summarizing the evidence -...
Post on 07-Mar-2018
218 Views
Preview:
TRANSCRIPT
Summarizing the Evidence
Jane Gagliardi, MD, MHS
Megan von Isenburg, MSLS
ASSESS
ASK
ACQUIRE
APPRAISE
APPLY
The 5 A’s
EBMCycle
MUST CONSIDER: - Patient preference- Access to care- Quality of life- Goals of care
WHAT’S GOING ON?- History and Physical- Initial Formulation
PICOTT- Patient /
Population- Intervention- Control- Outcome- Type of Question- Type of Study
LITERATURE SEARCH
VALIDITY CRITERIA- Methods- Results- Sources of Bias- Strength of evidence
The Evidence
Cycle
Objectives
• Recognize and use the evidence cycle
• Define a systematic review
• Define meta-analysis– Discuss what they can and can’t do for you
• Be able to explain:– Heterogeneity
– Weighting
– Publication Bias
• Draw and interpret a forest plot
• Critically appraise a systematic review
• Discuss teaching strategies and decision-points
The Evidence Pyramid
Scenario: Rounding on Gen Med
Why Do We Need EBM? Consider…
• A study of steel mill workers identified by
on-the-job screening program with
hypertension
– ½ sent to primary care providers for specific
treatment of hypertension
– ½ sent to on-the-job-site provider for
algorithm-based treatment of hypertension
Adapted from Virginia Moyer, 1/14/2014
• A study of steel mill workers identified by
on-the-job screening program with
hypertension
• Unexpectedly low rates of treatment by
primary care providers
Adapted from Virginia Moyer, 1/14/2014
Why Do We Need EBM? Consider…
Factors associated with likelihood of
prescription of an antihypertensive agent:
• Diastolic blood pressure
• Age
• Target end-organ damage
•
Adapted from Virginia Moyer, 1/14/2014
Why Do We Need EBM? Consider…
Factors associated with likelihood of
prescription of an antihypertensive agent:
• Diastolic blood pressure
• Age
• Target end-organ damage
• Time since graduation from medical school
Adapted from Virginia Moyer, 1/14/2014
Why Do We Need EBM? Consider…
Scenario: Rounding on Gen Med
Scenario: Pharmacy and Therapeutics
• For as long as anyone can remember, the
formulary has included metoprolol.
• Carvedilol was reviewed for formulary
status in 2003, at which time it was felt
to provide no specific benefit (but cost
more).
• You now are the multidisciplinary health
system Pharmacy and Therapeutics
Committee.
Scenario: Pharmacy and Therapeutics
Scenario: Pharmacy and Therapeutics
• Health system “nonformulary” report
includes large increase in the utilization of
carvedilol, particularly on the Gen Med
services for patients with heart failure.
• The Chair of the committee tasks us with
deciding which beta blocker will be
preferred for formulary use: Metoprolol or
Carvedilol? (Cost is now similar).
A = Metoprolol
B = Carvedilol
What Should the Health System Do?
What is the focused
clinical question? Among patients
with heart failure, is
carvedilol significantly
different than
metoprolol in
preventing all-cause
mortality?
Searching the Literature
Your Task
• The committee needs to decide.
• The Pharmacy administrator has a stack
of journal articles.
• Is there any alternative to looking at each
of 50 randomized controlled trials?
• Answers one focused clinical question
• Summarizes evidence using methods to minimize
the impact of bias
• The statistical method to combine data from
different studies = meta-analysis
• Not all systematic reviews have meta-analysis
(qualitative inferences only)
• Not all meta-analyses combine studies
assembled through a systematic review
What is a Systematic Review?
What systematic reviews can do for you
• Save time !!!
• Increase power to detect rare events– Obviate need for expensive mega-trials
– Detect harm
• Increase the precision of the estimate of effect
• Enhance the generalizability of the results if samples from different populations are included
• Look for important differences in effectiveness among subgroups of patients
Random Error Systematic Bias
What systematic reviews can’t do for you
Random Error Systematic Bias
What systematic reviews can’t do for you
…they also can’t tell you where TRUTH actually is
Exercise – Creating a Mini Meta-Analysis
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
Secondary analysis of RCT Randomized for CRT-D or ICD, not
M / C
Does Combining Studies Make Sense?
• Determination (before proceeding to math)
of whether or not it makes sense to
combine
• Otherwise known as
The Common Sense Test
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality
Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
M: 34.4% (21/61)
C: 27.8%(17/61)
RCTC+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
M: 40%(600/1518)
C: 34%(512/1511)
.83 (.74-.93)
RCTA
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
M: 22.1%(196/887)
C: 16.5%(146/887)
HR= .71 unadjHR = .78 adj
Retro.
Cohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
M: 11%(48/438)
C: 10%(104/1077)
HR= .72
2⁰ anal.RCT
Randomized for CRT-D or ICD, not M / C
OutcomeYes
OutcomeNo
ExposureAbsent
TIME
Cohort Study
ExposurePresent
Measure HERE
Does Combining Studies Make Sense?
• Determination (before proceeding to math)
of whether or not it makes sense to
combine
• Otherwise known as
The Common Sense Test
• Meta-analysis of all treatments for all heart disease?
• Meta-analysis of beta blockers for all heart disease?
• Meta-analysis of beta blockers for mortality in CHF?
• Meta-analysis of cohort studies and RCTs involving beta
blockers for mortality in CHF?
We Need a Volunteer
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
OR0.75 (0.36, 1.58)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
OR0.78(0.68, 0.91)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
HR0.78(0.61, 1.00)
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
OR0.87(0.60, 1.25)
Secondary analysis of RCT
Randomized for CRT-D or ICD, not M / C
RESULTS FOR COMBINING ARE REPORTED BELOW:
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
OR0.75 (0.36, 1.58)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
OR0.78(0.68, 0.91)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
HR0.78(0.61, 1.00)
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515 who got M or C
Out of 1820 total study pop
Metoprolol succinate
Carvedilol
1. Death
OR0.87(0.60, 1.25)
Secondary analysis of RCT
Randomized for CRT-D or ICD, not M / C
RESULTS FOR COMBINING ARE REPORTED BELOW:
Author/year Population Number of Subjects
Intervention and control
Outcome Measure(s) Results: Mortality Study Methodology
Grade of Evidence (A,B,C,D,F) & Why
Metra, et al2000
Italy Outpatient Ischemic or
nonischemiccardiomyopathy
Class II, III, IV ≥ 6 months
EF ≤ 35% Lasix + ACE
consistent
150
Metoprolol tartrate115±56 mg/d
Carvedilol44±17 mg/d
23±12 months
1. LVEF2. Hemodynamic
variables at rest and peak exercise, exercise tolerance, QOL, NYHA fx class, death, urgent transplantation
OR0.75 (0.36, 1.58)
RCT C+
F: 81%R: 1:1, CA?I: lost 14 in each groupS: seems to beB: yes, pts, cliniciansE: could modify if needed
Poole-Wilson, et al 2003
COMET
Europe Multicenter (341
centers) NYHA II, III, IV EF ≤ 35% diuretics + ACE
3029
Metoprolol tartrate50 mg 2x/day
Carvedilol25 mg 2x/day
58 months mean duration
1. All-cause mortality
OR0.78(0.68, 0.91)
RCT A
F: 10% loss to f/uR: permuted blocks, CAI: yesS: more CABG, ischemia MB: yesE: yes
Delea, et al2005
Constella database USA
CHF + C or M + age ≥ 35
1 outpt pharm claim for ACE + diuretic
? NYHA ?EF Death rate?
1774Metoprolol tartrate
Carvedilol
1. Death2. Hospitalization3. Death or
hospitalization
HR0.78(0.61, 1.00)
Retro-spectivecohort
B
Study sponsor helped author
Cohort differences: M older, less males, more
southern, more HTN, more arrhythmias, more renal
Ruwald et al2013
MADIT CRT
Patients enrolled in MADIT-CRT study on either M or C
Europe, US, Canada Class I, II EF ≤ 30% Choice of BB left to
treating physician
1515Metoprolol succinate
Carvedilol
1. Death
OR0.87(0.60, 1.25)
Secondary analysis of RCT
Randomized for CRT-D or ICD, not M / C
ANY OTHER DIFFERENCES TO CONSIDER?
Does Combining Results Make Sense?
Does Combining Results Make Sense?
Does Combining Results Make Sense?
Does Combining Results Make Sense?
Does Combining Results Make Sense?
Statistics:
• Test for Heterogeneity– A statistical test asking if study results are more
different than would be expected by chance alone
• I2 Test– A statistical test that describes the percentage of the
variability due to heterogeneity rather than sampling
error (chance).
Back to Pharmacy and Therapeutics
• Health system “nonformulary” report
includes large increase in the utilization of
carvedilol, particularly on the Gen Med
services for patients with heart failure.
• The Chair of the committee tasks you with
deciding which beta blocker will be
preferred for formulary use: Metoprolol or
Carvedilol? (Cost is now similar).
Systematic Reviews: Validity
1. Did the review explicitly address a
sensible clinical question?
First page, left column before METHODS
Systematic Reviews: Validity
2. Was the
search for
relevant
studies
detailed and
exhaustive?
• “Publication
Bias”
• “Funnel Plots”
First page, METHODS
Systematic Reviews: Validity
2. Was the
search for
relevant
studies
detailed and
exhaustive?
• “Publication
Bias”
• “Funnel Plots”
First page, METHODS
Publication Bias
p.1113, above RESULTS
What is a Funnel Plot Anyway?
A.K.A, “The Results”A.K
.A,
“In
cre
asin
g S
am
ple
Siz
e”
Line of Truth
Remember: The “truth is out there” but we don’t actually know what it is
What is a Funnel Plot Anyway?
A.K.A, “The Results”A.K
.A,
“In
cre
asin
g S
am
ple
Siz
e”
Line of Truth
Publication Bias
p.1114, bottom left column
Systematic Reviews: Validity
3. Were selection
and assessment
of studies
reproducible?
First page, right column, last 3 paragraphs
Data Table – p 1112
Systematic Reviews: Validity
4. Did the review address possible explanations of
between-study differences in results?
Discussion section
Systematic Reviews: Validity
5. Did the review present results that are ready for
clinical application?
Third page
Systematic Reviews: Validity
5. Did the review provide a rating for confidence in
effect estimates or provide information needed to
evaluate the confidence?
Third page
Data Table – p 1112
Systematic Review: Results
1. Were the results similar from study to
study?
• Clinical assessment of heterogeneity in
population, intervention, outcomes
• “Eyeball” test in Forest Plot
• Statistical test or I2
Eyeball Test for Heterogeneity
Statistical Tests for Heterogeneity
Eyeball Test for Heterogeneity
Statistical Tests for Heterogeneity
What are the Results?
2. What are the overall results of the
review?
– Forest plots and tables
3. How confident are you in the estimates?
– Confidence intervals
A = Metoprolol
B = Carvedilol
What Should the Health System Do?
RECAP
How can you tell if an article is a
“systematic review” rather than a
“general review” article?
A. Top journals only publish systematic reviews
B. It will cover all known information about the topic
(diagnosis, prognosis, treatment, etc)
C. It has a Methods Section
D. B and C
From which types of studies is it
possible to combine data (do a
“meta-analysis”)?
A. Randomized trials only
B. Randomized trials and cohort studies
C. Randomized trials, cohort studies, and case-control
studies
D. Randomized trials, cohorts studies, case-control
studies, and case series
A. Deciding whether it makes sense to combine them
based on your clinical knowledge
B. Seeing if a statistical test for heterogeneity among the
results of the studies is non-significant, or an I2 statistic
is <20%
C. Looking for overlapping confidence intervals on a forest
plot
D. A, B and C
You should assess for
heterogeneity between studies in a
systematic review by:
“Weighting” refers to:
A. Eating too many snacks during your EBM workshop
B. A mathematical adjustment which makes larger studies
contribute more to the combined result than smaller
ones
C. A mathematical adjustment which makes better quality
studies contribute more to the combined result than
smaller ones
D. B or C
Objectives
• Define a systematic review
• Define meta-analysis– Discuss what they can and can’t do for you
• Be able to explain:– Heterogeneity
– Weighting
– Publication Bias
• Draw and interpret a forest plot
• Critically appraise a systematic review
Teaching Decisions
• Planning
• Process vs Content
• Working With What You’ve Got– (Play To Your Strengths)
– Homo ridiculousness vs. Homo seriousness
• Knowing Your Audience
• To Mark or Not to Mark? – That is the Question
• Triage
Thanks!
• Evaluations
• https://www.youtube.com/watch?v=FqQ-
JuRDkl8
top related