.0
`36.6
`
`35.3
`6.5
`22.4
`35.8
`
`36.1
`5.7
`22.6
`35.6
`
`33.8
`5.9
`23.4
`36.9
`
`34.3
`5.8
`23.3
`36.5
`
`34.2
`5.7
`23.9
`36.2
`
`39.0
`5.7
`21.3
`34.0
`
`38.5
`5.3
`23.0
`33.2
`
`36.3
`5.9
`22.6
`35.2
`
`36.5
`5.2
`20.1
`38.2
`
`Figure. Patterns of patient adherence to concomitant therapy over 3 years. The index date was defined as the date concomitant therapy (ie, second drug) was
`initiated. Percentages at each date may not total 100 because of rounding. AH indicates antihypertensive; LL, lipid-lowering.
`
`analyses also were repeated within the same subset of pa-
`tients aged 45 to 84 years, with results stratified by whether
`patients were younger than 65 years or 65 years and older.
`While patients 65 years and older tended to have higher
`rates of comorbidity and health services use, no striking
`differences in patterns of compliance with AH or LL medi-
`cations were observed between subjects younger than 65
`years and those 65 years and older.
`The pattern of adherence observed in this study—a
`sharp decline in the first 6 months, followed by a more
`gradual decline over time—is consistent with previous
`longitudinal studies13,19,20 of adherence with AH or LL
`therapies. However, the rates of adherence observed in
`this study with concomitant AH and LL therapies, and
`with AH or LL therapy alone, were higher than those re-
`ported in previous studies12-14 that assessed adherence to
`either AH or LL medications. This difference may indi-
`cate the greater motivation to be adherent with therapy
`among patients who had multiple cardiovascular risk fac-
`tors, a finding reported in previous studies12-14 of drug
`adherence in patients with hypertension and dyslipid-
`emia. The higher adherence in our study may also be re-
`lated to the nature of the population studied, namely, a
`commercially insured cohort with pharmaceutical in-
`surance. Higher rates of adherence have been observed
`previously in commercially insured populations.10
`The sharp decline in adherence observed in the first
`6 months after initiation of therapy for AH and/or LL and
`the low overall rate of adherence to concomitant therapy
`are major concerns. Recent studies21-23 using meta-
`analysis and treatment algorithms have suggested that sub-
`stantial reductions in the risk of cardiovascular events
`may be obtained by simultaneously targeting hyperten-
`sion and dyslipidemia. Intensive treatment of modifi-
`able cardiovascular risk factors reduced the risk of car-
`diovascular and microvascular events by about 50% in
`patients at high risk of CVD, such as those with type 2
`diabetes mellitus and microalbuminuria.24 Thus, improv-
`ing adherence with concomitant AH and LL therapy will
`result in substantial health care benefits.
`
`The data obtained concerning predictors of adher-
`ence have potential to guide efforts and interventions for
`improving patient adherence with prescribed AH and LL
`medication. For example, the observation that approxi-
`mately one-fourth of the study population was adherent
`with one medication (usually AH therapy) but not the
`other demonstrates receptivity to, and partial adher-
`ence with, drug therapy to prevent CVD. Therefore, the
`potential exists for improved adherence with concur-
`rent AH and LL therapies. Any effective intervention
`among these partially adherent patients may potentially
`double the percentage of adherent concomitant AH and
`LL therapy users.
`Adherence declined most rapidly during the first 6
`months of concomitant AH and LL therapy, suggesting
`the importance of early interventions to maintain or im-
`prove adherence. Similarly, adherence was best when AH
`and LL therapies were initiated on or about the same date,
`suggesting benefit from concomitant initiation of therapy
`to treat these 2 cardiovascular risk factors.
`The number of other medications a patient was tak-
`ing in the pretreatment year was strongly and inversely
`associated with adherence with concomitant therapy, con-
`sistent with previous studies12-14 of the association be-
`tween the total number of medications administered and
`adherence with prescribed cardiovascular medications.
`Studies25,26 have suggested that simplifying a drug regi-
`men by eliminating even one pill (by using a fixed-dose
`combination AH product instead of 2-pill combination
`therapy) could improve adherence. Randomized clini-
`cal trials27 assessing the utility of combined AH and LL
`therapy in the treatment of concomitant hypertension and
`dyslipidemia have been completed and will provide fur-
`ther guidance on this issue.
`Our results should be interpreted in light of study limi-
`tations. First, the use of proportion of days covered may
`overestimate adherence, because it assumes that pa-
`tients take all of the medications for prescriptions that
`are filled. This method may also have overestimated ad-
`herence in patients prescribed AH regimens consisting
`
`(REPRINTED) ARCH INTERN MED/ VOL 165, MAY 23, 2005
`1150
`
`WWW.ARCHINTERNMED.COM
`
`©2005 American Medical Association. All rights reserved.
`
`Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/intemed/12030/ by a Cambridge Hospital User on 04/04/2017
`
`Par Pharm., Inc.
`Exhibit 1050
`Page 004
`
`

`

`Table 2. Predictors of Adherence With Concomitant AH and LL Medications
`
`Variable
`Time between start of AH and LL therapy, d
`0-30
`31-60
`61-90
`Time since the initiation of concomitant therapy, loge (mo)
`Demographics
`Age, y
`18-44
`45-54
`55-64
`65-74
`ⱖ75
`Female sex
`Clinical history in the baseline year
`Coronary artery disease
`None
`Level 1 (angina or coronary angiography)
`Level 2 (PTCA, CABG, or chronic CHD)
`Level 3 (acute MI)
`Stroke
`Congestive heart failure
`Depression
`Dementia
`Diabetes mellitus
`Health services used in the baseline year
`No. of other prescription medications
`0
`1
`2
`3-5
`ⱖ6
`Outpatient physician encounters (all cause)
`0-1
`2
`3-5
`ⱖ6
`Hospitalized
`
`Unadjusted Results
`
`Adjusted Results*
`
`Odds Ratio (95% CI)
`
`P Value
`
`Odds Ratio (95% CI)
`
`P Value
`
`1.52 (1.39-1.66)
`0.74 (0.66-0.82)
`0.66 (0.58-0.75)
`0.87 (0.84-0.90)
`
`0.73 (0.63-0.85)
`0.95 (0.86-1.05)
`1.33 (1.21-1.45)
`1.00 (0.92-1.08)
`0.87 (0.79-0.96)
`0.85 (0.79-0.92)
`
`0.87 (0.80-0.94)
`0.83 (0.64-1.08)
`1.15 (1.05-1.27)
`1.15 (1.02-1.30)
`1.10 (0.97-1.26)
`1.22 (1.06-1.40)
`0.83 (0.69-1.00)
`0.89 (0.61-1.32)
`0.99 (0.90-1.08)
`
`1.73 (1.56-1.90)
`1.25 (1.13-1.39)
`0.96 (0.86-1.07)
`0.87 (0.79-0.94)
`0.65 (0.59-0.71)
`
`1.16 (1.07-1.26)
`0.95 (0.85-1.06)
`1.02 (0.94-1.11)
`0.84 (0.77-0.92)
`0.95 (0.87-1.04)
`
`⬍.001
`⬍.001
`⬍.001
`⬍.001
`
`⬍.001
`.27
`⬍.001
`.94
`.006
`⬍.001
`
`⬍.001
`.16
`.004
`.03
`.14
`.006
`.05
`.57
`.77
`
`⬍.001
`⬍.001
`.41
`.001
`⬍.001
`
`⬍.001
`.39
`.59
`⬍.001
`.24
`
`1.34 (1.18-1.52)
`1.09 (0.94-1.27)
`1.00†
`0.86 (0.83-0.89)
`
`1.00†
`1.24 (1.05-1.47)
`1.56 (1.32-1.84)
`1.27 (1.08-1.49)
`1.14 (0.96-1.36)
`0.91 (0.84-0.98)
`
`1.00†
`0.96 (0.74-1.24)
`1.20 (1.07-1.34)
`1.28 (1.09-1.50)
`1.20 (1.04-1.39)
`1.24 (1.06-1.45)
`0.94 (0.78-1.13)
`0.89 (0.61-1.30)
`1.06 (0.96-1.17)
`
`1.96 (1.72-2.25)
`1.61 (1.40-1.84)
`1.30 (1.14-1.49)
`1.23 (1.10-1.38)
`1.00†
`
`1.00†
`0.93 (0.82-1.05)
`1.03 (0.93-1.14)
`0.97 (0.87-1.09)
`0.83 (0.73-0.94)
`
`⬍.001
`.25
`NA
`⬍.001
`
`NA
`.01
`⬍.001
`.004
`.14
`.02
`
`NA
`.73
`.001
`.003
`.02
`.008
`.51
`.55
`.23
`
`⬍.001
`⬍.001
`⬍.001
`⬍.001
`NA
`
`NA
`.22
`.60
`.61
`.003
`
`Abbreviations: AH, antihypertensive; CABG, coronary artery bypass graft; CHD, coronary heart disease; CI, confidence interval; LL, lipid-lowering;
`MI, myocardial infarction; NA, not applicable; PTCA, percutaneous transluminal coronary angioplasty.
`*Each odds ratio was adjusted for all other factors in the table.
`†Reference group.
`
`of 2 or more AH medications. A given day was assumed
`to be covered if any drug for the indication of interest
`was available. Such an approach is likely to be accurate
`for LL therapy, which in most patients consists of stat-
`ins alone. In contrast, multidrug therapy is common in
`the treatment of hypertension. The observed greater ad-
`herence with AH relative to LL medications may, thus,
`be partly a function of the measurement technique used.
`Second, this analysis assumes that all patients received
`prescription medications only through their primary
`health insurance plan. There are several possible sce-
`narios under which medication use might not be cap-
`tured by the plan (eg, physician-provided samples or
`claims submitted through other coverage), but these are
`unlikely to occur frequently among commercially in-
`sured patients with a pharmaceutical benefit. Third, a limi-
`tation of this study is that patient-level benefit struc-
`tures and changes were not available in the data. Health
`
`plans may have altered pharmacy benefits during the
`study, and increased co-payments or coverage caps could
`lead to decreased persistence or adherence in the af-
`fected patients.
`Nevertheless, the results of this analysis have impor-
`tant implications for clinicians and other decision mak-
`ers responsible for treating patients with comorbid hy-
`pertension and dyslipidemia. Long-term adherence with
`concomitant AH and LL therapy in managed care pa-
`tients was poor. This is extremely concerning given the
`high risk of cardiovascular events in patients with con-
`comitant hypertension and dyslipidemia16 and the ben-
`efits of treating these 2 risk factors optimally. The fac-
`tors observed to predict adherence in this study, all of
`which are available to the physician at initiation of therapy,
`provide useful information about which patients are likely
`to be poorly adherent with prescribed therapy and the
`potential means to improve the management of concomi-
`
`(REPRINTED) ARCH INTERN MED/ VOL 165, MAY 23, 2005
`1151
`
`WWW.ARCHINTERNMED.COM
`
`©2005 American Medical Association. All rights reserved.
`
`Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/intemed/12030/ by a Cambridge Hospital User on 04/04/2017
`
`Par Pharm., Inc.
`Exhibit 1050
`Page 005
`
`

`

`tant hypertension and dyslipidemia. Clinicians should be
`aware of the factors likely to be associated with poor ad-
`herence, such as time taking therapy, young age, female
`sex, and the absence of cardiovascular events, and should
`target interventions to increase compliance accord-
`ingly. For example, because of the sharp decline in ad-
`herence in the first 6 months of concomitant therapy, in-
`terventions to promote adherence are more likely to have
`significant impact if initiated soon after treatment be-
`gins. In addition, physicians may be able to improve medi-
`cation adherence substantially by reducing the number
`of concomitant medications and by initiating AH and LL
`medications together or close in time. Any improve-
`ment in adherence with concomitant AH and LL medi-
`cations is likely to be associated with substantial public
`health care benefits.
`
`Accepted for Publication: December 7, 2004.
`Correspondence: Richard H. Chapman, PhD, ValueMed-
`ics Research, LLC, 300 N Washington St, Suite 303, Falls
`Church, VA 22046 (rick.chapman@valuemedics.com).
`Funding/Support: This study was supported by a grant
`from Pfizer Inc, New York, NY (ValueMedics Research,
`LLC).
`Previous Presentation: This study was presented as a
`poster at the American Heart Association’s Scientific Ses-
`sions, November 11, 2003, Orlando, Fla; and at the An-
`nual Meeting of the International Society for Pharma-
`coeconomics and Outcomes Research, May 18, 2004,
`Arlington, Va.
`Acknowledgment: We thank Dan Pettitt, DVM, MSc, for
`developing the initial concept and design of this study.
`
`REFERENCES
`
`1. American Heart Association. Heart Disease and Stroke Statistics: 2004 Update.
`Dallas, Tex: American Heart Association; 2003.
`2. Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary pre-
`vention of coronary heart disease: meta-analysis of randomised trials. BMJ. 2000;
`321:983-986.
`3. Ross SD, Allen IE, Connelly JE, et al. Clinical outcomes in statin treatment trials:
`a meta-analysis. Arch Intern Med. 1999;159:1793-1802.
`4. Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Treatment Trial-
`ists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-
`pressure–lowering drugs: results of prospectively designed overviews of ran-
`domised trials. Lancet. 2000;356:1955-1964.
`5. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density li-
`poprotein cholesterol, ischaemic heart disease, and stroke: systematic review
`and meta-analysis. BMJ. 2003;326:1423-1426.
`6. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treat-
`ment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ.
`2003;326:1427-1431.
`7. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group.
`Major outcomes in moderately hypercholesterolemic, hypertensive patients ran-
`
`domized to pravastatin vs usual care: the Antihypertensive and Lipid-Lowering
`Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002;288:2998-
`3007.
`8. Sever PS, Dählof B, Poulter NR, et al. Prevention of coronary and stroke events
`with atorvastatin in hypertensive patients who have average or lower-than-
`average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Out-
`comes Trial–Lipid-Lowering Arm (ASCOT-LLA): a multicentre randomised con-
`trolled trial. Lancet. 2003;361:1149-1158.
`9. Berg JS, Dischler J, Wagner DJ, Raia JJ, Palmer-Shevlin N. Medication compli-
`ance: a healthcare problem. Ann Pharmacother. 1993;27(suppl):S1-S24.
`10. Andrade SE, Walker AM, Gottlieb LK, et al. Discontinuation of antihyperlipid-
`emic drugs: do rates reported in clinical trials reflect rates in primary care settings?
`N Engl J Med. 1995;332:1125-1131.
`11. Simons LA, Levis G, Simons J. Apparent discontinuation rates in patients pre-
`scribed lipid-lowering drugs. Med J Aust. 1996;164:208-211.
`12. Avorn J, Monette J, Lacour A, et al. Persistence of use of lipid-lowering medi-
`cations: a cross-national study. JAMA. 1998;279:1458-1462.
`13. Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J. Long-
`term persistence in statin therapy in the elderly. JAMA. 2002;288:455-461.
`14. Monane M, Bohn RL, Gurwitz JH, Glynn RJ, Levin R, Avorn J. The effects of ini-
`tial drug choice and comorbidity on antihypertensive therapy compliance: re-
`sults from a population-based study in the elderly. Am J Hypertens. 1997;10:
`697-704.
`15. Eaton CB, Feldman HA, Assaf AR, et al. Prevalence of hypertension, dyslipid-
`emia, and dyslipidemic hypertension. J Fam Pract. 1994;38:17-23.
`16. Neaton JD, Wentworth D; Multiple Risk Factor Intervention Trial Research Group.
`Serum cholesterol, blood pressure, cigarette smoking, and death from coronary
`heart disease: overall findings and differences by age for 316,099 white men.
`Arch Intern Med. 1992;152:56-64.
`17. Monane M, Bohn RL, Gurwitz JH, Glynn RJ, Levin R, Avorn J. Compliance with
`antihypertensive therapy among elderly Medicaid enrollees: the roles of age, gen-
`der, and race. Am J Public