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,

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


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


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


n=17,429n=17,429CR CR


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


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


Heart Failure Heart Failure

Medications (%)Medications (%)CarvediloCarvedilo

ll

n=17,42n=17,4299


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


Selected Other Selected Other

Medications (%)Medications (%)CarvedilolCarvedilol

n=17,429n=17,429CR CR


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


n=17,42n=17,4299


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


n=13,08n=13,083 (75%)3 (75%)


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 %

Documents

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,