# Presentation: 878284

- 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 Metoprolol versus Carvedilol as Prescribed for Veterans with Heart Failure**

**Notes:**
Effectiveness of Controlled-Release Metoprolol versus Carvedilol as Prescribed for Veterans with Heart Failure

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

- 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 Objectives

**Notes:**
Research Objectives

- 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

- 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 Identification

**Notes:**
Methods: Cohort Identification

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

- 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 Identification

**Notes:**
Methods: 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

- 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 Variables

**Notes:**
Methods: Baseline Variables

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

- 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-up

**Notes:**
Methods: Follow-up

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  

- 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 Analysis

**Notes:**
Methods: Data Analysis

- 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

- Results: Cohort Identification

| Criterion | Carvedilol | CR Metoprolol |
| --- | --- | --- |
| First VA β-B Rx 
Oct 99-Sept 03 | 37,662 | 44,380 |
| VA HF Dx | 29,229 (78%) | 13,746 (40%) |
| FFS Medicare | 17,759 (47%) |   8,910 (20%) |
| Alive outpatient | 17,429 (46%) |   8,683 (20%) |

**Notes:**
Results: Cohort Identification

Table

- Results: Initiation of -Blockers

|  | Carvedilol
n=17,429 | CR Metoprolol
n=8,683 |
| --- | --- | --- |
| 1999
2000
2001
2002
2003 |   2%
19
28
28
23  | <1%
  6
16
37
40 |
| Initial Dose | 0.125 (0.125-0.25)a | 0.125 (0.125-0.25) |

**a**Median (IQR) expressed as fraction of target doses of 50 mg/day of
-  carvedilol and 200 mg/day of CR metoprolol

**Notes:**
Results: Initiation of -Blockers

Table

- Results: Continuation of Initial -Blocker

|  | Carvedilol
n=17,429 | CR Metoprolol
n=8,683 |
| --- | --- | --- |
| Multiple Rx | 15,799 (91%) | 7,379 (85%) |
| Months | 24 (7-38) | 14 (3-28) |
|   Last Dose | 0.25 (0.125-0.50) | 0.25 (0.125-0.25) |
|   Up-titration | 7,076 (41%) | 2,281 (25%) |
|   Target Dose | 3,476 (22%) |  307 (4%) |

**Notes:**
Results: Continuation of Initial -Blocker
Table

- Results: Continuation of Initial -Blocker

|  | Carvedilol
n=17,429 | CR Metoprolol
n=8,683 |
| --- | --- | --- |
| Switched β-Blockers | 2409 (14%) | 3004 (35%) |
| Months to switch | 15 (6-26) | 12 (4-22) |
| Switched to
  carvedilol
  CR metoprolol
  metoprolol tartrate
  other (atenolol, etc) | 
-
  819 (5%)
1108 (6%)
  482 (3%) | 
 691 (8%)
-
2012 (23%)
301 (4%) |

**Notes:**
Results: Continuation of Initial -Blocker

table

- Results: Baseline Characteristics

|  | Carvedilol
n=17,429 | CR Metoprolol
n=8,683 |
| --- | --- | --- |
| Age (yrs) | 74 (69-79) | 75 (69-80) |
| Male (%) | 99 | 98 |
| Race, Ethnicity (%)
  white, not hispanic
  black, not hispanic
  other | 
88
10
  2 | 
86
12
  2 |

**Notes:**
Results: Baseline Characteristics

Table

- Results: Baseline Characteristics

| 
Selected Co-morbidity (%) | Carvedilol
n=17,429 | CR Metoprolol
n=8,683 |
| --- | --- | --- |
|   Hypertension | 84  | 86 |
|   Ischemic heart disease | 86 | 79 |
|   Cardiac valve disease | 40 | 32 |
|   Cardiac arrhythmia  | 64 | 58 |
|   Chronic pulmonary disease | 46 | 45 |
|   Diabetes mellitus | 46 | 45 |
|   Renal disease | 18 | 16 |
|   Depression | 16 | 18 |

**Notes:**
Results: Baseline Characteristics
Table

- Results: Baseline Characteristics

| Heart Failure 
Medications (%) | Carvedilol
n=17,429 | CR Metoprolol
n=8,683 |
| --- | --- | --- |
|   Loop diuretic | 66  | 53 |
|   ACE inhibitor | 67 | 62 |
|   Angiotensin receptor blocker | 10 |   9 |
|   Spiranolactone | 16 | 10 |
|   Digoxin | 49 | 33 |

**Notes:**
Results: Baseline Characteristics

Table

- Results: Baseline Characteristics

| Selected Other 
Medications (%) | Carvedilol
n=17,429 | CR Metoprolol
n=8,683 |
| --- | --- | --- |
|   Nitrate | 39 | 34 |
|   Calcium channel blocker | 25  | 33 |
|   Antiarrhythmic | 11 |   8 |
|   Warfarin | 26 | 22 |
|   Diabetes therapy | 34 | 33 |
|   Respiratory therapy | 25 | 27 |
|   Antidepressant | 22 | 24 |
|   Lipid lowering | 51 | 52 |

**Notes:**
Results: Baseline Characteristics

Table

- Results: Baseline Hospital Admissions

|  | Carvedilol
n=17,429 | CR Metoprolol
n=8,683 |
| --- | --- | --- |
|   Any diagnosis (%)
     none
     1
     2
     > 2 | 
46
30
13
11 | 
47
31
13
  9 |
|   Heart failure diagnosis (%)
     none
     1
     > 1 | 
77
18
  5 | 
85
12
  3 |

**Notes:**
Results: Baseline Hospital Admissions

Table

- Results: Unadjusted Intent-to-Treat Analysis of Survival without Hospital Admission

**Notes:**
Results: Unadjusted Intent-to-Treat Analysis of Survival without Hospital Admission

Graph

- Results: Main Diagnoses for Hospital Admission Endpoints

| 
 | Carvedilol
n=13,083 (75%) | CR Metoprolol
n=6,130 (71%) |
| --- | --- | --- |
|   Heart failure | 25%  | 19% |
|   Dyspnea, pulm. edema, fatigue  |   5 |   4 |
|   Ischemic heart disease | 17 | 19 |
|   Cardiac arrhythmia/conduction  | 10 |   9 |
|   Pneumonia/Respiratory | 11 | 12 |
|   Hypotension |   7 |   5 |
|   Renal dysfunction |   2 |   2 |
|   Other | 23 | 30 |

**Notes:**
Results: Main Diagnoses for Hospital Admission Endpoints

Table

- Results: Unadjusted Intent-to-Treat Analysis of Survival

**Notes:**
Results: Unadjusted Intent-to-Treat Analysis of Survival

Graph

- Results: Hazards of CR Metoprolol Relative to Carvedilol

| 
 | Survival without
Hospitalization | 
Survival |
| --- | --- | --- |
| Unadjusted
   intent-to-treat
   on-treatment | 
0.99 (0.95 to 1.04)
0.98 (0.94 to 1.04) | 
0.86 (0.79 to 0.92)
0.88 (0.80 to 0.96) |
| Adjusted
   intent-to-treat
   on-treatment | 
0.99 (0.96 to 1.03)
0.97 (0.93 to 1.01) | 
0.91 (0.85 to 0.96)
0.90 (0.83 to 0.98) |

- Hazard ratio (95% confidence interval)

**Notes:**
Results: Hazards of CR Metoprolol Relative to Carvedilol

Table

- Results: Sensitivity of Survival Hazard Ratio to Unmeasured Confounder(s)

| HR for Confounder |  Presence with Carvedilol | 
HR (95% CI)  |
| --- | --- | --- |
| - | - | 0.91 (0.85 to 0.96) |
| 1.25 |   5 | 0.92 (0.86 to 0.97) |
| 1.50 |   5 | 0.93 (0.87 to 0.98) |
| 2.00 |   5 | 0.95 (0.89 to 1.00) |
| 1.25 | 10 | 0.93 (0.87 to 0.98) |
| 1.50 | 10 | 0.96 (0.90 to 1.01) |

**Notes:**
Results: Sensitivity of Survival Hazard Ratio to Unmeasured Confounder(s)

Table

- 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

**Notes:**
Summary of Key Observations

- 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. 

- 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

**Notes:**
Conclusions

- 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

- Baseline Differences Between Carvedilol & CR Metoprolol in Propensity Score Strata

|  | All
Subjects | 0 to 0.099
Stratum | 0.5 to 0.599
Stratum |
| --- | --- | --- | --- |
| Number | 17429/8683 | 12/256 | 1832/1609 |
| Mean Propensity | 0.74/0.53 | 0.07/0.05 | 0.55/0.55 |
| Start Year 2001
               2003 | 11.6 %
-17.4 % | 9.0 %
1.8 % | -1.5 %
1.5 % |
| HF admission | 8.2 % | 4.2 % | 1.3 % |
| Digoxin | 16.7 % | <1 % | <1 % |
| Ischemic heart disease | 7.2 % | 14.8 % | 1.5 % |

**Notes:**
Baseline Differences Between Carvedilol & CR Metoprolol in Propensity Score Strata

Table