Compliance with Antihypertensive Therapy in the Elderly

Am J Cardiovasc Drugs 2008; 8 (1): 45-50ORIGINAL RESEARCH ARTICLE 1175-3277/08/0001-0045/$48.00/0

© 2008 Adis Data Information BV. All rights reserved.

Compliance with Antihypertensive Therapy inthe ElderlyA Comparison of Fixed-Dose Combination Amlodipine/Benazepril versusComponent-Based Free-Combination Therapy

Michael Dickson1 and Craig A. Plauschinat2

1 College of Pharmacy, University of South Carolina, Columbia, South Carolina, USA2 Novartis Pharmaceuticals, East Hanover, New Jersey, USA

Background: Treatment regimens that require fewer dosage units and less frequent dosing to decrease theAbstractcomplexity and cost of care are among the strategies recommended to improve compliance with antihypertensivetherapy. Simplifying therapy may be particularly important for elderly patients, who are more likely to have co-morbid conditions and to be taking multiple medications.Objective: To determine rates of compliance with antihypertensive therapy and total costs of care among elderlyMedicaid recipients treated with fixed-dose combination amlodipine besylate/benazepril versus a dihydropyri-dine calcium channel antagonist and ACE inhibitor prescribed as separate agents (free combination).Study design: A longitudinal, retrospective, cohort analysis of South Carolina Medicaid claims for ambulatoryservices, hospital services, Medicare crossover, and prescription drug for the years 1997–2002. Follow-up was12 months from the index date, defined as the first prescription dispensing date for a study drug.Patients: South Carolina Medicaid beneficiaries aged ≥65 years.Main outcome measure: Outcomes variables included compliance defined as the medication possession ratio(MPR), which was the total days’ supply of drug (excluding last prescription fill) divided by the length of follow-up (with number of hospital days subtracted from the numerator and denominator). We hypothesized that elderlyindividuals receiving fixed-dose combination amlodipine besylate/benazepril HCl would be more compliantwith therapy than those receiving a dihydropyridine calcium channel antagonist and ACE inhibitor as freecombination.Results: There were 2336 individuals in the fixed-combination group and 3368 in the free-combination group.The mean age was 76.0 ± 7.2 years, and 82.6% were female. Compliance rates were significantly higher withfixed-dose versus free-combination therapy (63.4% vs 49.0%; p < 0.0001). The average total cost of care forpatients receiving the fixed-dose combination was $US3179 compared with $US5236 (2002 values) for the free-combination regimen. In multivariate regression analyses on the log of total cost of care, average total costsincreased by 0.5% for each 1-unit increase in MPR, and for each additional co-morbidity (measured by thechronic disease score) there was an increase of 10.4%. However, average total costs were reduced by 12.5% forpatients using fixed-dose versus free-combination therapy (p < 0.003).Conclusion: Use of fixed-dose amlodipine besylate/benazepril HCl by elderly Medicaid recipients wasassociated with improved compliance and lower healthcare costs compared with a dihydropyridine calciumchannel antagonist and ACE inhibitor prescribed as separate agents.

According to the National Health and Nutrition Examination quarters of these individuals with hypertension are aged ≥50Survey (NHANES) 1999–2000, 65 million adult Americans or years.[1] The risks of inadequately controlled hypertension, includ-31% of the adult population of the US have hypertension. Three- ing increased rates of myocardial infarction, heart failure, stroke,

46 Dickson & Plauschinat

and kidney disease, are well established, as are the benefits of quiring fewer dosage units and less frequent dosing to reduce thelowering BP to reduce these risks.[2,3] Antihypertensive therapy in complexity and cost of care are among the strategies recommen-patients aged ≥60 years has been shown to reduce total mortality, ded to improve compliance with antihypertensive therapy and maycardiovascular morbidity/mortality, stroke, and coronary events. be particularly important for elderly patients, who are more likelyThese benefits are even more pronounced in patients aged ≥70 to have co-morbid conditions and take multiple medications.[2,13,14]

years.[3] In addition to improving compliance, uninterrupted antihyperten-sive therapy has been shown to reduce total healthcare costs in aA comparison between NHANES III (1988–94) and NHANESpopulation of Medicaid recipients.[15] The use of lower-dose com-1999–2002 showed that the use of antihypertensive medicationbination therapy with two complementary agents has the potentialamong hypertensive adults increased significantly during thatto increase efficacy, decrease adverse effects, reduce medicationtime;[4] nevertheless, more than one-third of hypertensive adultscosts, and increase patient compliance with therapy.[12]remain untreated.[5] Recognizing the need for more than one

The objectives of this study, therefore, were to determine theantihypertensive agent to achieve BP goals in the majority ofrates of compliance and total costs of care among elderly Medicaidpatients, the use of ACE inhibitor-based combination therapy alsorecipients treated with a fixed-dose combination of amlodipinesignificantly increased over the past decade.[4] In both NHANESbesylate and benazepril HCl versus a dihydropyridine calciumsurveys, antihypertensive medication use was greater among olderchannel antagonist (DHP-CCA) and ACE inhibitors prescribed asthan younger adults and increased significantly in the groups agedseparate agents.50–59 years and ≥70 years. Hypertension treatment and rates of

control both increased significantly for men (p < 0.001 for bothdimensions), but did not change significantly for women. In spite Methodsof the evidence for increased use of antihypertensive therapy in theelderly population, individuals aged >60 years still showed the This was a longitudinal, retrospective, cohort study using thelowest rate of BP control, including those receiving antihyperten- South Carolina Medicaid database for the period 1997–2002. Thesive treatment.[2,6]

number of Medicaid beneficiaries varied by year and month but, inBoth physician-related and patient-related factors contribute to general, there was an average of about 700 000 Medicaid benefi-

poor BP control in the elderly. Physicians may be reluctant to treat ciaries throughout the study period. Claims for the study includedelderly patients because of concern about adverse events and drug ambulatory care, hospital care, prescription drug claims, andinteractions, and consequently may not prescribe the most effec- Medicare crossover claims for patients selected during the studytive antihypertensive agents at the most effective doses.[7] Accord- period. Although patients may have had claims in more than 1ing to a study of medication use in a representative US sample, year, each patient was included only once in the study and fol-23% of women and 19% of men aged ≥65 years reported taking lowed for 12 months (the follow-up period) from the date of thefive or more prescription drugs.[8] The presence of common co- first prescription of study drug (the index date). Prescriptions maymorbid conditions, including asthma/chronic obstructive pulmon- be for any quantity of medication up to a 3-month supply. Allary disease, depression, gastrointestinal disorders, and osteoarthri- personal identifiers were removed before data analyses to protecttis, has been associated with reduced use of antihypertensive the confidentiality of study participants in conformance with themedications in the elderly, even in the presence of compelling Health Insurance Portability and Accountability Act (HIPAA).indications for therapy (e.g. coronary artery disease or stroke).[9] In Medicaid is a state-federal jointly funded program to provideaddition, physicians may accept a higher SBP level in their pa- healthcare services to those who qualify based on a means test. Atients than is currently recommended by JNC 7 (Seventh Report of full range of healthcare services is included largely through privatethe Joint National Committee on Prevention, Detection, Evalua- sector providers who submit claims for payment. Medicaid pa-tion, and Treatment of High Blood Pressure) guidelines because tients may be asked for a modest copayment (but they are notthey consider DBP to be more clinically relevant.[10] However, required to pay), but they do not pay for services and then seekSBP continues to increase with increasing age, whereas DBP tends reimbursement. For example, pharmacies submit claims for pre-to decrease or normalize; as a result, more than 90% of individuals scriptions dispensed for Medicaid beneficiaries. While there wereaged ≥50 years may be staged on the basis of SBP alone.[11] some limitations on the drug benefit during the time of this study,

these did not influence the availability of antihypertensive medica-Patient compliance with treatment regimens decreases as thetions.number of drugs taken and the cost of medication increase.[12] The

inconvenience and confusion associated with taking multiple Patients were included in the study if they were aged at least 65drugs also reduces compliance. Simpler treatment regimens re- years but <100 years on the index date, had received at least two

© 2008 Adis Data Information BV. All rights reserved. Am J Cardiovasc Drugs 2008; 8 (1)

Compliance with Antihypertensive Therapy 47

was used as a measure of compliance, defined as the percentage oftime in days that a patient had the study drugs available (excludingthe last prescription fill) during the 1-year follow-up period. Thenumber of hospital days were subtracted from the numerator anddenominator. MPR is one of several commonly used metrics formeasuring medication adherence. It is used in this study because itis the most generic of adherence measures.[16,17] The number ofdays of hospitalization, if any, was subtracted from the number ofdays of drug supply (numerator) and the number of days of follow-up (denominator) to account for non-use of drug while hospital-ized and possible prescription changes upon discharge. For pa-

Table I. Patient characteristics

Characteristic Fixed-dose Free Totalcombination combination (n = 5704)(n = 2336) (n = 3368)

Age (y) [mean ± SD] 75.6 ± 7.1 76.2 ± 7.3 76.0 ± 7.2

Sex (% female) 82.5 82.7 82.6

Race (% African 72.0 70.1 70.9American)

Residency (% urban) 89.3 90.8 90.2

Chronic disease score 4.8 ± 2.3 5.0 ± 2.3 4.9 ± 2.3(mean ± SD)

tients in the free-combination group, days of drug possession wereprescriptions for study drugs in one of the selection years counted only if both drugs were available on the same day. Total(1997–2001), and were continuously eligible for Medicaid for 12 cost of care was defined as the sum of payments for Medicaidmonths following the index date. Patients were excluded if they claims for ambulatory care (Healthcare Financing Administrationhad >180 days of hospitalization, <30 days of study drug supply, [HCFA] 1500 claims), hospital care claims (UB-92 claims), pre-or any nursing home claims during the 12-month follow-up period. scription drug claims, and Medicare crossover claims.

Two cohorts of patients were defined by their use of antihyper-tensive therapy: patients prescribed combination amlodipine besy- Statistical Methodslate/benazepril HCl (fixed-dose combination) and patients pre-scribed any combination of a DHP-CCA plus an ACE inhibitor as A logistic regression using pre-index period data (the 1-yearseparate agents (free combination). In the fixed-dose combination period prior to the index date) was used to calculate a propensitygroup, patients could not have switched to another combination score for each patient to control for selection bias and con-during the follow-up period. In the free-combination group, pa- founding.[18] This was done to minimize potential selection biastients could switch among other ACE inhibitors and DHP-CCAs, resulting from the nonrandom assignment of patients to treatmentbut could not have used a fixed-dose combination of amlodipine groups and to account for differences in prior use of antihyperten-besylate with benazepril or other fixed-dose combination anti- sive drug therapy. Variables used in the propensity score includedhypertensive product at any time during the follow-up period. patient demographic characteristics (age, sex, race, county ofDHP-CCAs included amlodipine, felodipine, isradipine, ni- residence – rural vs urban), chronic disease score (CDS), used as acardipine, nifedipine, nimodipine, and nisoldipine; ACE inhibitors measure of co-morbidity to provide an indication of the overallincluded benazepril, captopril, enalapril, lisinopril, quinapril, and medical condition of the patient, percentage of ambulatory visits toramipril. Dispensing dates for the two drugs could be a maximum cardiac specialists for cardiovascular disease diagnoses, averageof 30 days apart for study eligibility, and the index date was the total number of claims per month, average total healthcare expen-date of initiation of the first antihypertensive agent. We required diture per month, average monthly expenditure for each type ofthe second prescription drug to be available within 30 days of the claim, average monthly expenditure on other cardiovascular drugs,first prescription drug to ensure that the two agents were being and average monthly expenditure on the fixed-dose and free-used together. Prescriptions for the two agents were not required to combination study drugs. Medicare crossover claims for duallybe dispensed on the same date because this was not necessarily eligible patients included both Part A and Part B claims, whichrepresentative of how prescriptions were dispensed in real-world were separated into their respective components (ambulatory andpractice. In addition, the 30-day period was allowed because one hospital). To control for potential differences in eligibility in theof the prescribed drugs could have been received during the periodprior to the index date. The exact time window to use is arbitrarybut 30 days is reasonable given that many prescriptions are for a30-day supply.

Outcome Variables

Outcome variables included compliance and average total costof care for the two groups. The medication possession ratio (MPR)

Table II. Medication compliance by study group

Study group Mean (SD) Median Minimum Maximum

Fixed-dose 0.634 (0.294) 0.658 0.082 0.981combination(n = 2336)

Free combination 0.490 (0.234) 0.482 0.082 1.000(n = 3368)



Results

Patient characteristics of the study population as of the indexdate are shown in table I. A total of 5704 Medicaid recipients aged≥65 years were included in the study, including 2336 in the fixed-dose combination group and 3368 in the free-combination group.The mean age of patients was 76.0 ± 7.2 years, 82.6% werefemale, and 70.9% were African American. The demographics ofthe two groups were similar.

Compliance

As shown in table II and graphically presented in figure 1,compliance with antihypertensive therapy measured by MPR wassignificantly higher for patients in the fixed-dose combinationgroup compared with those in the free-combination group (63.4%vs 49.0%; p < 0.05). These compliance rates are lower than aredesired, but the fixed-dose combination group did demonstrate a

100

80

60

40

20

0

Fixed-dose combination therapyFree-combination therapy

MP

R (

%)

Fig. 1. Compliance rates, calculated as medication possession ratio(MPR), in the fixed-dose combination and free-combination therapygroups. MPR was significantly higher for patients receiving fixed-dosecombination therapy compared with free-combination therapy (63.4% vs49%; p < 0.05). MPR was calculated as total days’ drug supply (excludinglast prescription fill) divided by 365 days (with number of hospital dayssubtracted from the numerator and denominator). significantly higher rate of compliance than the free-combination

group.pre-index period, each of these variables was standardized by the

Total Healthcare Costsnumber of months of pre-period eligibility.

The CDS has been implemented by researchers in several ways. The average total cost of care for the fixed-dose combinationWe implemented the chronic disease concept using the method group was $US3179 (2002 value) compared with $US5236 (2002described by Clark et al.[19] Clark’s method is a modification of value) for the free-combination group (p < 0.0001) [figure 2]. Forwork by VonKorf and colleagues,[20] who created a CDS that was each type of claim, including ambulatory, drug, and hospitalbased on pharmacy claims and weighted by expert panel judg- claims, costs were lower for the fixed-dose combination than forment. Clark’s modification of VonKorf’s measure was to derive the free-combination group. Ambulatory, drug, and other costsweights using a regression model rather than expert opinion.Because nonstandardized regression coefficients cannot be gener-alized to other situations, it was not possible to use those weights,and the work of Schneeweiss and others suggests that simplecounts of different prescription drugs received during the past year“… appear to be well performing comorbidity measures in epide-miological studies.”[21] Therefore, we used an unweighted CDSderived using the therapeutic categories described in the 1995Clark et al.[19] paper. Patients may have multiple prescriptions forthe same chronic condition, but each condition is counted onlyonce in the CDS for this study.

Patient-level data were used to calculate the MPR; a two-sample t-test was used to compare compliance rates between thetwo treatment groups. Multivariate analyses were performed toassess the relationship between compliance and total healthcarecost in the 12-month follow-up period (log of total healthcarecost), controlling for study year of enrollment, MPR, CDS, race,sex, and study group (fixed combination vs free combination). Alldata management and statistical analyses were performed usingSAS, version 8.2 (SAS Institute, Inc., Cary, NC, USA).

7 500

5 000

2 500

0

Cos

ts o

f car

e ($

US

)

OtherHospitalDrugAmbulatory

Fixed-dosecombination

therapy

Free-combination

therapy

Fig. 2. Average total cost of care for patients receiving fixed-dose combina-tion therapy vs free-combination therapy. The average total cost of care forthe fixed-dose combination therapy group was $US3179 compared with$US5236 (2002 values) for the free-combination therapy group. Compo-nent costs for fixed-dose vs free-combination therapy groups were$US1120 vs $US1646 for ambulatory claims, $US1322 vs $US1952 fordrug costs, $US334 vs $US410 for hospital costs and $US402 vs $US1229for other costs (Medicare cross-over costs).


Compliance with Antihypertensive Therapy 49

were significantly different between the two treatment groups patients aged ≥18 years.[22] In an earlier retrospective study of a(p < 0.0001), but there was no significant difference in hospital managed-care patient population that was younger on averagecost (p = 0.5022). Results of the multivariate analyses on the log of (mean age 53 years, 50% female), patients prescribed fixed-dosetotal cost of care for the 1-year follow-up period are presented in combination amlodipine besylate/benazepril also demonstratedtable III. Controlling for year of study enrollment, MPR, CDS, significantly higher compliance rates and lower per-patient aver-race, and sex, patients using the fixed-dose combination had an age costs of cardiovascular-related care than those prescribedaverage total cost of care increase of 0.5% (p < 0.0001) for each concomitant DHP-CCA and ACE inhibitors as separate agents.[23]

one unit increase in MPR, and a 10.4% (p < 0.0001) increase for This study is subject to several limitations. The potential foreach additional co-morbidity (as measured by the CDS). We selection bias exists because of the retrospective, nonrandomizedwould expect increased medication compliance to increase the study design; however, propensity scores and covariates theoreti-average cost of the drug used, and patients with more co-morbidi- cally associated with the outcomes of interest were used to controlties to have, in general, higher healthcare costs. However, the for potential confounding factors. Using a Medicaid population aseffect of being in the fixed-combination group mitigated these a source of data offers the advantages of completeness of informa-increases. There was a 12.5% lower total cost of care for the fixed- tion and stable enrollment, but may limit the ability to generalizecombination group compared with the free-combination group (p results to the general population; in this analysis, the population< 0.003). There was no statistically significant relationship be- studied was predominantly African American and female. Thetween race and sex and the cost of care (p = 0.6343 and p = 0.7614, study also excluded patients with extended hospital or nursingrespectively). home stays and thus may not be representative of all elderly

people. Finally, assessment of compliance was based on prescrip-tion records and there was no confirmation that the study drugsDiscussionwere taken, nor was there documentation of clinical outcomes.

In this study of elderly Medicaid recipients, patients prescribeda fixed-dose combination of amlodipine besylate/benazepril had Conclusionhigher rates of compliance and lower total healthcare costs thanthose receiving a free-combination of the same component drug This analysis shows that elderly Medicaid patients receiving aclasses. These results are consistent with those seen in a larger fixed-dose combination of amlodipine besylate/benazepril werestudy of the South Carolina Medicaid population that included all significantly more compliant with antihypertensive therapy and

Table III. Regression on the log of total cost of carea

Dependent variable: log(total cost of care), mean = 7.8837, n = 5704

independent variable coefficientsb SE t p > t

Intercept 7.2018 0.0607 118.69 <0.0001

Propensity score –0.1434 0.0441 –3.25 –0.0551

Year –0.1354 0.0091 –14.90 <0.0001

MPR 0.0050 0.0005 9.53 <0.0001

Group (fixed dose = 1)c –0.1274 0.0431 –2.96 0.0031

Chronic disease score 0.1044 0.0068 15.42 <0.0001

Race (White = 1)c 0.0137 0.0282 0.48 0.6343

Sex (male = 1)c 0.0100 0.0330 0.30 0.7614

a Adjusted R2 = 0.6649; Model F = 385.4, p < 0.001.

b Coefficients for dummy variables (Group, Race, and Sex), are interpreted by multiplying the coefficient by 100 to obtain a percentage. This valuerepresents the increase in cost for dummy variable when it is equal to 1. For large proportionate changes a more precise estimate is obtained by:100*[exp(coef)–1]. For example, when Group = 1 (the the fixed-combination group) cost is is 12.74% lower (–0.1274) than the free-combinationgroup or, more precisely, –11.96%. Coefficients for the continuous variables Year, MPR, and Chronic disease score, are multiplied by 100 to yieldthe percentage change in cost for each unit change in the independent variable.

c The variables Group, Race, and Sex are dummy variables where, 1 = fixed-combination, White, and male, respectively, for each variable.Otherwise the value is zero.

MPR = medication possession ratio; SE = standard error; t denotes calculated from the t-test.



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a division of US Medical and Regulatory Affairs. 14. Elliott WJ. Compliance -and improving it -in hypertension. Manag Care 2003; 12(8 Suppl. Hypertension): 56-61Dr Dickson was responsible for the conceptualization, design, and statisti-

cal analysis of this study as well as drafting the manuscript. Dr Plauschinat’s 15. McCombs JS, Nichol MB, Newman CM, et al. The costs of interrupting antihyper-tensive drug therapy in a Medicaid population. Med Care 1994; 32 (3): 214-26role includes assistance with the design of the study, and assistance with

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Compliance with Antihypertensive Therapy in the Elderly