Current Medical Research & Opinion Vol. 27, No. 9, 2011, 1719–1731

0300-7995 Article FT-0131.R1/589434

doi:10.1185/03007995.2011.589434 All rights reserved: reproduction in whole or part not permitted

Original articleLong-term clinical and economic outcomesassociated with angiotensin II receptorblocker use in hypertensive patients

Jason P. SwindlePaul BuzinecSerban R. IorgaInnovus, Eden Prairie, MN, USA

Krishnan RamaswamySumeet PanjabiDaiichi Sankyo Inc., Parsippany, NJ, USA

Address for correspondence:Jason P. Swindle PhD, Innovus, 200 W. Madison

Street, Suite 2000, Chicago, IL 60606, USA.

Tel.: þ1 312-429-3923;

jason.swindle@innovus.com

Key words:ARB – Healthcare cost – Healthcare utilization –

Health outcomes – Hypertension

Accepted: 16 May 2011; published online: 18 July 2011

Citation: Curr Med Res Opin 2011; 27:1719–31

Abstract

Objective:

To examine clinical and economic outcomes associated with angiotensin II receptor blockers (ARB).

Methods:

Retrospective claims data were analyzed for hypertensive adults with �1 year follow-up from first ARB

claim. Subjects were stratified into four cohorts: olmesartan (OM); valsartan (VAL); losartan (LOS); and

irbesartan (IRB), which represented the full sample. Analyses were also conducted with the ‘‘limited

sample,’’ which excluded subjects with pre-existing conditions in the period before first ARB. Time to

follow-up cardiac event was modeled using Cox proportional hazards regression; follow-up healthcare

resource utilization and costs were examined using generalized linear models.

Results:

The full and limited samples consisted of 118,700 and 65,579 subjects, respectively. Mean follow-up

ranged from 861 to 933 days. Baseline characteristics including the Quan–Charlson comorbidity score

differed by cohort. In both the full and limited samples, respectively, multivariate models predicted a

higher adjusted risk of follow-up cardiac event for VAL cohort (hazard ratio [HR]¼ 1.261 and 1.242,

p50.001), LOS cohort (HR¼ 1.307 and 1.178, p50.01), and IRB cohort (HR¼ 1.222 and 1.179,

p� 0.016) compared to OM cohort. Adjusted risk (full sample) of follow-up ambulatory and inpatient

visits (all-cause and hypertension-attributable) was higher in VAL, LOS, and IRB cohorts compared to

OM. Adjusted risk (limited sample) of follow-up ambulatory visits (all-cause and hypertension-

attributable) was greater for VAL, LOS and IRB cohorts relative to OM, but inpatient visit risk was

greater only in VAL and LOS cohorts. Compared to the OM cohort, follow-up all-cause adjusted

healthcare costs (limited sample) were higher in VAL (cost ratio [CR]¼ 1.067, p¼ 0.001) and IRB

cohorts (CR¼ 1.062, p¼ 0.045).

Conclusions:

In this large national US health plan, treatment with OM was associated with lower risk of cardiac events

and lower healthcare resource utilization and costs versus VAL, LOS, and IRB over a mean follow-up of

2.5 years. Association, rather than causality, to cardiac outcomes may be inferred from these observational

claims data.

Introduction

In the US, the prevalence of hypertension among adults aged �20 years is esti-mated at 76.4 million1,2. Uncontrolled hypertension can have serious healthconsequences, and is a major risk factor for various micro- and macro-vascularcomplications including myocardial infarction, heart failure, stroke and othercerebrovascular disease, end-stage renal disease, and death3,4. High-risk patients

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with uncontrolled hypertension can incur incrementalcosts when compared to patients with adequately con-trolled blood pressure5,6. In 2010, the American HeartAssociation estimated that the combined direct and indi-rect cost of high blood pressure was $76.6 billion4.

Numerous treatment options are available to lowerblood pressure for a majority of patients to within goallevels recommended in The Seventh Report of the JointNational Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pressure(JNC 7)7. Of these, angiotensin II receptor blockers(ARBs) represent a widely used class of drugs with an effi-cacy profile akin to angiotensin-converting enzyme (ACE)inhibitors and placebo-like tolerability8.

Eight ARBs (losartan [LOS], valsartan [VAL], irbesar-tan [IRB], olmesartan [OM], candesartan, telmisartan,eprosartan, and azilsartan) are available for treating hyper-tension in the US9. However, only select ARBs areapproved by the US Food and Drug Administration(FDA) for indications including stroke, heart failure, myo-cardial infarction, or diabetes. However, recent guidancefrom the FDA potentially broadens the label for most anti-hypertensive medications to include a statement that‘‘lowering blood pressure reduces the risk of fatal andnon fatal cardiovascular events,’’ irrespective of whethera product has demonstrated these outcomes in clinicalstudies10.

There is a paucity of data examining the real-worldclinical and economic outcomes associated with the useof ARBs especially over extended periods of treatment.One study examined ARB-treated patients in terms ofcosts and a subset in terms of costs and blood pressureoutcomes11; however, our search revealed no large USpopulation-based studies that systematically examined dif-ferences in clinical and economic outcomes associatedwith initial ARB use in hypertensive patients.Consequently, the objective of the present study is toexamine cardiac outcomes, healthcare resource utilization,and costs for hypertensive individuals initiated on themost frequently used ARBs (OM, VAL, LOS, IRB) overa relatively extended timeframe.

Patients and methods

Data source

A retrospective observational study was conducted usingdata from medical and pharmacy claims for the period ofJuly 1, 2002 to March 31, 2009 within a large US managedcare health plan affiliated with Ingenix. Member coverageis geographically diverse, with coverage across all USCensus regions. Since individual identities or medicalrecords were not disclosed, and data were accessed using

methods consistent with the Health Insurance Portabilityand Accountability Act12, Institutional Review Boardapproval was not required for this study.

Subject identification

The process involved in arriving at the study sample isoutlined in Figure 1. The study sample included commer-cial health plan and Medicare Advantage Part D enrolleesaged 18 years or older, who initiated single-agent ARBtherapy with OM, LOS, VAL or IRB, or two-agentfixed-dose combination of these ARBs with hydrochloro-thiazide (HCTZ) between January 1, 2003 and March 31,2008. The index date was the date of initiation of firstARB therapy with no evidence of an ARB claim in theprior 6 months. Subjects were included in a cohort if theyhad �2 claims with the following ARB therapies: (1) OMcohort (OM or OM/HCTZ); (2) VAL cohort (VAL orVAL/HCTZ); (3) LOS cohort (LOS or LOS/HCTZ);and (4) IRB cohort (IRB or IRB/HCTZ).

Subjects included in the study were continuouslyenrolled in the plan for a minimum of 6 months prior tothe index date (baseline period) and 1 year following theindex date (follow-up period) with medical and pharmacycoverage. Subjects had a primary or secondary diagnosiscode for hypertension during the baseline period (ICD-9-CM diagnosis codes: essential hypertension, 401.x; hyper-tensive heart disease, 402.xx; hypertensive chronic kidneydisease, 403.xx; hypertensive heart and chronic kidneydisease, 404.xx). Selection criteria also required at least60 days of total ARB supply, and a gap smaller than 60days (if any) between the first two ARB pharmacy claims.Subjects were excluded if they had any pharmacy claimsfor any ARB during the baseline period, or any pharmacyclaims for non-index ARBs or other fixed-dose combina-tion antihypertensive medications during the follow-upperiod. Subjects with any ICD-9 diagnosis or procedurecodes, or Current Procedural Terminology (CPT) codesfor pregnancy, labor or delivery during the study periodwere also excluded.

Since the study objectives included comparisons of car-diac outcomes between ARB cohorts, subjects with somepre-existing conditions or CV events could confound theclinical outcomes. Therefore, in our limited sample, indi-viduals were excluded if they had any baseline evidence ofdiabetes, heart failure, stroke, transient ischemic attack,myocardial infarction, ischemic heart disease (other thanmyocardial infarction), chronic kidney disease, otherkidney disease, or any baseline pharmacy claims for aß-blocker. This sample was defined as the ‘limited studysample’. The ‘full sample’ was also examined that did notexclude individuals with these confounding pre-existingconditions or risk factors.

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Study measures

Outcome measuresAll outcomes were measured in the follow-up period,inclusive of the index date. Follow-up duration was calcu-lated for each subject as number of days from the indexdate to the end of the follow-up period. Adherence withARB was measured using a medication possession ratio(MPR) calculated as the ratio of days supply of the indexARB to total days of follow-up.

The first observed occurrences of clinically significantcardiac events in the follow-up were identified usingICD-9 diagnosis and procedure codes, and CPT codes inthe primary or secondary position. However, we also exam-ined the results using only primary codes as a post hoc

sensitivity analysis. These included heart failure (ICD-9diagnosis codes: 428.0, 428.1, 428.21, 428.23, 428.31,428.33, 428.41, 428.43, 428.20, 428.30, 428.40, and428.9; or 428.20, 428.30, 428.40, and 428.9 if none ofthese codes occurred in the prior 60 days); stroke (ICD-9diagnosis codes, during inpatient stay: 430, 431, 432.x,433.x1, 434.x1, 436); myocardial infarction (ICD-9 diag-nosis codes, during inpatient stay: 410.xx); acute ischemicheart disease diagnosis (other than myocardial infarction;ICD-9 diagnosis codes, during inpatient stay: 411.1,411.8x); or surgery related to myocardial infarction/ische-mic heart disease (including percutaneous coronary inter-vention; CPT codes: 33510–33523, 33533–33536, 33572,92980–92981, 92982–92984, 92995–92996, 92973,

Enrollees ≥ 18 yrs with ≥ 1 pharmacy fill for an ARB(between January 1, 2003 and March 31, 2008); 1 st

pharmacy fill for an ARB defined as index filln = 1,006,371

Enrollees with medical and pharmacy benefits for 180 dprior to index fill (baseline period) and ≥ 365 d following

index fill (follow-up period)n = 396,976

≥ 1 follow-up fill for same ARB as index fill; ≥ 60 d totalsupply; gap in therapy for index and 2nd fill required < 60 d

n = 283,466

No diagnosis of HTN during baselineperiodClaims for pregnancy, labor or deliveryduring study periodAny ARB fills during baseline period

Total excluded: n = 164,766

OM Cohortn = 21,494

VAL Cohortn = 27,364

Abbreviations: ARB=angiotensin II receptor blocker; d=day; HTN=hypertension; OM=olmesartan;HCTZ=hydrochlorothiazide; VAL=valsartan; LOS=losartan; IRB=irbesartan; FDC=fixed dose combination

LOS Cohortn = 10,874

IRB Cohortn = 8,847

Full sample: OM, VAL, LOS, IRB Initiatorsn = 118,700

Limited study sample: subjects without pre-existingconditions or risk factors

n = 65,579

Index ARB other than OM, OM/HCTZ,VAL, VAL/HCTZ, LOS, LOS/HCTZ, IRB,IRB/HCTZ; any fills for non-index ARBs orother FDC antihypertensive medicationsduring follow-up period

Figure 1. Study sample selection process. A total of 1,006,371 adults were identified during January 2003 to March 2008 as having at least one pharmacyclaim for an ARB. After applying study selection criteria, 118,700 individuals were identified as initiators of OM, VAL, LOS or IRB of whom 65,579 were withoutpre-existing conditions or risk factors, including: baseline evidence of diabetes, heart failure, stroke, transient ischemic attack, myocardial infarction,ischemic heart disease (other than myocardial infarction), chronic kidney disease, other kidney disease, or any baseline pharmacy claims for a ß-blocker.

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G0290–G0291, S2205–S2209; ICD-9 procedure codes:00.66, 36.01–36.02, 36.03, 36.05, 36.06, 36.07, 36.09,36.1x). Also assessed was a composite measure of thesefive clinically significant cardiac events.

Economic outcomes were assessed as per-member-per-month (PMPM) healthcare resource utilization andPMPM healthcare costs (all-cause and hypertension-attri-butable). Hypertension-attributable medical resource uti-lization and costs were defined based on claims associatedwith ICD-9 diagnosis and procedure codes, CPT codes,revenue codes for hypertension; while hypertension-attri-butable pharmacy resource utilization and costs weredefined based on pharmacy claims for antihypertensivemedications. Healthcare resource utilization included:ambulatory visits (office and outpatient), emergencydepartment visits, hospital (inpatient) stays, hospital(inpatient) days, and pharmacy claims. Healthcare costswere computed as the combined health plan- and patient-paid costs in the follow-up period and included medicaland pharmacy costs. Costs were adjusted to 2008 USDusing the annual medical care component of theConsumer Price Index to reflect inflation between 2002and 200813; 2009 costs were not adjusted.

Patient characteristicsSubject demographic characteristics including age, gender,insurance type, geographic region, and race/ethnicity werecaptured. The following baseline comorbidities were cap-tured using ICD-9 diagnosis and procedure codes, CPTcodes, revenue codes, and pharmacy claims: depression;diabetes; hypercholesterolemia or hypertriglyceridemia;stroke or transient ischemic attack; myocardial infarction;ischemic heart disease (other than myocardial infarction);peripheral vascular disease; left ventricular hypertrophy(cardiomegaly); cerebrovascular disease other than strokeor transient ischemic attack; chronic kidney disease; andother kidney disease. Additionally, ICD-9 diagnosis codeswere used to identify baseline comorbid conditions asdefined by Quan et al., which were used to score theQuan–Charlson comorbidity index14,15. Baseline PMPMall-cause healthcare resource utilization and healthcarecosts were also captured.

Analytic strategy

All study variables, including baseline and outcome mea-sures, were analyzed descriptively and results are presentedstratified by index ARB cohort. Chi-square tests were usedto examine cohort differences in categorical baseline char-acteristics (e.g., subject demographic, clinical characteris-tics) and in the distributions of follow-up clinicallysignificant cardiac events. Kaplan–Meier curves wereused to visually inspect the estimated time to events bycohort, using the Kaplan–Meier failure estimates of the

hazard function. One-way analysis of variance was usedto evaluate cohort differences in mean age, Quan–Charlson comorbidity score, baseline and follow-upeconomic characteristics, and length of follow-up.

Multivariate analyses examined the associationbetween ARB cohort and follow-up clinically significantcardiac events, healthcare resource utilization, and PMPMhealthcare costs adjusting for covariates. Time to firstfollow-up clinically significant cardiac event was analyzedusing semi-parametric Cox proportional hazards models;follow-up healthcare resource utilization outcomes weremodeled with negative binomial regression; and follow-up healthcare costs were analyzed using generalizedlinear models with a gamma distribution and log-link func-tion. The gamma distribution and log-link account for theskewed distribution of costs. Analyses were adjusted forbaseline demographic and clinical characteristics thatincluded: age; gender; geographic region; race/ethnicity;and number of baseline non-ARB hypertension medica-tion classes (diuretics; ACE inhibitors; calcium channelblockers; �-blockers; aldosterone antagonists; renin inhib-itors; adrenolytics; a-blockers; reserpine; vasodilators; andACE inhibitor plus calcium channel blocker). Modelswere further adjusted in the following ways: eventmodels were adjusted for baseline comorbidities (definedabove); resource utilization models were adjusted for base-line all-cause healthcare resource utilization, baselineQuan–Charlson comorbidity score, and select baselinecomorbidities not overlapping with the Quan comorbidityalgorithms (depression, hypercholesterolemia or hypertri-glyceridemia, ischemic heart disease other than myocar-dial infarction, and non-chronic kidney disease); andcost models were adjusted for log-transformed baselineall-cause medical costs and pharmacy costs, baselineQuan–Charlson comorbidity score, and select base-line comorbidities not overlapping with the Quan comor-bidity algorithms.

Estimated hazard ratios (HRs), incidence rate ratios(IRRs) and cost ratios (CRs) were used (along with 95%confidence intervals) to assess the association betweenindependent variables and follow-up outcomes (cardiacevents, healthcare resource utilization and costs,respectively).

Results

Subject characteristics

A total of 118,700 enrollees were identified as initiatorsof OM or OM/HCTZ; VAL or VAL/HCTZ; LOS or LOS/HCTZ; or IRB or IRB/HCTZ, which represented the fullsample. Of these subjects, 65,579 (55.2%) had no baselineevidence of diabetes, heart failure, stroke or transientischemic attack, myocardial infarction, ischemic heart

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disease (other than myocardial infarction), chronic kidneydisease, other kidney disease, or baseline pharmacy claimsfor a ß-blocker, which constitutes the limited study sample.

Full sampleAmong all initiators (full sample), the VAL cohort wasmost populous (41.9%; n¼ 49,698), followed by the OM(28.7%, n¼ 34,123), LOS (19.5%, n¼ 23,164), and IRB(9.9%, n¼ 11,715) cohorts. On average, patients in theOM cohort were younger and had fewer comorbidities atbaseline. For example, the mean baseline Quan–Charlsoncomorbidity score was 0.59 in the OM cohort, and signif-icantly lower than the VAL, LOS, and IRB cohorts (0.83,1.03, and 0.93, respectively; p50.001).The proportion ofsubjects with baseline diabetes, which represents a highrisk and cost subset, was lower in the OM cohort(14.54%) than the VAL, LOS and IRB cohorts (20.67%,

25.59% and 25.01%, respectively). Similarly, disparitieswere observed in baseline proportions for subjects withheart failure (OM: 2.32%, VAL: 5.36%, LOS: 7.15%,and IRB: 4.89%; p50.001); stroke or transient ischemicattack (OM: 2.15%, VAL: 2.96%, LOS: 3.48%, and IRB:3.18%; p50.001); myocardial infarction (OM: 0.36%,VAL: 1.01%, LOS: 1.38%, and IRB: 1.00%; p50.001);and ischemic heart disease (other than MI;OM: 8.84%, VAL: 13.76%, LOS: 16.79%, and IRB:15.71%; p50.001).

Limited study sampleIn the limited study sample, the distribution of subjectsbetween ARB cohorts remained relatively similar: OM(32.8%; n¼ 21,494); VAL (41.7%; n¼ 27,364); LOS(16.6%; n¼ 10,874); or IRB (8.9%; n¼ 5847). Table 1displays the baseline subject demographic and clinical

Table 1. Baseline demographic, clinical, and economic characteristics by ARB therapy – limited study samplea.

OM cohort(n¼ 21,494)

VAL cohort(n¼ 27,364)

LOS cohort(n¼ 10,874)

IRB cohort(n¼ 5847)

p-value

Age (years), mean (SD) 51.8 (11.5) 53.7 (12.1) 54.8 (12.5) 54.4 (12.3) 50.001Males (%) 53.08 46.88 46.41 51.87 50.001MAPD enrollee (%) 4.69 6.81 8.43 8.45 50.001Region (%)

Northeast 7.10 8.45 9.03 12.71 50.001Midwest 21.92 23.44 30.70 22.44South 59.66 58.44 49.48 56.53West 11.31 9.68 10.80 8.31

Race/ethnicity (%)Caucasian 64.33 64.90 63.84 63.18 50.001African-American 6.50 7.70 7.19 7.66Asian 1.37 1.35 1.74 1.37Hispanic 5.02 4.68 4.63 4.72Other 0.53 0.59 0.82 0.84Missing 22.25 20.78 21.79 22.23

Comorbidities of interest (%)Depression 7.33 7.14 7.42 6.38 0.062Hypercholesterolemia or hypertriglyceridemia 46.45 47.57 46.92 50.33 50.001Peripheral vascular disease 1.48 1.76 2.19 2.24 50.001Left ventricular hypertrophy (cardiomegaly) 1.06 1.03 1.37 1.18 0.029Cerebrovascular disease other than stroke or TIA 0.95 1.21 1.40 1.47 50.001

Quan–Charlson comorbidity score, mean (SD) 0.26 (0.66) 0.30 (0.71) 0.34 (0.78) 0.34 (0.79) 50.001Index prescriptions (%)

Single-agent ARB 53.47 47.17 50.99 54.51 50.001Two-agent fixed-dose combination ARB/HCTZ 46.53 52.83 49.01 45.49

Indicators for baseline non-ARB medication useDiuretics (single-agent diuretic or fixed-dose

combination potassium-sparing diureticþ HCTZ)12.70 12.68 16.08 12.35 50.001

ACE inhibitors (single-agent ACE inhibitor or fixed-dosecombination ACE inhibitorþ HCTZ)

16.57 15.44 20.89 15.19 50.001

Calcium channel blockers (single-agentcalcium channel blocker)

11.97 11.99 13.68 14.28 50.001

PMPM all-cause healthcare resource utilization, mean (SD)Ambulatory visits 1.16 (1.10) 1.19 (1.16) 1.23 (1.20) 1.21 (1.20) 50.001ED visits 0.05 (0.25) 0.05 (0.26) 0.05 (0.21) 0.05 (0.28) 0.054Hospital stays 0.00 (0.03) 0.01 (0.03) 0.01 (0.03) 0.01 (0.04) 50.001

PMPM all-cause healthcare costs, mean (SD)Medical costs $326 (871) $352 (904) $360 (975) $357 (935) 0.002Pharmacy costs $95 (180) $88 (181) $101 (198) $100 (192) 50.001

aARB therapy includes single-agent or two-agent fixed-dose combination with hydrochlorothiazide.ACE, angtiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ED, emergency department; HCTZ, hydrochlorothiazide; IRB, irbesartan; LOS, losartan;MAPD, Medicare Advantage Part D; OM, olmesartan; PMPM, per-member-per-month; SD, standard deviation; TIA, transient ischemic attack; VAL, valsartan.

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characteristics by ARB cohort. Statistically significant dif-ferences between the four ARB cohorts were detected forall baseline subject demographics characteristics. Subjectsin the OM cohort were slightly younger, and had the high-est proportion of males and commercial enrollees. Baselineclinical and economic characteristics differed by cohorts,except for the percentage of subjects with evidence ofdepression and the mean PMPM all-cause emergencydepartment visits. While the baseline Quan–Charlsoncomorbidity score differed by ARB cohort in the limitedstudy sample (p50.001), the range of mean values acrosscohorts were in a narrower range (0.26 to 0.34) than in thefull sample (0.59 to 1.03).

ARB therapy characteristics and follow-upcardiac events

Results describing follow-up clinical outcomes for the fulland limited samples are presented next; Table 2 presentsclinical, cost, and resource use outcomes for the limitedstudy sample.

Full sampleIn the full sample, subjects had a mean follow-up rangingfrom 860 days in the OM cohort to 932 days in the LOScohort. The proportion of subjects with at least one cardiacevent in the follow-up differed by cohort (p50.001), with

the OM cohort containing the lowest proportion of indi-viduals experiencing an event (7.40%) compared to theVAL, LOS and IRB cohorts (12.50%, 16.18% and 13.36%,respectively). Similar differences existed among the OM,VAL, LOS and IRB cohorts for individual cardiac eventcomponents of the above composite: heart failure (4.69%,9.03%, 12.02% and 9.30%, respectively; p50.001); stroke(1.49%, 2.50%, 3.14% and 2.77%, respectively;p50.001); myocardial infarction (1.11%, 1.69%, 2.24%and 1.71%, respectively; p50.001); acute ischemic heartdisease diagnosis (1.18%, 1.83%, 2.47% and 2.18%,respectively; p50.001); and myocardial infarction/ische-mic heart disease-related surgery (1.90%, 2.49%, 3.22%and 3.17%, respectively; p50.001).

Results from Cox proportional hazards regressionmodels controlling for baseline demographics and clinicalcharacteristics are presented in Table 3, displaying risk ofa follow-up cardiac event by ARB cohort. The model pre-dicted a higher adjusted risk of cardiac event for subjects inthe VAL cohort (HR¼ 1.261, p50.001), LOS cohort(HR¼ 1.307, p50.001), and IRB cohort (HR¼ 1.222,p50.001) compared to subjects in the OM cohort.Further, this model showed that baseline comorbiditiesincluding heart failure (HR¼ 5.367, p50.001) andstroke or transient ischemic attack (HR¼ 1.388,p50.001) were predictors with large coefficients, but base-line myocardial infarction was not a significant predictor(HR¼ 1.109, p¼ 0.121). Since CV event outcomes were

Table 2. Follow-up clinical and economic outcomes by ARB therapy – limited study samplea.

OM cohort(n¼ 21,494)

VAL cohort(n¼ 27,364)

LOS cohort(n¼ 10,874)

IRB cohort(n¼ 5847)

p-value

Length of follow-up (days), mean (SD) 860.7 (425.4) 862.8 (453.3) 933.1 (474.8) 890.1 (449.0) 50.001MPR, mean (SD) 0.80 (0.19) 0.82 (0.18) 0.83 (0.18) 0.81 (0.19) 50.001Clinical outcomes, n (%)

Cardiac event 736 (3.42) 1315 (4.81) 603 (5.55) 302 (5.17) 50.001Heart failure 373 (1.74) 741 (2.71) 352 (3.24) 171 (2.92) 50.001Stroke 172 (0.80) 308 (1.13) 148 (1.36) 74 (1.27) 50.001MI 145 (0.67) 204 (0.75) 86 (0.79) 36 (0.62) 0.471Acute IHD diagnosis 131 (0.61) 217 (0.79) 90 (0.83) 49 (0.84) 0.048MI/IHD-related surgery 226 (1.05) 341 (1.25) 123 (1.13) 74 (1.27) 0.204

PMPM all-cause healthcare resource utilization, mean (SD)Ambulatory visits 0.98 (0.94) 1.06 (1.00) 1.10 (1.02) 1.09 (1.06) 50.001ED visits 0.05 (0.20) 0.05 (0.20) 0.05 (0.18) 0.05 (0.20) 0.642Hospital stays 0.01 (0.02) 0.01 (0.03) 0.01 (0.03) 0.01 (0.03) 50.001

PMPM all-cause healthcare costs, mean (SD)Overall costs $552 ($1058) $593 ($1164) $607 ($1317) $607 ($1.277) 50.001Medical costs $388 ($994) $417 ($1100) $426 ($1260) $423 ($1197) 0.005Pharmacy costs $164 ($208) $176 ($217) $181 ($218) $184 ($282) 50.001

PMPM HTN-attributable healthcare costs, mean (SD)Overall costs $209 ($626) $239 ($801) $236 ($978) $229 ($774) 50.001Medical costs $161 ($625) $182 ($800) $180 ($977) $177 ($774) 0.018Pharmacy costs $48 ($27) $57 ($31) $56 ($30) $52 ($31) 50.001

aARB therapy includes single-agent or two-agent fixed-dose combination with hydrochlorothiazide.Limited study sample excludes subjects with baseline evidence of diabetes, heart failure, stroke, transient ischemic attack, myocardial infarction, ischemic heartdisease (other than myocardial infarction), chronic kidney disease, other kidney disease, or any baseline pharmacy claims for a ß-blocker.ARB, angiotensin II receptor blocker; ED, emergency department; HTN, hypertension; IHD, ischemic heart disease; IRB, irbesartan; LOS, losartan; MI, myocardialinfarction; MPR, medication possession ratio; OM, olmesartan; PMPM, per-member-per-month; SD, standard deviation; VAL, valsartan.

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identified on the basis of primary and secondary diagnosiscodes, a univariate sensitivity analysis was conducted todetermine differences in the rate of events on the basis ofprimary diagnosis only. The trend was similar with theproportion of patients with the observed composite CVevents on the basis of primary diagnosis only being thelowest in the OM cohort (4.24%) relative to VAL(7.13%), LOS (9.41%), and IRB (7.55%).

Limited study sampleSubjects in the limited study sample had a mean follow-upranging from 861 days in the OM cohort to 933 days in theLOS cohort (Table 2). The mean medication possessionratio (MPR) differed across cohorts; however, the observedcohort values were close (OM¼ 0.80; VAL¼ 0.82;LOS¼ 0.83; and IRB¼ 0.81; p50.001).

The percentage of subjects identified as having afollow-up cardiac event was considerably lower in eachof the ARB cohorts in the limited study sample, comparedto the full sample and the percentage continued to be thelowest in OM cohort. Of the events included in the cardiacevent composite variable, the proportion of individualsexperiencing a follow-up event was 3.42% in the OMcohort, 4.81% in the VAL cohort, 5.55% in the LOScohort, and 5.17% in the IRB cohort (Table 2). Figure 2presents failure estimates (experiencing a cardiac event)by ARB cohort for the Kaplan–Meier function, whichshows a separation between the OM and other ARBcohorts starting around the 1-year mark.

Cox proportional hazards regression models of firstfollow-up cardiac event are presented for the limitedstudy sample in Table 3. The model predicted a higheradjusted risk of composite cardiac event for subjects inthe VAL cohort (HR¼ 1.242, p50.001), LOS cohort

(HR¼ 1.178, p¼ 0.003), and IRB cohort (HR¼ 1.179,p¼ 0.016) compared to subjects in the OM cohort.Compared to subjects in the OM cohort, the model pre-dicts a higher adjusted risk for heart failure for subjectsin the VAL (HR¼ 1.300, p50.001), LOS (HR¼ 1.242,p¼ 0.004), and IRB (HR¼ 1.228, p¼ 0.027) cohorts.ARB cohorts did not differ significantly with respect tostroke, myocardial infarction, or myocardial infarction/ischemic heart disease-related surgery; however, theadjusted estimated risk of acute ischemic heart diseasediagnosis event was higher for subjects in the VALcohort (HR¼ 1.256, p¼ 0.041) compared to subjects inthe OM cohort. Univariate sensitivity analysis was con-ducted to determine differences in the rate of events on thebasis of primary diagnosis only. Similar to the full sample,the proportion of patients with observed composite CVevents on the basis of primary diagnosis only was thelowest in the OM cohort (2.11%) relative to VAL(2.86%), LOS (3.26%), and IRB (2.94%).

Follow-up healthcare resource utilization

Full sampleFor the full sample, adjusted results from the negativebinomial regression models controlling for baseline demo-graphics and clinical characteristics indicated that the rateof follow-up all-cause ambulatory visits and inpatient staysand the rate of HTN-attributable ambulatory visits, emer-gency department visits, and hospital stays was higher inthe VAL, LOS, and IRB cohorts relative to the OM cohort(Table 4). The rates of all-cause inpatient days were higherin the VAL and LOS cohorts, but not the IRB cohortscompared to OM.

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Table 3. Cox regression results modeling first follow-up cardiac event.

Modela Limited study sample Full sample

HR 95% CI p-value HR 95% CI p-value

Cardiac event compositeARB cohort (Ref¼ OM)b

VAL 1.242 1.134 1.361 50.001 1.261 1.200 1.326 50.001LOS 1.178 1.057 1.312 0.003 1.307 1.236 1.382 50.001IRB 1.179 1.031 1.348 0.016 1.222 1.142 1.308 50.001

Heart failureARB cohort (Ref¼ OM)b

VAL 1.300 1.147 1.474 50.001 1.309 1.230 1.393 50.001LOS 1.242 1.074 1.438 0.004 1.365 1.274 1.463 50.001IRB 1.228 1.024 1.472 0.027 1.248 1.147 1.358 50.001

Acute IHD diagnosisARB cohort (Ref¼ OM)b

VAL 1.256 1.009 1.564 0.041 1.182 1.049 1.331 0.006LOS 1.135 0.866 1.488 0.359 1.283 1.126 1.461 50.001IRB 1.198 0.862 1.667 0.282 1.230 1.049 1.442 0.011

aMultivariate models were adjusted for age, gender, geographic region, race/ethnicity, insurance type, ARB therapy type, number of baseline non-ARB hypertensionmedication classes, and baseline comorbidities; covariate results are not presented.bARB therapy includes single-agent or two-agent fixed-dose combination with hydrochlorothiazide.Limited study sample excludes subjects with baseline evidence of diabetes, heart failure, stroke, transient ischemic attack, myocardial infarction, ischemic heartdisease (other than myocardial infarction), chronic kidney disease, other kidney disease, or any baseline pharmacy claims for a ß-blocker.ARB, angiotensin II receptor blocker; CI, confidence interval; HR, hazard ratio, IHD, ischemic heart disease; IRB, irbesartan; LOS, losartan; OM, olmesartan; Ref,reference; TIA, transient ischemic attack; VAL, valsartan. Model results for outcomes including stroke, MI, and MI/IHD related surgery events not presented as thesewere non-significant.

Table 4. Negative binomial regression models of follow-up healthcare resource utilization.

Modela Limited study sample Full sample

IRR Wald 95% CI p-value IRR Wald 95% CI p-value

All-cause ambulatory visitsOM cohort 1.000 1.000VAL cohort 1.030 1.017 1.043 50.001 1.039 1.029 1.049 50.001LOS cohort 1.035 1.018 1.053 50.001 1.056 1.044 1.069 50.001IRB cohort 1.034 1.013 1.056 0.002 1.038 1.023 1.053 50.001

All-cause ED visitsOM cohort 1.000 1.000VAL cohort 1.001 0.961 1.043 0.955 1.026 0.997 1.056 0.078LOS cohort 0.956 0.906 1.008 0.095 1.020 0.985 1.056 0.261IRB cohort 1.076 1.007 1.150 0.030 1.058 1.014 1.105 0.010

All-cause hospital staysOM cohort 1.000 1.000VAL cohort 1.092 1.038 1.149 0.001 1.099 1.063 1.135 50.001LOS cohort 1.106 1.038 1.178 0.002 1.163 1.119 1.207 50.001IRB cohort 1.000 0.922 1.084 1.000 1.069 1.019 1.122 0.006

HTN-attributable ambulatory visitsOM cohort 1.000VAL cohort 1.054 1.040 1.067 50.001 1.054 1.044 1.064 50.001LOS cohort 1.052 1.036 1.069 50.001 1.062 1.050 1.074 50.001IRB cohort 1.035 1.014 1.056 0.001 1.037 1.023 1.052 50.001

HTN-attributable ED visitsOM cohort 1.000 1.000VAL cohort 1.220 1.133 1.314 50.001 1.208 1.152 1.267 50.001LOS cohort 1.357 1.240 1.486 50.001 1.326 1.256 1.400 50.001IRB cohort 1.177 1.049 1.321 0.006 1.163 1.086 1.246 50.001

HTN-attributable hospital staysOM cohort 1.000 1.000VAL cohort 1.081 1.026 1.140 0.004 1.096 1.060 1.134 50.001LOS cohort 1.106 1.036 1.180 0.002 1.169 1.124 1.215 50.001IRB cohort 1.011 0.930 1.099 0.805 1.085 1.034 1.140 0.001

aMultivariate models were adjusted for age, gender, geographic region, race/ethnicity, insurance type, ARB therapy type, number of baseline non-ARB hypertensionmedication classes, baseline all-cause healthcare resource utilization, baseline Quan–Charlson comorbidity score, and select baseline comorbidities not over-lapping with the Quan–Charlson comorbidity algorithms (depression, hypercholesterolemia or hypertriglyceridemia, ischemic heart disease other than myocardialinfarction [for full sample], and non-chronic kidney disease [for full sample]); covariate results are not presented.Limited study sample excludes subjects with baseline evidence of diabetes, heart failure, stroke, transient ischemic attack, myocardial infarction, ischemic heartdisease (other than myocardial infarction), chronic kidney disease, other kidney disease, or any baseline pharmacy claims for a ß-blocker.ARB, angiotensin II receptor blocker; CI, confidence interval; ED, emergency department; HTN, hypertension; IRB, irbesartan; IRR, incidence rate ratio; LOS,losartan; OM, olmesartan; VAL, valsartan.

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Limited study sampleFor the limited study sample, descriptive analyses sug-gested ARB cohort differences in follow-up healthcareresource utilization (Table 2). Adjusted results from thenegative binomial regression models controlling for base-line demographics and clinical characteristics indicatedthat the rate of follow-up all-cause ambulatory visitswere higher in the VAL (IRR¼ 1.030, p50.001), LOS(IRR¼ 1.035, p50.001), and IRB (IRR¼ 1.034,p¼ 0.002) cohorts compared to the OM cohort(Table 4). Similar results were observed in the case ofhypertension-attributable ambulatory visits. Utilizationof all-cause emergency department visits was higher forthe IRB cohort versus the OM cohort (IRR¼ 1.076,p¼ 0.030), but not different versus the LOS and VALcohorts. However, hypertension-attributable emergencydepartment visits were higher in the VAL (IRR¼ 1.220,p50.001), LOS (IRR¼ 1.357, p50.001), and IRB (1.177,p¼ 0.006) cohorts compared to the OM cohort. The ratesof both all-cause and hypertension-attributable inpatientstays were higher in the VAL (all-cause: IRR¼ 1.092,p¼ 0.001; hypertension-attributable: IRR¼ 1.081,p¼ 0.004) and LOS (all-cause: IRR¼ 1.106, p¼ 0.002;hypertension-attributable: IRR¼ 1.106, p¼ 0.002)cohorts compared to the OM cohort; there were no differ-ences between the OM and IRB cohorts. Utilization ofall-cause inpatient days was higher in the VAL cohortcompared to the OM cohort (IRR¼ 1.130, p¼ 0.002),but there were no differences between OM and the LOSand IRB cohorts.

Follow-up healthcare costs

Full sampleIn the full sample, adjusted results from generalized linearmodel regression analyses controlling for baseline demo-graphics and clinical characteristics predicted lowerall-cause PMPM costs across all cost categories (overall,medical, inpatient, pharmacy) for the OM cohort com-pared to other ARB cohorts with the exception of thecomparison between OM and IRB for medical and inpa-tient costs. The predicted mean all-cause PMPM costs(estimated from covariate-adjusted generalized linearmodels) were lower for overall costs (OM: $810, VAL:$865, LOS: $871, IRB: $853), medical costs (OM: $578,VAL: $612, LOS: $615, IRB: $600), inpatient costs (OM:$202, VAL: $229, LOS: $224, IRB: $208), and pharmacycosts (OM: $226, VAL: $247, LOS: $247, IRB: $247).

Limited study sampleFor the limited study sample, adjusted results from gener-alized linear model regression analyses predicted higheradjusted follow-up PMPM overall healthcare costs in theVAL (all-cause: CR¼ 1.067, p¼ 0.001; hypertension-

attributable: CR¼ 1.123, p50.001) and IRB cohorts(all-cause: CR¼ 1.062, p¼ 0.045) compared to the OMcohort (Table 5). Further stratification of costs suggestedthat only subjects in the VAL cohort had higher medicalcosts (all-cause: CR¼ 1.055, p¼ 0.038; hypertension-attributable: 1.111, p¼ 0.014) compared to the OMcohort. Pharmacy costs, which included the cost of theindex ARB and any other drug were higher in the VAL(all-cause: CR¼ 1.098, p50.001; hypertension-attributa-ble: CR¼ 1.164, p50.001), LOS (all-cause: CR¼ 1.077,p50.001; hypertension-attributable: CR¼ 1.127,p50.001), and IRB (all-cause: CR¼ 1.076, p50.001;hypertension-attributable: CR¼ 1.073, p50.001) cohortscompared to the OM cohort. The predicted mean all-causeand hypertension-attributable PMPM costs were lower forOM compared to other ARB cohorts across all cost cate-gories, overall, medical, and pharmacy costs.

Discussion

This study examined cardiac and economic outcomes forindividuals who were initiated on an ARB, specifically,OM or OM/HCTZ, LOS or LOS/HCTZ, VAL or VAL/HCTZ, and IRB or IRB/HCTZ. Key outcomes assessedwere time to first clinically significant cardiac event, all-cause and hypertension-attributable healthcare resourceutilization and costs. The results suggested that for subjectsinitiated on an ARB, OM was associated with a lower riskof follow-up clinically significant cardiac events, whenadjusting for covariates. In particular, OM was associatedwith a lower risk of heart failure event compared to VAL,LOS, and IRB after controlling for subject demographicand baseline clinical characteristics. There were no cohortdifferences found in the risk of stroke, myocardial infarc-tion, or myocardial infarction/ischemic heart disease-related surgery (including percutaneous coronary inter-vention); however, VAL was associated with a higheradjusted risk of acute ischemic heart disease event com-pared to OM. While hazard ratios associated with the car-diac event outcomes in the limited study sample were notas large compared to those of the full sample, there wasconsistency in terms of the treatment-related associationwith cardiac events in both samples. As a cross check,multivariate models were also run using the limited studysample as shown, but relaxing the criteria to include thosepatients with evidence of comorbid diabetes during thebaseline. This resulted in a slightly larger ‘limitedþ diabe-tes’ sample of 78,505 subjects; 24,503 subjects initiated onOM, 32,870 on VAL, 13,782 on LOS and 7350 on IRB.Cox proportional hazards regression models predicted ahigher adjusted risk of cardiac event for subjects in theVAL cohort (HR¼ 1.197, p50.001), LOS cohort(HR¼ 1.184, p50.001), and IRB cohort (HR¼ 1.213,p¼ 0.001). Thus the association between ARB therapy

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and risk for cardiac events appears to be robust and con-sistent with reference to the ARB-treated population atlarge and for various subsets.

Multivariate analyses indicated that initiation on OMwas associated with the utilization of fewer healthcareresources; on average, subjects in the OM cohort hadfewer ambulatory visits than the VAL, LOS, and IRBcohorts, and fewer inpatient stays than the VAL andLOS cohort. Subjects in the OM cohort had, on aver-age, lower all-cause costs than the VAL and IRBcohorts; however, mean all-cause medical costs werelower compared to the VAL cohort only. All-causeand hypertension-attributable pharmacy costs, on aver-age, were lower in the OM cohort compared to subjectsin the other ARB cohorts.

The predicted (estimated) mean all-cause PMPM over-all costs (limited sample) were $555 for OM, $590 forVAL, $577 for LOS, and $592 for the IRB cohort, basedon covariate-adjusted models; translating to a lower pre-dicted all-cause PMPM overall costs that ranged from $21

to $37, or $257 to $444 per-member-per-year, relative toinitiation on one of the other ARBs. Additional descrip-tive results indicated that the mean PMPM cost of ARBalone was $42 for OM, $50 for VAL, $48 for LOS, and $45IRB at branded prices. Since LOS is now available in gen-eric form, and the differences above are based on brandedprices of all ARBs, it would be reasonable that projectedcost savings will diminish upon factoring the price for thegeneric. Assuming the monthly cost of generic LOS is $10,the net incremental monthly cost of OM over the generic($42–$10¼ $32) should be factored into the projectedsavings. On an annualized basis, it is estimated that useof OM relative to generic LOS may be associated with anincremental cost of �$132 per member per year to a sav-ings of �$60 per member per year. These calculationsassume an annual incremental drug cost of $384 for OMrelative to the generic, and all-cause cost savings thatrange annually from $252 to $444. The projected savings,however, would still apply in comparisons between otherbranded ARBs.

Table 5. Generalized linear model regression results of follow-up healthcare costs.

Modela Limited Study sample Full sample

Costratio

95% confidenceinterval

p-value Predictedcosts

Costratio

95% confidenceinterval

p-value Predictedcosts

All-cause PMPM overall costsOM 1.000 $555.34 1.000 $809.73VAL 1.067 1.028 1.106 0.001 $592.31 1.068 1.039 1.098 50.001 $864.83LOS 1.039 0.991 1.089 0.116 $576.75 1.076 1.040 1.113 50.001 $871.26IRB 1.062 1.001 1.127 0.045 $589.90 1.053 1.009 1.098 0.016 $852.65

All-cause PMPM medical costsOM 1.000 $389.61 1.000 $577.55VAL 1.055 1.003 1.109 0.038 $410.93 1.059 1.019 1.100 0.003 $611.54LOS 1.024 0.960 1.093 0.468 $399.10 1.065 1.017 1.116 0.007 $615.33IRB 1.057 0.975 1.147 0.179 $411.98 1.039 0.980 1.101 0.198 $599.91

All-cause PMPM pharmacy costsOM 1.000 $162.69 1.000 $225.80VAL 1.098 1.077 1.118 50.001 $178.56 1.095 1.072 1.116 50.001 $247.21LOS 1.077 1.051 1.103 50.001 $175.21 1.094 1.076 1.111 50.001 $246.93IRB 1.076 1.044 1.108 50.001 $174.99 1.094 1.072 1.116 50.001 $246.94

HTN-attributable PMPM overall costsOM 1.000 $212.56 1.000 $324.03VAL 1.123 1.056 1.194 50.001 $238.61 1.108 1.058 1.161 50.001 $359.13LOS 1.057 0.976 1.144 0.174 $224.61 1.085 1.026 1.147 0.004 $351.46IRB 1.070 0.969 1.183 0.180 $227.54 1.027 0.958 1.101 0.457 $332.71

HTN-attributable PMPM medical costsOM 1.000 $163.43 1.000 $268.20VAL 1.111 1.021 1.208 0.014 $181.50 1.096 1.031 1.165 0.003 $293.91LOS 1.037 0.931 1.156 0.509 $169.49 1.069 0.993 1.152 0.076 $286.83IRB 1.074 0.937 1.230 0.305 $175.45 1.011 0.921 1.109 0.818 $271.13

HTN-attributable PMPM pharmacy costsOM 1.000 $48.67 1.000 $56.82VAL 1.164 1.153 1.175 50.001 $56.64 1.153 1.071 1.097 50.001 $65.51LOS 1.127 1.113 1.140 50.001 $54.84 1.125 1.115 1.136 50.001 $63.95IRB 1.073 1.057 1.089 50.001 $52.21 1.084 1.071 1.097 50.001 $61.58

aMultivariate models adjusted for age, gender, geographic region, race/ethnicity, insurance type, ARB therapy type, number of baseline non-ARB hypertensionmedication classes, log-transformed baseline all-cause medical costs and pharmacy costs, baseline Quan–Charlson comorbidity score, and select baselinecomorbidities not overlapping with the Quan–Charlson comorbidity algorithms (depression, hypercholesterolemia or hypertriglyceridemia, ischemic heart diseaseother than myocardial infarction [for full sample], and non-chronic kidney disease [for full sample]); covariate results are not presented.Limited study sample excludes subjects with baseline evidence of diabetes, heart failure, stroke, transient ischemic attack, myocardial infarction, ischemic heartdisease (other than myocardial infarction), chronic kidney disease, other kidney disease, or any baseline pharmacy claims for a ß-blocker.ARB, angiotensin II receptor blocker; HTN, hypertension; IRB, irbesartan; LOS, losartan; OM, olmesartan; PMPM, per-member-per-month; VAL, valsartan.

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How reasonable is it to expect, on average, the proj-ected cost differences? In this study, the observed differ-ences in healthcare resource utilization and costs may bepartially attributable to the generally lower incidence ofselect clinically significant cardiac events. In a previouscomparison between LOS and candesartan16,17, it wasdemonstrated that fewer cardiac events were associatedwith lower healthcare resource utilization. Numerous stud-ies have established the efficacy of ARBs in heart failure;the association between renin angiotensin system inhibi-tion and heart failure risk reduction was established in the‘Effects of high-dose versus low-dose losartan on clinicaloutcomes in patients with heart failure (HEAAL)’,wherein a higher dose of LOS was associated with a 10%risk reduction for hospitalizations and death due to heartfailure18. Two studies comparing candesartan with placeboin patients who were on ACE inhibitors or could not tol-erate ACE inhibitors showed that treatment with the ARBwas associated with reductions in hospitalizations for heartfailure19,20.

There may be various plausible explanations for thelower risk of cardiac events in the OM cohort, which arediscussed next. Differences in adherence rates to the ARBscould contribute to variations in outcomes; however, itwas observed that mean medication possession ratio andpersistence with therapy was quite similar betweencohorts. Uncontrolled hypertension is a major risk factorfor adverse cardiovascular outcomes, including the devel-opment of heart failure. In the absence of blood pressuredata, it is plausible to speculate that variation in bloodpressure levels following treatment or baseline differencesin blood pressure or disease severity could contribute toobserved differences in cardiac event rates. There aresome data to suggest that in a real-world setting, OM isassociated with greater reductions in blood pressure rela-tive to LOS, VAL, and IRB. A comparative effectivenessstudy using electronic medical records with blood pressureoutcomes data from 73,012 patients showed significantlygreater reductions in blood pressure and JNC 7 goal attain-ment with OM compared to LOS, VAL, and IRB21. Inanother observational study using data from a large nation-ally representative health plan, Miller et al. linked patientchart data to claims data, and showed that a greaterproportion of patients treated with OM achieved bloodpressure goal versus LOS, VAL, and IRB11. Other datahave demonstrated the clinical relevance of systolicblood pressure differences, and the implications for long-term cardiovascular outcomes. In a large meta-analysis,Staessen et al. have reported that between group systolicblood pressure differences of 2.0 mmHg, 2.2 mmHg and2.3 mmHg may lower the odds of observed cardiovascularevents by between 2% and 30%22.

In addition, differences in the percentage of patients onstage A or B of the HF classification could also influencethe lower risk of heart failure event in the OM cohort23.

Both stages include patients at risk for developing heartfailure, and differences in the presence of other risk factorsnot assessed in this study sample (e.g. metabolic syndrome,obesity, the use of cardiotoxins, a family history of cardio-myopathy) and/or differences in the type and severity ofstructural heart disease (e.g. unknown coronary artery dis-ease, asymptomatic valvular heart disease, type and sever-ity of left ventricular dysfunction) may have occurred.

To the extent that there were baseline differencesacross cohorts, these were adjusted by excluding a largeproportion of subjects with baseline evidence of diabetes,heart failure, stroke or transient ischemic attack, myocar-dial infarction, ischemic heart disease, chronic kidney dis-ease, or other kidney disease, which could all influence thelikelihood of follow-up cardiac events. Additionally sub-jects with any baseline pharmacy claims for a ß-blockerwere excluded; all of which resulted in ARB cohorts thatwere relatively healthy and similar in terms of their base-line clinical profile. Removing these baseline conditionsdid result in a lower proportion of subjects experiencingfollow-up cardiac event, with percentages narrowingbetween ARB cohorts. Whether the lower risk of clinicallysignificant cardiac events and consequently lower costs forsubjects who were initiated on OM are a function of supe-rior blood pressure control, differences in other risk factorsor in the type/severity of structural heart disease cannot beestablished definitively with the current data. Lastly,another rationale for differences in cardiovascular out-comes between ARBs is the individual pleiotropic effectof each drug, which is independent of the effect on bloodpressure lowering. Clinical trials have demonstrated differ-ences in cardiovascular event outcomes that have beenindependent of the effect of blood pressure, and attribut-able to the pharmacological action of the anti-hyperten-sive24–26. Differences in the pharmacodynamic propertiesof specific ARBs could contribute to variable treatmentresponse and observed differences in outcomes. For exam-ple, OM, IRB, and telmisartan have a longer half-life thanLOS, VAL, candesartan and eprosartan27–29. Moreover,OM binds to the AT1 receptor with a high degree ofinsurmountability and with greater affinity than mostother ARBs with the exception of telmisartan30. The indi-vidual pharmacodynamic properties of each ARB may fur-ther contribute to the observed benefits in cardiovascularoutcomes.

Administrative claims are a strong data asset that allowsevidence-based examination of healthcare utilization andexpenditures and typically provide robust sample sizes cou-pled with diverse patient make-ups. Nonetheless, theyhave some intrinsic limitations that should be consideredin the context of this retrospective study. Due to the obser-vational nature of claims data, evidence of a pharmacy filldoes not guarantee that a subject adhered to the regimen.Furthermore, clinically significant cardiac events mayresult from a multitude of factors, and no causal link to

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treatment may be inferred from claims data. Futureresearch of potential importance would involve the mea-surement of blood pressure change in the ARB cohorts andtheir association with cardiac event outcomes. Anotherlimitation of this study is the potential selection bias asso-ciated with subjects included in each cohort due to varia-tions in the indications of each study ARB, physicianprescribing patterns, and differences in the reimbursementstatus of each ARB. The analyses attempted to minimizethis limitation by stratifying subjects in each cohort whowere relatively healthy, and excluding subjects with vari-ous baseline comorbidities that could confound the results.This approach added to the internal validity of the study byminimizing the variation in baseline characteristics acrosscohorts. On the other hand, the exclusion of the patientswith baseline comorbidities (diabetes, heart failure, stroke,transient ischemic attack, myocardial infarction, ischemicheart disease) to form the limited sample also resulted inthe exclusion of the majority of events from the analysis,i.e., the total number of patients with composite CVevents excluded (n = 11,093) represented 79% of patientswith a composite CV event in the full population (n =14,049). The CV event rate trend observed across cohortsin the full and limited sample was also observed in thissubset of patients with the baseline comorbidities.Patients in the OM cohort had the lowest proportion ofcomposite CV events (14.17%) compared to patients inthe VAL (21.92%), LOS (25.59%), and IRB (21.52%)cohorts. The clinical findings from this research may begeneralizable to other populations, given the cohort sizeand representativeness of the plan across the US, but mustbe considered in light of the above study limitations.Economic outcomes may be less generalizable to otherregions of the world and healthcare systems where reim-bursement may be capitated or greater risk is assumed bythe provider.

Conclusion

In our study sample from a large nationally representativeUS health plan, patients with a diagnosis of hypertensionwho were initiated on treatment with OM experiencedfewer cardiac events, in particular heart failure events,when compared to hypertensive subjects initiated onVAL, LOS or IRB, over an average follow-up thatranged between 861 to 933 days across cohorts.Individuals initiated on OM also experienced lowerfollow-up healthcare resource utilization and costs whencompared to the other ARBs.

TransparencyDeclaration of fundingThis study and manuscript preparation were funded by DaiichiSankyo Inc., Parsippany, NJ, USA.

Declaration of financial relationshipsJ.S., P.B., and S.I. are employees of Innovus, which was con-tracted by the sponsor to conduct the study. K.R. and S.P. areemployees of the sponsor.

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