Cost Analysis of Amlodipine versusEnalapril in Patients with Coronary ArteryDisease and Normal Blood PressureFindings from the CAMELOT Economic Substudy

Joseph Menzin,1 Luke Boulanger,1 Simon Tang,2 Kamlesh Thakker2 and Steven E. Nissen3

1 Boston Health Economics, Inc., Waltham, Massachusetts, USA

2 Pfizer Inc., New York, New York, USA

3 Cleveland Clinic Foundation, Cleveland, Ohio, USA

Abstract Objectives: To analyse 2-year hospitalization and cost data collected during a

prospective, double-blind, randomized, controlled trial comparing amlodi-

pine, enalapril and placebo in normotensive patients with coronary artery

disease (CAD).

Methods: All patients who were enrolled in the CAMELOT study were in-

cluded in this economic substudy. Patients with CAD and normal blood

pressure were randomized to amlodipine, enalapril or placebo, and followed

up for 24 months (between 1999 and 2004). Data on hospitalizations and

medication use were obtained from the clinical trial. Costs were assigned from

secondary sources. Total costs ($US, year 2004 values) were estimated as the

sum of costs associated with cardiovascular hospitalizations, study medica-

tions and concomitant cardiovascular medications. Costs and resource use

were analysed by treatment arm overall and for selected patient subgroups.

Cost differences were evaluated using nonparametric bootstrap techniques.

Results: Of 1991 patients enrolled, 663 were treated with amlodipine, 673

were treated with enalapril and 655 were treated with placebo. Significantly

fewer patients were hospitalized for cardiovascular reasons in the amlodipine

group (16.4%) than in the placebo group (22.7%; p < 0.01), but not compared

with the enalapril group (20.1%; p = 0.09). The amlodipine group also had

numerically fewer days in hospital per patient (1.1) than the enalapril (1.3)

and placebo (1.5) groups. Mean 2-year per-patient costs in the amlodipine

group were estimated to be $US609 and $US717 lower than for the placebo

and enalapril groups, respectively.

Conclusions: These results suggest that use of amlodipine may reduce costs of

care among CAD patients with normal blood pressure.

ORIGINAL RESEARCH ARTICLEAppl Health Econ Health Policy 2008; 6 (2-3): 157-162

1175-5652/08/0002-0157/$48.00/0

ª 2008 Adis Data Information BV. All rights reserved.

Background and Objectives

The CAMELOT (Comparison of Amlodipineversus Enalapril to Limit Occurrences ofThrombosis) study was a multicentre, double-blind, randomized, controlled trial designed tocompare the efficacy of a calcium channel an-tagonist (amlodipine) with that of an ACE in-hibitor (enalapril) and with placebo to evaluatewhether patients with coronary artery disease(CAD) and normal blood pressure can benefitfrom further antihypertensive therapy.[1,2] Thestudy found that, over 2 years, participantsrandomized to amlodipine had a significantly(p< 0.05) lower likelihood of cardiovascularevents than those administered placebo, butnot significantly lower than those administeredenalapril (p= 0.09).[1]

Economic outcomes are increasingly collectedalongside health outcomes in clinical trials, aspayers grow more interested in the cost effec-tiveness of available therapies.[3] While differ-ences in the number of cardiovascular events maytranslate into differences in hospitalization ratesand costs, the cost of drug therapy needs to beplaced in the context of these potential benefits.For this reason, we undertook a prospectiveeconomic substudy in conjunction with CAME-LOT. The objectives were to document the ratesof cardiovascular-related hospitalizations andcosts of care during the 2 years of each patient’sparticipation in the study.

Methods

All patients who were randomized to receivetreatment during the CAMELOT trial were in-cluded in this economic substudy. The patientcharacteristics and methods of the CAMELOTstudy have been reported previously.[1] Briefly, atotal of 1991 patients with CAD (defined as >20%stenosis by coronary angiography) and normaldiastolic blood pressure (defined as <100 mmHg)were randomized in a double-blind manner toreceive amlodipine besylate (10 mg), enalapril(20 mg) or placebo for 24 months. The study wasconducted between April 1999 and March 2004at 100 study sites in the US, Canada and Europe.

Study Measures

Resource utilization data were prospectivelycollected in the CAMELOT clinical trial todocument hospitalizations (cardiovascular andother), study medications and concomitantcardiovascular-related medications. Several sec-ondary sources of data were employed toestimate unit costs for cardiovascular hospitali-zations andmedications. Overall, cardiovascular-related costs of care were estimated as the sumof costs for study medications, concomitantcardiovascular medications and cardiovascularhospitalizations.

Hospitalization data were obtained for allacute-care admissions that occurred during the2 years after study enrollment. Both overall andICU lengths of stay were calculated for eachhospitalization. Cardiovascular hospitalizationswere defined as acute-care admissions for one ormore of the following major coronary events pre-specified in the CAMELOT protocol as end-points: myocardial infarction, congestive heartfailure, resuscitated cardiac arrest, coronary re-vascularization, new-onset peripheral vasculardisease, hospitalized angina, non-fatal stroke andtransient ischaemic attack. When multiple trialendpoint events occurred during a single hospi-talization, multiple reasons for admission wereassigned to the stay (e.g. angina and revascular-ization occurring during same stay were countedas both angina and revascularization).

Secondary sources of data were used to esti-mate costs. For cardiovascular hospitalizations,the mean total charge per stay was estimatedbased on discharge diagnoses and proceduresused for acute-care hospital stays included in theHealthcare Cost and Utilization Project (HCUP)database.[4] Charges were converted to costsusing hospital-specific cost-to-charge ratios[5]

and the costs for inpatient physician services wereassigned using the Medicare physician fee sche-dule.[6] These costs per stay were then calculatedas the cost per day of inpatient treatment andapplied to the number of hospital days docu-mented for CAMELOT participants for the samediagnosis. The HCUP database did not containICU days, so the estimated mean daily costs were

158 Menzin et al.

ª 2008 Adis Data Information BV. All rights reserved. Appl Health Econ Health Policy 2008; 6 (2-3)

based on the overall length of stay for each admis-sion. Average wholesale prices were obtainedfrom the RED BOOK� database[7] to assign unitcosts to study medications and other cardiovas-cular medications used by CAMELOT partici-pants. Generic prices were used where applicable,including for enalapril. Costs incurred in thesecond year of follow-up were discounted at arate of 3%. All costs were expressed in $US,year 2004 values.

Data Analyses

The proportion of patients in each study armwho experienced at least one cardiovascular hos-pitalization was analysed using the Cochran-Mantel-Haenszel test. This was the only economicmeasure that was tested, as specified prospectivelyin the substudy analytic plan. In addition, a de-scriptive analysis of this measure was undertakenfor patient subgroups defined by the followingbaseline characteristics: age (<65 vs ‡65 years); sex;sitting systolic blood pressure (relative to theCAMELOT study mean); statin dispensed versusnot dispensed; and presence of diabetes mellitus,metabolic syndrome and impaired fasting glucose.

To estimate 95% confidence intervals for costs,nonparametric bootstrapping techniques wereused, as cost data were notNormally distributed.[8]

Based on the simulated distribution of costs, wealso calculated the likelihood that amlodipinewas cost saving relative to placebo and enalapril.[9]

All data analyses were conducted using SASversion 9.1 (SAS Institute, Cary, NC, USA).

Results

There were 663 patients in the amlodipinegroup, 673 in the enalapril group and 655 in theplacebo group. In all three study arms, the meanage was approximately 57 years, and the majorityof patients were White males (table I). Studyparticipants had high use rates of concomitantmedications, with 95% taking aspirin, 83% usingstatins and 76% using b-adrenoceptor antago-nists (b-blockers). The mean baseline bloodpressure was approximately 129/77 mmHg for allthree treatment arms.[1]

Hospitalizations

During the 2-year study period, the propor-tion of patients who were hospitalized for anycardiovascular cause was lower in the amlodipinegroup than in the placebo group (p < 0.01) but notlower than in the enalapril group (p = 0.09)[table II]. The amlodipine group also hadnumerically fewer hospital days per patient (1.1)

Table I. Demographics of study participants

Measure Amlodipine

(n= 663)Enalapril

(n = 673)Placebo

(n =655)

Age

<65 y (%) 73.5 70.1 76.0

‡65 y (%) 26.6 29.9 24.0

mean age (y) 57.3 58.5 57.2

SD 9.7 9.9 9.5

Male (%) 76.3 71.9 73.0

White (%) 89.4 89.3 89.0

Days of follow-up

mean 719.9 728.0 729.3

SD 124.6 122.4 115.6

Table II. Cardiovascular-related hospital admissions for study

patients, by treatment arm

Parameter Amlodipine

(n =663)Enalapril

(n =673)Placebo

(n =655)

Percentage of patients

hospitalized for:

angina and no

revascularization

5.0 7.1 8.1

angina and

revascularization

3.8 7.4 6.3

myocardial infarction 2.1 1.6 2.9

other cardiovascular

disease diagnoses

1.5 2.2 2.0

revascularization only 7.1 7.4 10.1

any reasona,b 16.4 20.1 22.7

Mean cardiovascular-

related hospitalizations

per patient (95% CI)

0.25

(0.21, 0.29)

0.32

(0.28, 0.36)

0.36

(0.31, 0.40)

a Some patients were in more than one category.

b Proportion hospitalized was significantly lower for amlodipine vs

placebo (p <0.01), but not for amlodipine vs enalapril (p =0.09).

Findings from the CAMELOT Economic Substudy 159

ª 2008 Adis Data Information BV. All rights reserved. Appl Health Econ Health Policy 2008; 6 (2-3)

than the enalapril (1.3 days) and placebo (1.5days) groups (table III). The largest benefits ofamlodipine in terms of the likelihood of cardio-vascular hospitalization were seen in women,patients aged >65 years, patients with diabetesmellitus and those who were dispensed HMG-CoA reductase inhibitors (statins) [table IV].

Costs

The mean inpatient costs assigned to the staysobserved in the CAMELOT study are shown intable V. The average cost per stay ranges fromabout $US5900 for angina without revascular-ization to $US30 100 for coronary artery bypassgraft. Mean daily costs are highest for anginawith percutaneous transluminal coronary angio-plasty and stent, and lowest for congestive heartfailure.

The overall mean cost per patient over 2 yearswas $US8152 for the amlodipine group, whichwas an average of $US717 less than for theenalapril group and $US609 less than for theplacebo group (table VI). Use of amlodipineresulted in cost savings versus placebo andenalapril in 74% and 81% of bootstrap simula-tions, respectively.

Mean costs varied among patient subgroups.For females, patients aged ‡65 years, statin usersand patients with metabolic syndrome, mean2-year per-patient costs of cardiovascular-relatedcare were estimated to be approximately$US1000–5000 lower with amlodipine than withenalapril, and approximately $US1000–2000lower than with placebo; however, the effects ofamlodipine versus enalapril or placebo on the

Table III. Cardiovascular-related hospital days per patient, by

treatment arm

Cardiovascular-related

hospital days

Amlodipine

(n = 663)Enalapril

(n =673)Placeboa

(n= 654)

ICU or CCU days

Mean 0.3 0.4 0.4

SD 1.5 1.8 1.8

Non-ICU and non-CCU days

Mean 0.8 0.9 1.0

SD 2.8 2.9 3.3

Total

Mean 1.1 1.3 1.5

SD 3.5 3.8 4.0

Minimum 0 0 0

Median 0 0 0

Maximum 41 46 41

a One patient was excluded from this analysis due to missing

admission and discharge dates.

CCU = coronary care unit.

Table IV. Cardiovascular hospitalizations by treatment arm and patient subgroup

Patient subgroup Cardiovascular hospitalizations (%) Rate ratio (95% CI)

AML ENA PL AML vs ENA AML vs PL

<65 years old 16.8 18.6 21.5 0.90 (0.63, 1.23) 0.78 (0.54, 1.02)

‡65 years old 15.3 23.4 26.8 0.66 (0.35, 1.00) 0.57 (0.29, 0.85)

Male 17.4 18.2 22.6 0.96 (0.68, 1.31) 0.77 (0.53, 0.99)

Female 13.4 24.9 23.2 0.54 (0.26, 0.82) 0.58 (0.29, 0.91)

Blood pressure < CAMELOT mean 15.0 19.1 21.2 0.79 (0.50, 1.12) 0.71 (0.44, 0.97)

Blood pressure ‡CAMELOT mean 18.0 21.2 24.4 0.85 (0.55, 1.20) 0.74 (0.46, 1.00)

Statin dispensed 16.7 21.8 24.1 0.77 (0.53, 0.97) 0.69 (0.47, 0.85)

Statin not dispensed 15.2 12.2 15.5 1.24 (0.61, 2.72) 0.98 (0.46, 2.04)

Diabetes mellitus 19.1 29.7 29.2 0.64 (0.30, 1.03) 0.65 (0.31, 1.04)

No diabetes mellitus 15.9 18.0 21.1 0.88 (0.63, 1.18) 0.75 (0.52, 0.96)

Metabolic syndrome 14.9 23.4 21.9 0.64 (0.37, 0.88) 0.68 (0.40, 0.96)

No metabolic syndrome 17.6 17.9 23.3 0.98 (0.67, 1.41) 0.75 (0.49, 1.00)

Impaired fasting glucose 12.6 19.8 23.1 0.64 (0.29, 1.19) 0.55 (0.24, 0.95)

Normal fasting glucose 17.4 20.1 22.7 0.86 (0.62, 1.13) 0.76 (0.53, 0.97)

AML = amlodipine; ENA = enalapril; PL =placebo.

160 Menzin et al.

ª 2008 Adis Data Information BV. All rights reserved. Appl Health Econ Health Policy 2008; 6 (2-3)

cost of cardiovascular care were limited foryounger patients, males, those without metabolicsyndrome and those not dispensed a statin (datanot shown).

Discussion

In this prospective cost analysis conducted aspart of the CAMELOT trial, we found thatamlodipine reduces the risk of cardiovascularhospitalization significantly more than placebo,and numerically more than enalapril. The riskof cardiovascular-related hospitalization was

reduced most in women, patients aged ‡65 years,those dispensed statins and those with diabetesmellitus. Overall 2-year mean costs of cardiovas-cular hospitalization and medications wereapproximately $US600–700 lower with amlodi-pine than with enalapril or placebo.

Our findings, which showed a reduction in thelikelihood of cardiovascular hospitalization withamlodipine, closely align with the main clinicalfindings from CAMELOT regarding the primarycomposite endpoint, as would be expected. In themain study, it was suggested that the anti-anginalproperties of amlodipine and blood pressurereductions observed (relative to placebo) arepossible explanations of the clinical benefitsobserved.[1]

Our analysis has several limitations. First,logistical considerations meant that not all ele-ments of resource use were captured. We limitedour analysis to the resources that were pro-spectively captured in the CAMELOT study,which were medications and hospitalizations. Wedid not examine the use or costs of other services,such as outpatient physician visits or laboratorytests. We also did not evaluate indirect costs, suchas the value of time lost from work due to illnessor the possible quality-of-life benefits of avoidinghospitalizations.

While our study had the advantage of pro-spective collection of resource utilization datawithin the CAMELOT trial, our findings aresubject to the accuracy with which we appliedcosts to the resources used. For cost estimation,we primarily relied upon a database of hospital

Table V. Mean overall and daily costs ($US, year 2004 values) of

inpatient care for most common reasons for admission

Reason for

hospitalization

Mean inpatient

cost per stay

Mean length

of stay (days)

Mean

cost per

day

Angina without

revascularization

5 884 2.7 2 210

Angina with PTCA

and stent

13 251 1.6 8 373

Angina with PTCA

and no stent

12 200 1.5 7 873

Congestive heart

failure

10 205 5.6 1 822

Stroke or transient

ischemic attack

8 980 4.9 1 847

Peripheral

vascular disease

9616 4.6 2 106

CABG 30 077 8.2 3 685

PTCA with stent 14 220 2.1 6 689

CABG = coronary artery bypass graft; PTCA = percutaneous trans-

luminal coronary angioplasty.

Table VI. Mean costs ($US, year 2004 values) per patient, by component and treatment group

Measure Amlodipine Enalapril Placebo

Patients (n) 663 673 655

Cardiovascular-related admissions [mean (SD)] 4 590 (14 885) 5 878 (16 115) 6 387 (17 406)

Study medications [mean (SD)] 1 343 (636) 815 (419) 0 (0)

Concomitant medications [mean (SD)] 2 219 (2 233) 2 176 (1 544) 2 373 (1 978)

Overall costs [mean (SD)] 8 152 (15 104) 8 869 (16 419) 8 761 (17 647)

Incremental cost [mean (95% CIa)]

amlodipine minus enalapril -717 (-2398, 963) NA NA

amlodipine minus placebo -609 (-2360, 1 194) NA NA

a Obtained via nonparametric bootstrapping technique.

NA= not applicable.

Findings from the CAMELOT Economic Substudy 161

ª 2008 Adis Data Information BV. All rights reserved. Appl Health Econ Health Policy 2008; 6 (2-3)

discharge summaries, which are vulnerable tocoding inaccuracies.[10] Furthermore, approxi-mately 10% of subjects were from non-UScentres. We applied US costs to all observedhospitalizations regardless of country. Finally,the CAMELOT trial was powered around clin-ical rather than economic outcomes, and costdata often exhibit considerable variability. Forthis reason, cost data were analyzed descriptively.However, it is notable that nonparametric boot-strap analyses suggest that amlodipine is reason-ably likely to be cost saving.

Our results align with the conclusions of pre-vious model-based economic analyses that foundcost savings and lower cardiovascular hospitali-zation rates with amlodipine. Casciano et al.[11]

constructed a Markov model using data fromPREVENT (Prospective Evaluation of the Vas-cular Effects of Norvasc Trial), a pilot study forCAMELOT. As in CAMELOT, PREVENTparticipants had CAD and were randomized toeither amlodipine or placebo. In the model,healthcare payers saved $US2566 when CADpatients were administered amlodipine over a3-year period (year 1999 value). Most of thesesavings were realized through reductions in car-diovascular hospitalizations.

Conclusion

This economic substudy of the CAMELOTtrial suggests that amlodipine may reduce costs ofcare among CAD patients with normal bloodpressure. Further analyses of the cost effective-ness of amlodipine in this patient population arewarranted.

Acknowledgements

The authors gratefully acknowledge Lisa M. Lines, MPH,ELS, of Boston Health Economics for editorial assistancewith the manuscript. Financial support for this studywas provided by Pfizer Inc., Global Outcomes Research,

New York, NY, USA, to Boston Health Economics, Inc. Jo-seph Menzin and Luke Boulanger received research fundingfrom Pfizer Inc. Simon Tang and Kamlesh Thakker are em-ployees of Pfizer Inc. For Steven E. Nissen’s conflicts of in-terest, please see the supplementary material [‘ArticlePlus’] athttp://healtheconomics.adisonline.com.

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Correspondence: Dr Joseph Menzin, Boston Health Eco-nomics, Inc., 20 Fox Road, Waltham, MA 02451, USA.E-mail: jmenzin@bhei.com

162 Menzin et al.

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