thomas s. rector, phd, inder s. anand, md, david nelson, phd, kristine ensrud, md and ann bangerter,...
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Thomas S. Rector, PhD, Inder S. Anand, MD, David Nelson, PhD,
Kristine Ensrud, MD and Ann Bangerter, MS
CHF QUERI NETWORK
November 8, 2007
VA Medical Center, Minneapolis, MN
Supported by HSR&D Grant #05-243-1
Effectiveness of Controlled-Release Effectiveness of Controlled-Release Metoprolol versus Carvedilol as Metoprolol versus Carvedilol as Prescribed for Veterans with Heart FailurePrescribed for Veterans with Heart Failure
Describe the prescribing of carvedilol and CR metoprolol for veterans with heart failure
Test the null hypothesis that the time to hospitalization or death after the first prescription of CR metoprolol versus carvedilol would not be different
Research ObjectivesResearch Objectives
National PBM data searched for first VA prescription for either beta-blocker in the period from Oct 1999 to Sept 2003– Excluded if had prescription for any
beta-blocker in prior year– Excluded if did not have any VA
prescriptions in prior year– Date first prescription dispensed = index
date
Methods: Cohort IdentificationMethods: Cohort Identification
National VA inpatient and outpatient administrative records searched to confirm a diagnosis of heart failure within 2 years before the index date
Required enrollment in fee-for-service Medicare during year prior to index date for more complete ascertainment of health care utilization and co-morbidity
Methods: Cohort IdentificationMethods: Cohort Identification
Demographics including VA station Outpatient VA prescriptions
– Grouped by 37 VA formulary classes – Prescribed dose of beta-blocker extracted
from prescription records Diagnoses listed on inpatient and
outpatient records from VA and Medicare– Published algorithm used to define co-
morbidity variables for chronic conditions
Methods: Baseline VariablesMethods: Baseline Variables
Censored as at end of Dec 2004 based on available Medicare data– Censored before if disenrolled from FFS
Searched VA and Medicare records for first hospital admission after index date– Extracted primary diagnosis
Searched VA Vital Status file for dates of death
Methods: Follow-upMethods: Follow-up
Intent-to-treat & on-treatment censored after last or different beta-blocker prescription
Logistic regression on baseline variables to estimate propensity to prescribe carvedilol
Cox proportional hazard regression for time to outcome event within 7 propensity score strata where beta-blocker groups were balanced with respect to baseline variables
Sensitivity to unmeasured confounders
Methods: Data AnalysisMethods: Data Analysis
Results: Cohort IdentificationResults: Cohort Identification
CriterionCriterion CarvedilolCarvedilol CR CR MetoprololMetoprolol
First VA First VA ββ--B B Rx Rx
Oct 99-Sept Oct 99-Sept 0303
37,66237,662 44,38044,380
VA HF DxVA HF Dx 29,229 29,229 (78%)(78%)
13,746 13,746 (40%)(40%)
FFS MedicareFFS Medicare 17,759 17,759 (47%)(47%)
8,910 8,910 (20%)(20%)
Alive Alive outpatientoutpatient
17,429 17,429 (46%)(46%)
8,683 8,683 (20%)(20%)
Results: Initiation of Results: Initiation of -Blockers-Blockers
CarvedilolCarvedilol
n=17,429n=17,429CR MetoprololCR Metoprolol
n=8,683n=8,683
19991999
20002000
20012001
20022002
20032003
2%2%
1919
2828
2828
23 23
<1%<1%
66
1616
3737
4040
Initial Initial DoseDose
0.125 (0.125-0.125 (0.125-0.25)0.25)aa
0.125 (0.125-0.125 (0.125-0.25)0.25)
aaMedian (IQR) expressed as fraction of target doses of 50 mg/day of carvedilol and 200 mg/day of CR metoprolol
Results: Continuation of Initial Results: Continuation of Initial --BlockerBlocker
CarvedilolCarvedilol
n=17,429n=17,429CR MetoprololCR Metoprolol
n=8,683n=8,683
Multiple RxMultiple Rx 15,799 (91%)15,799 (91%) 7,379 (85%)7,379 (85%)
MonthsMonths 24 (7-38)24 (7-38) 14 (3-28)14 (3-28)
Last DoseLast Dose 0.25 (0.125-0.50)0.25 (0.125-0.50) 0.25 (0.125-0.25 (0.125-0.25)0.25)
Up-Up-titrationtitration
7,076 (41%)7,076 (41%) 2,281 (25%)2,281 (25%)
Target Target DoseDose
3,476 (22%)3,476 (22%) 307 (4%)307 (4%)
Results: Continuation of Initial Results: Continuation of Initial --BlockerBlocker
CarvedilolCarvedilol
n=17,429n=17,429CR CR
MetoprololMetoprolol
n=8,683n=8,683
Switched Switched ββ--BlockersBlockers
2409 (14%)2409 (14%) 3004 (35%)3004 (35%)
Months to switchMonths to switch 15 (6-26)15 (6-26) 12 (4-22)12 (4-22)
Switched toSwitched to
carvedilolcarvedilol
CR metoprololCR metoprolol
metoprolol metoprolol tartratetartrate
other (atenolol, other (atenolol, etc)etc)
--
819 (5%)819 (5%)
1108 (6%)1108 (6%)
482 (3%)482 (3%)
691 (8%)691 (8%)
--
2012 (23%)2012 (23%)
301 (4%)301 (4%)
Results: Baseline CharacteristicsResults: Baseline Characteristics
CarvedilolCarvedilol
n=17,429n=17,429CR CR
MetoprololMetoprolol
n=8,683n=8,683
Age (yrs)Age (yrs) 74 (69-79)74 (69-79) 75 (69-80)75 (69-80)
Male (%)Male (%) 9999 9898
Race, Ethnicity (%)Race, Ethnicity (%)
white, not hispanicwhite, not hispanic
black, not hispanicblack, not hispanic
otherother
8888
1010
22
8686
1212
22
Results: Baseline CharacteristicsResults: Baseline Characteristics
Selected Co-morbidity Selected Co-morbidity (%)(%)
CarvediloCarvediloll
n=17,42n=17,4299
CR CR MetoprololMetoprolol
n=8,683n=8,683
HypertensionHypertension 84 84 8686
Ischemic heart diseaseIschemic heart disease 8686 7979
Cardiac valve diseaseCardiac valve disease 4040 3232
Cardiac arrhythmia Cardiac arrhythmia 6464 5858
Chronic pulmonary diseaseChronic pulmonary disease 4646 4545
Diabetes mellitusDiabetes mellitus 4646 4545
Renal diseaseRenal disease 1818 1616
DepressionDepression 1616 1818
Results: Baseline CharacteristicsResults: Baseline Characteristics
Heart Failure Heart Failure
Medications (%)Medications (%)CarvediloCarvedilo
ll
n=17,42n=17,4299
CR CR MetoprololMetoprolol
n=8,683n=8,683
Loop diureticLoop diuretic 66 66 5353
ACE inhibitorACE inhibitor 6767 6262
Angiotensin receptor Angiotensin receptor blockerblocker
1010 99
SpiranolactoneSpiranolactone 1616 1010
DigoxinDigoxin 4949 3333
Results: Baseline CharacteristicsResults: Baseline Characteristics
Selected Other Selected Other
Medications (%)Medications (%)CarvedilolCarvedilol
n=17,429n=17,429CR CR
MetoprololMetoprolol
n=8,683n=8,683 NitrateNitrate 3939 3434
Calcium channel Calcium channel blockerblocker
25 25 3333
AntiarrhythmicAntiarrhythmic 1111 88
WarfarinWarfarin 2626 2222
Diabetes therapyDiabetes therapy 3434 3333
Respiratory therapyRespiratory therapy 2525 2727
AntidepressantAntidepressant 2222 2424
Lipid loweringLipid lowering 5151 5252
Results: Baseline Hospital Results: Baseline Hospital AdmissionsAdmissions
CarvediloCarvediloll
n=17,42n=17,4299
CR CR MetoprololMetoprolol
n=8,683n=8,683
Any diagnosis (%)Any diagnosis (%)
nonenone
11
22
> 2> 2
4646
3030
1313
1111
4747
3131
1313
99
Heart failure diagnosis (%)Heart failure diagnosis (%)
nonenone
11
> 1> 1
7777
1818
55
8585
1212
33
Results: Unadjusted Intent-to-Treat Results: Unadjusted Intent-to-Treat Analysis of Survival without Hospital Analysis of Survival without Hospital AdmissionAdmission
0.0
00
.20
0.4
00
.60
0.8
01
.00
Pro
ba
bili
ty o
f S
urv
iva
l with
ou
t H
osp
italiz
atio
n
0 12 24 36 48 60Months of Follow-up
carvedilolCR metoprolol
Results: Main Diagnoses for Hospital Results: Main Diagnoses for Hospital Admission EndpointsAdmission Endpoints
CarvediloCarvediloll
n=13,08n=13,083 (75%)3 (75%)
CR CR MetoprololMetoprolol
n=6,130 n=6,130 (71%)(71%)
Heart failureHeart failure 25% 25% 19%19%
Dyspnea, pulm. edema, Dyspnea, pulm. edema, fatigue fatigue
55 44
Ischemic heart diseaseIschemic heart disease 1717 1919
Cardiac Cardiac arrhythmia/conduction arrhythmia/conduction
1010 99
Pneumonia/RespiratoryPneumonia/Respiratory 1111 1212
HypotensionHypotension 77 55
Renal dysfunctionRenal dysfunction 22 22
OtherOther 2323 3030
Results: Unadjusted Intent-to-Treat Results: Unadjusted Intent-to-Treat Analysis of SurvivalAnalysis of Survival
0.0
00
.20
0.4
00
.60
0.8
01
.00
Pro
ba
bili
ty o
f S
urv
iva
l
0 12 24 36 48 60Months of Follow-up
carvedilolCR metoprolol
Results: Hazards of CR Metoprolol Results: Hazards of CR Metoprolol Relative to CarvedilolRelative to Carvedilol
Survival Survival withoutwithout
HospitalizatioHospitalizationn
SurvivalSurvival
UnadjustedUnadjusted
intent-to-intent-to-treattreat
on-on-treatmenttreatment
0.99 (0.95 to 0.99 (0.95 to 1.04)1.04)
0.98 (0.94 to 0.98 (0.94 to 1.04)1.04)
0.86 (0.79 to 0.86 (0.79 to 0.92)0.92)
0.88 (0.80 to 0.88 (0.80 to 0.96)0.96)
AdjustedAdjusted
intent-to-intent-to-treattreat
on-on-treatmenttreatment
0.99 (0.96 to 0.99 (0.96 to 1.03)1.03)
0.97 (0.93 to 0.97 (0.93 to 1.01)1.01)
0.91 (0.85 to 0.91 (0.85 to 0.96)0.96)
0.90 (0.83 to 0.90 (0.83 to 0.98)0.98)
Hazard ratio (95% confidence interval)
Results: Sensitivity of Survival Results: Sensitivity of Survival Hazard Ratio to Unmeasured Hazard Ratio to Unmeasured Confounder(s)Confounder(s)
HR for HR for ConfoundConfound
erer
Presence Presence with with
CarvedilolCarvedilolHR (95% CI) HR (95% CI)
-- -- 0.91 (0.85 to 0.96)0.91 (0.85 to 0.96)
1.251.25 55 0.92 (0.86 to 0.97)0.92 (0.86 to 0.97)
1.501.50 55 0.93 (0.87 to 0.98)0.93 (0.87 to 0.98)
2.002.00 55 0.95 (0.89 to 1.00)0.95 (0.89 to 1.00)
1.251.25 1010 0.93 (0.87 to 0.98)0.93 (0.87 to 0.98)
1.501.50 1010 0.96 (0.90 to 1.01)0.96 (0.90 to 1.01)
Doses of β-blockers prescribed for thousands of veterans with heart failure remained well below target doses after several prescriptions
Use of CR metoprolol was associated with significantly better survival than carvedilol. However, the observed difference could be explained by plausible differences in unmeasured confounders.
Summary of Key Observations Summary of Key Observations
The results do not provide strong evidence for preferential use of CR metoprolol rather than carvedilol for patients with heart failure
Whether or not the effectiveness of β-blockers being prescribed for veterans with heart failure can be improved by efforts to increase doses warrants further study
Conclusions Conclusions
Baseline Differences Between Baseline Differences Between Carvedilol & CR Metoprolol in Carvedilol & CR Metoprolol in Propensity Score StrataPropensity Score Strata
AllAll
SubjectsSubjects0 to 0 to
0.0990.099
StratumStratum
0.5 to 0.5 to 0.5990.599
StratumStratumNumberNumber 17429/8617429/86
838312/25612/256 1832/16091832/1609
Mean Mean PropensityPropensity
0.74/0.530.74/0.53 0.07/0.050.07/0.05 0.55/0.550.55/0.55
Start Year Start Year 20012001
20032003
11.6 %11.6 %
-17.4 %-17.4 %9.0 %9.0 %
1.8 %1.8 %-1.5 %-1.5 %
1.5 %1.5 %
HF admissionHF admission 8.2 %8.2 % 4.2 %4.2 % 1.3 %1.3 %
DigoxinDigoxin 16.7 %16.7 % <1 %<1 % <1 %<1 %
Ischemic heart Ischemic heart diseasedisease
7.2 %7.2 % 14.8 %14.8 % 1.5 %1.5 %