Download Handout to Beta blocker therapy in heart failure in the elderly

Target dose vs highest tolerated dose: Beta blocker therapy in heart failure
in the elderly
https://www.newscientist.com
Jasmine Peterson, PharmD
PGY-2 Ambulatory Care Resident
CommUnityCare Clinic
University of Texas College of Pharmacy at Austin
October 7, 2016
Objectives:
1. Understand the epidemiology and pathophysiology of heart failure
2. Describe the challenges of managing heart failure in elderly patients
3. Summarize the literature regarding the controversy behind achieving target doses of beta blockers in
elderly heart failure patients
Peterson, Page 1 of 20
I.
Definition of elderly27
A. A consensus definition of elderly does not exist
i. No general agreement on the age at which a person becomes old
ii. May vary in underdeveloped countries
B. According to the World Health Organization (WHO), most developed countries have accepted the
chronological age of ≥65 years as a definition of elderly
II.
Heart Failure (HF)1-4
A. Background
a. Defined as a complex clinical syndrome in which the heart has an inability to properly fill with
and eject blood to the rest of the body
b. HF may result from disorders of the pericardium, myocardium, endocardium, or heart valves
B. Definitions/Types1-4
a. HF with reduced ejection fraction (HFrEF)
i. Also referred to as systolic dysfunction
ii. Occurs as a result of dilated left ventricle leading to its inability to pump oxygen rich
blood to the rest of the body
iii. Defined as left ventricular ejection fraction (LVEF) ≤40%
iv. Randomized controlled trials have demonstrated efficacious therapies in this patient
population
v. Coronary artery disease (CAD) is the most common cause although many other risk
factors may lead to systolic dysfunction
b. HF with preserved ejection fraction (HFpEF)
i. Also referred to as diastolic dysfunction
ii. Occurs when the left ventricle loses its ability to relax properly therefore leading to
impaired ventricular filling
iii. Defined as LVEF ≥50% (however further research is needed to characterize these
patients)
1. Other definitions
a. HFpEF borderline (LVEF 41-48%)
b. HFpEF improved (LVEF >40%)
i. Patients with HFpEF who previously had HFrEF
c. Patient characteristics, treatments, and outcomes are similar to those of
HFpEF
iv. Currently, efficacious therapies have not shown proven mortality benefit
v. Hypertension (HTN) remains the most common cause of HFpEF
vi. These patients are mainly treated for underlying risk factors and comorbidities similar to
guideline directed medical therapy (GDMT) use in patients with HFrEF
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C. Classifications 1
Table 1.
ACCF/AHA
NYHA
A
At high risk for HF but without structural
heart disease or symptoms of HF
None
B
Structural heart disease but without
signs and symptoms of HF
I
No limitation on physical activity
C
Structural heart disease but with prior or
current symptoms of HF
I
No limitation on physical activity
II
Slight limitation of physical activity
III
Marked limitation of physical activity
IV
Unable to carry on any physical activity
without symptoms of HF
IV
Unable to carry on any physical activity
without symptoms of HF
D
Refractory HF requiring specialized
interventions
American Heart Association (AHA); American College of Cardiology Foundation (ACCF) ; New York Heart Association(NYHA)
D. Epidemiology 1,3,4
a. Prevalence
i. The lifetime risk of developing HF is 20% for patients ≥40yo
ii. In the US, the incidence is >650,000 new HF cases each year
iii. Large percentage of patients suffering from HF are elderly with both incidence and
prevalence increasing
Figure 1.
Darish Mozaffarian et al. Circulation.2016;133:e133:e38-e360
Percentage
Prevalence of HF by sex and age (National Health and
Nutrition Examination Survey 2009-2012)
16
14
12
10
8
6
4
2
0
13.5
10.6
6.6
Male
4.8
0.2 0.6
20-39
Female
1.5 1.2
40-59
60-79
Age (years)
80+
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iv. Factors contributing to the rise and incidence of HF 8-11,18
1. Age- related cardiovascular changes
a. Reduced responsiveness to Beta-adrenergic stimulation
b. Increased vascular stiffness
2. High prevalence of cardiovascular disease
3. Improved therapy for coronary heart disease
a. With pharmacologic therapies more patients survive to eventually
develop HF
b. Mortality
i. Absolute mortality rates of HF are about 50% within 5 years of diagnosis
1. Increase exponentially with advancing age
c. Hospitalizations
i. 75% occur in patients >65yo
ii. HF is the primary diagnosis in more than 1 million hospitalizations per year
iii. In the US, the total cost of HF care is over $30 billion annually
B. Pathophysiology (Appendix A)1,3,4
a. Initially:
i. Myocardial injury produces an initial decline in the heart's pumping capacity which leads
to the activation of compensatory mechanisms (renin angiotensin aldosterone system
(RAAS), sympathetic nervous system (SNS), and natriuretic peptide system (NPS)) to
restore cardiovascular function and prevent further damage
ii. During this time the patient usually remains asymptomatic
b. Over time:
i. The sustained activation of these systems leads to worsening left ventricular
remodeling, sustained impaired pumping capacity, and inadequate renal perfusion.
ii. Poor renal perfusion triggers sodium and water retention which leads to congestive
signs and symptoms often associated with HF
C. Clinical Presentation 1,3,84,8-11
a. The cardinal symptoms of HF include:
i. Dyspnea
ii. Fatigue
iii. Exercise intolerance
D. Risk Factors 1,3,4
a. Common etiologies of HF in the elderly
i. Coronary artery disease (CAD)
ii. Uncontrolled chronic disease (i.e. HTN)
iii. Valvular heart disease
iv. Cardiomyopathy
1. Cardiotoxins (i.e. Alcohol, anthracyclines)
v. Myocarditis
vi. Pericardial disease
vii. Age-related cardiovascular changes
E. Challenges of managing HF in the elderly 8-10,26
Peterson, Page 4 of 20
a. Physiological age-related changes
i. Influence drug pharmacokinetics and dynamics
b. More complex comorbidities (i.e. HTN, atrial fibrillation, peripheral vascular disease, CAD,
valvular disease, renal dysfunction)
i. Higher risk for drug-related side effects
ii. Polypharmacy
c. Social issues
i. Limited access to caregivers and specialists
ii. Cognitive impairment
iii. Financial problems affect therapy adherence
1. Low functional status, low body weight, frailty, cognitive impairment, and
dementia  all of which are associated with worse clinical outcomes
F. Guidelines (Appendix B) 1,2
a. 2013 ACCF/AHA guideline for the management of HF
b. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for HF: an update of the
2013 ACCF/AHA guideline
G. Management 1-3,5
a. Non- Pharmacologic
i. Patient education
ii. Restrict sodium intake (1.5- 2 gram/day)
iii. Weight control
iv. Manage/control underlying causes
v. Intensive follow-up
vi. Smoking cessation
vii. Restrict alcohol
H. Pharmacologic Therapies
i. Stage A
1. Goals: Prevent structural heart damage and promote heart healthy lifestyle
a. Angiotensin Converting Enzyme Inhibitor (ACEI)/Angiotensin Receptor
Blocker (ARB) in patients with vascular disease or diabetes
ii. Stage B
1. Goals: Prevent HF symptoms and further cardiac remodeling
a. ACEI/ARB and beta blockers as appropriate
iii. Stage C (HFrEF)
1. Goals: control symptoms, prevent morbidity and mortality, and slow
progression of worsening cardiac function
a. Diuretics, ACEI/ARB, Angiotensin Receptor Neprilysin Inhibitor (ARNI),
beta blockers (BBs), aldosterone antagonists, hydralazine/isosorbide
dinitrate, digoxin, ivabradine
iv. Stage D
1. Goals: control symptoms, improve quality of life (QOL), reduce hospital
admissions, establish end-of-life goals
Peterson, Page 5 of 20
a. Advanced care measures, heart transplant, chronic inotropes,
implantable cardiac device, palliative care
III.
Review of BBs
A. Background
a. First multicenter randomized trial was published in 1993
b. Slow acceptance related to negative inotropic effect and risk of decompensation in HF
patients
B. Proposed mechanism of action/beneficial effects in HF
a. Antagonize the SNS reduce harmful effects of continuous expression of neurohormones
(i.e. norepinephrine) on the heart
b. Reduce HR, blood pressure, and potential for arrhythmias
C. Pharmacology (Appendix C) 7,8,21
a. Onset, absorption, metabolism, excretion, contraindications, drug interactions, dosing, etc.
D. Safety 6, 16,17
a. Generally well tolerated
b. Refer to Appendix C for common adverse reactions and contraindications
IV.
Current recommendations regarding BB use in HF 1,2
A. The 2013 ACCF/AHA guideline states:
i. “Use of 1 of the 3 beta blockers proven to reduce mortality (i.e. bisoprolol, carvedilol, and
sustained-release metoprolol succinate) is recommended for all patients with current or
prior symptoms of HFrEF, unless contraindicated, to reduce morbidity and mortality.” (Class
I, Level of evidence A)
1. Class I: Recommendation that treatment is effective/beneficial
2. Level of evidence A: Data derived from multiple randomized controlled trials (RCTs)
a. Refer to Appendix D
ii. “Clinicians should make every effort to achieve the target doses of the beta blockers shown
to be effective in major clinical trials.”
V.
BB use in the elderly19-21,24,25
A. Mostly underrepresented in large randomized controlled trials (RCTs) where therapeutic agents
have demonstrated clinical efficacy
i. Refer to Appendix D
B. Previous studies and surveys have demonstrated that the underuse of BBs are evident in the elderly
mostly due to:
i. More comorbidities, less frequently referred to cardiologist for optimal management, and
less tolerance to medications
VI.
Evidence evaluating titrations of BB to target doses in elderly HF patients
A. CIBIS-ELD trial
i. Objective: This was a randomized, double blind trial with the primary endpoint tolerability
of BBs when used at recommended target doses
1. Bisoprolol (10mg daily) vs carvediolol (25mg BID)
ii. Inclusion criteria:
1. ≥65yo LVEF ≤45% and NYHA class II, BB naive or on <25% of the recommended
target dose
Peterson, Page 6 of 20
iii. Results:
1. 75.7% of the subjects with mean age 72.8 years did not reach the primary endpoint
a. Bisoprolol 24% vs carvedilol 25%
2. No significant difference between the two groups in the incidence of worsening HF,
hospital admission, hypotension, and mortality
3. Older age and NYHA class III-IV were associated with not achieving target dose
4. Significant differences in adverse events included: bradycardia (bisoprolol) and
pulmonary events (carvedilol)
iv. This trial demonstrated that up-titration of BBs in the elderly is difficult
v. Short follow-up therefore unable to determine correlation between tolerability to the target
dose and mortality
VII.
Evidence evaluating effect of BBs on mortality in elderly HF patients
A. Meta-analysis27
i. Evaluated all-cause mortality data involving elderly and non-elderly chronic HF patients from
5 completed BB clinical trials
1. Revealed no statistically significant difference in mortality reduction between
elderly and non-elderly HF patients
2. Trials evaluated in this analysis included 12,729 patients with HF; only 4,617
patients (36.3%) were classified as elderly
a. Mean age <65 yrs old
b. 2 trials excluded patients >80yo
c. Percentage of patients >70yo was not reported in 2 trials
d. See Appendix E
B. Further studies are needed to determine whether elderly HF patients benefit clinically from uptitration to the maximal tolerated dose of BBs
VIII.
THE BIG CLINICAL QUESTION!!!!!: Is achieving target doses of BBs in elderly
patients with HF associated with better clinical outcomes?
Peterson, Page 7 of 20
IX.
Literature Review:
Table 7. Sin D., McAlister F., et al. The effects of beta-blockers on morbidity and mortality in a population-based
cohort of 11,942 elderly patients with heart failure. Am J Med. 2002;113:650–656
Purpose
Study Design
Inclusion criteria
Exclusion criteria
Outcomes
Methods
Statistics
Results
Author’s
Conclusions
Evaluate the associations between BBs and outcomes in older HF patients
Retrospective cohort study
 All residents of Alberta, Canada ≥ 65 years old who had at least 1 hospitalization for HF
between 1994 and 1999
 Patients who died during the index hospitalization
 Patients who had been hospitalized for HF in the 2 years before the index hospitalization
 All-cause mortality
 HF hospitalization
 Followed patients from the date of their index hospitalization until the date of their death,
first rehospitalization for HF, or December 31, 1999, whichever came first
 Obtained prescription information through Alberta Blue Cross program
 Divided the daily dose of BBs into 3 categories:
o Not dispensed, lower dose (<50% of target dose) , and higher dose (≥50% of target
dose)
 Sensitivity analysis:
o Examined effects of BB therapy in the youngest and healthiest subgroup (65-74 yo
with no documented comorbid conditions)
 Continuous variables Tukey test
 Ordinal and dichotomous variables  chi-squared test
 Cox proportional hazards model
 Kaplan-Meier analyses
 Sensitivity analysis to minimize effects of confounding variables
 P value <0.05 = statistical significance
 Male (~50%)
 +80 years old (58%)
 Of 11,942 patients of whom 2569 (22%) had Charlson comorbidity scores of at least 2
 Median follow-up was 21 months
 1162 patients (10%) received BB therapy
 Most frequently prescribed BB was metoprolol (n = 488 (42%))
 Of the patients prescribed BBs, 519 (45%) received lower doses and 643 (55%) received
higher doses
 BB use was associated with significant reductions in all-cause mortality (HR 0.72; 95% CI:
0.65 to 0.80), mortality due to HF (HR 0.65; 95% CI: 0.47 to 0.90), and hospitalizations for
HF (HR 0.82; 95% CI: 0.74 to 0.92)
 Patients were less likely to be prescribed a BB if:
o they were older, had several comorbid conditions, had COPD, or a history of
bradycardia/atrioventricular block (all P<0.05)
 Patients were more likely to be prescribed BBs if:
o they had ischemic heart disease or HTN, or if they were taking other medications
for HF, particularly ACEIs or loop diuretics (all P<0.05)
 Patients were more likely to receive lower doses if:
o they had a history of heart block, were taking lower doses of ACEIs, or were also
receiving digoxin (all P<0.05)
The benefits of BBs seen in randomized trials extend to a broader population of elderly
patients with HF
Peterson, Page 8 of 20
Comments
Strengths
 Large sample size
 Baseline characteristics similar between groups
 Evaluated BB dose associations with mortality and morbidity
Limitations
 Retrospective study
 Unable to monitor adherence (Refills does not guarantee adherence)
 Did not collect data on functional status/ severity of HF
 Did not determine if patients had systolic or diastolic dysfunction
 Included BBs not proven to reduce morbidity and mortality in HF
 Did not report number of clinical events per dosing group (i.e. number of deaths in each BB
group)
Table 8. Barywani S., Ergatoudes C., et al. Does the target dose of neurohormonal blockade matter for outcome
in systolic heart failure in octogenarians?. Intl J Cardiology 2015. 187:666-672.
Purpose
Study Design
Inclusion criteria
Exclusion
criteria
Outcomes
Methods
Statistics
To investigate whether elderly HF patients receiving ≥50% target dose outperform those
receiving <50% target dose, despite maximum up-titration, and whether the target dose
outperforms all other doses
Retrospective chart review of 2 outpatient HF clinics
 ≥80 yo
 LVEF ≤40%
 LVEF >40%
Primary:
 All-cause mortality after ≥ 5 years
Secondary:
 5-year cardiac mortality
 Hospitalization due to worsening HF
 185 patients aged ≥80 years with HF and LVEF ≤40% referred between January 2000 and
January 2008 to 2 HF outpatient clinics
 Up-titrations of HF medications
o Done by HF specialized nurses according to a prespecified schedule and after
discussion with a cardiologist over a 3-6 month period
o Titration was stopped after reaching the target dose or highest tolerated dose
which was based on the following vital signs
 HR <55 bpm, SBP <100 mmHg, and increase in SCr of >40% or serum
potassium >5.5 mmol/L
 Definition of groups according to doses
o Low dose = <50% of the target dose, intermediate= ≥ 50% of target dose but less
than the target dose, and the highest dose group = target dose
 Common BBs used: metoprolol succinate (84%), bisoprolol (12%), carvedilol (4%)
 Baseline characteristics descriptive statistics
 Continuous variables  once-way analysis of covariance
 Categorical variables Chi-squared test
 Cox proportional-hazard survival model  mortality analysis
 P value <0.05 = statistical significance
 Kaplan-Meier analysis and univariable Cox proportional-hazard regression analysis were
used to build multivariable models for 3 doses of each agent
Peterson, Page 9 of 20
Results
Author’s
Conclusions
Comments
Primary:
 All-cause mortality was 76.8% (142 events)
Secondary:
 Cardiac mortality was 60.6% (86 events)
Doses after titrations:
 50% received <50% of target dose
 29% received ≥50% of target dose
 21% received target dose
Main reasons for not reaching target doses
 Symptomatic bradycardia (53%), symptomatic hypotension (<100mmHg, 46%), and
worsening pulmonary obstruction symptoms (1%)
Relationship between dose level and outcome:
 No significant difference in survival between the target dose and lower dose (<50% of target
dose) groups, or between those receiving >50% of the target dose and the lower dose,
regardless of all-cause mortality (HR =0.6, 95%CI 0.3-1.1, P =0.115), or cardiac mortality (HR
= 0.7, 95%CI 0.4-1.4, P =0.401)
 No significant differences in non-cardiac deaths or hospital readmissions between the 3
different dose-groups
 No significant differences in HR between the all 3 groups after up-titration
The clinical outcome of BB therapy is independent of BB dose when the target HR is achieved
Strengths:
 Evaluated elderly patients with multiple comorbidities (increased generalizability of results)
 Evaluated optimal clinical outcomes (mortality/morbidity)
 Appropriate duration (5 year follow-up)
 Used guideline recommended BBs
Limitations:
 Small sample size
 Retrospective study
 Differences in baseline characteristics
Table 9. Pelaez J., Garcia M., et al. Relationship between different doses of beta-blockers and prognosis in
elderly patients with reduced ejection fraction. Intl J Cardiology 2016.220: 219–225.
Purpose
Study Design
Inclusion criteria
Exclusion criteria
Outcomes
Methods
To determine the impact of different doses of BBs on survival and admission for HF in elderly
patients with reduced ejection fraction (REF)
Single-center observational study
 Age ≥ 75yo
 LVEF ≤ 35%
 Patients who died or suffered a major cardiovascular event (HF admission requiring
intravenous diuretics or sustained ventricular arrhythmia) within this time period
Primary
 Time to all-cause death
Secondary
 Time to first HF admission requiring intravenous diuretics
 Between January 2008 to June 2014, 784 patients were assessed for eligibility
Peterson, Page 10 of 20


Statistics
Results
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Six months after diagnosis, patients were divided into 3 groups depending on BB dose: no
BB (NBB), low dose(LD) <50% of the target dose, and high dose (HD) ≥50% of the target
dose
The maximal tolerated doses of carvedilol, bisoprolol, metoprolol, and nebivolol were
recorded for calculations of the ratio of maximal tolerated dose/recommended target dose
(50 mg daily for carvedilol, 10 mg for bisoprolol and nebivolol, and 200 mg for metoprolol
succinate)
Quantitative datamedian and interquartile range (IQR)
ANOVA comparison between quantitative variables
Linear association X2 test and likelihood ratio X2 test compare qualitative variables
Kaplan Meier survival curves
Log- rank test comparison between groups
Multivariate Cox proportional hazard and propensity-score matched analysis  avoid
potential cofounding factors
Significance P<0.05
Out of 784 patients, 559 were included with a median age of 81.3 years, 134 of whom
(24.0%) were not taking BBs, 259 (46.3%) were taking <50% of the target dose, and 166
(29.7%) were taking 50% or more of the target dose
 Baseline characteristics between the groups were similar with significant
differences in age, QRS complex width, resting HR, chronic obstructive pulmonary
disease (COPD), cognitive impairment, functional disability, ischemic etiology of
REF, NYHA class, in the use of implantable cardioverter defibrillator (ICD), and
ivabradine
Reported reasons for lack of BB treatment were the following: COPD (35.1%),
bradyarrhythmia (13.4%), symptomatic hypotension (6.0%), concomitant use of sotalol
(6.0%), and unknown causes (39.5%)
Bisoprolol was the most frequently used BB (59.3%), followed by carvedilol (37.4%),
metoprolol succinate (2.4%), and nebivolol (0.9%)
Median follow-up was ~30 months
Primary Outcome:
o 212 deaths (NBB: 70 (52.2%); LD: 94 (36.3%); HD: 48 (28.9%))
 Cause of death was unknown in 93 (43.9%) patients, 79 (37.3%) died from
non-cardiac causes, 6 (2.8%) from sudden death, and 34 (16%) from nonsudden cardiac death
Secondary Outcome:
o 171 HF admissions (NBB: 42 (31.3%); LD: 85 (32.8%); HD: 44 (26.5%))
Both LD and HD were associated with improved survival, with no differences between
them (HD vs. NBB = 0.67, 95% CI (0.46–0.98), P= 0.037; HD vs. LD = 1.03, 95% CI (0.72–
1.46), P= 0.894; and LD vs. NBB = 0.65, 95% CI (0.48–0.90), P= 0.009)
BB therapy failed to show benefits in HF admissions
Peterson, Page 11 of 20
Author’s
Conclusions
Comments
BB therapy was associated with a significant reduction in mortality and was not associated
with a decrease in HF admissions among elderly patients with REF, regardless of dose
Strengths:
 Appropriate statistics (i.e. propensity score matching)
 Representative of elderly population reflection of real- world clinical practice (comorbidities, +/- BB target doses)
 Assessed optimal clinical outcomes (mortality/morbidity)
Limitations:
 Single- center observational study
 Excluded patients with serious events in the first 6 months after diagnosis  limits
applicability of results to elderly patients with severe REF
 Did not collect data on changes in BB doses during follow-up
 Included BB (nebivolol) not shown to reduce mortality
 Did not evaluate safety  reasons for up-titration failure
Peterson, Page 12 of 20
A. Literature review summary
i. 2002 Sin et al.
1. Reported a 28% reduction in mortality and 18% reduction in hospitalizations which
was consistent with the data from the previous trials of BBs
2. All doses of BBs were associated with benefit, but there was a trend towards greater
benefit in patients receiving higher doses
ii. 2015 Barywani et al.
1. Recommend patients receive the highest tolerable doses of BB vs target doses
a. No statistically significant differences in survival or morbidity were observed
between the different BB dosing groups
iii. 2016 Pelaez et al.
1. Provide evidence that BB treatment improved survival, at low or high doses, in the
elderly (≥75 yo) patients with HF (LVEF ≤35%)
a. This effect of BB on survival is independent of the target dose reached
2. BB treatment in this patient population has no relationship to probability of HF
hospitalizations
B. Literature review discussion 11-13, 20-23
i. Survival is independent of BB dose in the elderly
ii. Trials suggest HR may be an appropriate indicator for optimized therapy
iii. BB doses may not be associated with reductions in HF admissions due to this patient
population having a high number of comorbidities that may mask or mimic HF symptoms
iv. Proposed that achieving target BB doses in the elderly does not always guarantee optimal
treatment
X.
Safety
A. Studies suggests that BBs are mostly well-tolerated in the elderly
B. Most common reported reasons for up-titration failure include:
i. Symptomatic bradycardia, symptomatic hypotension, and pulmonary adverse events
XI.
Conclusion
A. Up-titration of BBs to target doses in the elderly is challenging
i. Limited by age, polypharmacy, bradycardia, hypotension, etc.
B. According to current literature, achieving target doses in the elderly is not associated with better
survival outcomes
i. Benefit on morbidity is inconsistent
C. Randomized controlled trials are needed to determine the optimal BB doses in elderly HF patients
D. Would recommend to initiate BBs in this patient population at low doses and titrate up to the
highest tolerated dose based on HR and BP
Peterson, Page 13 of 20
XII.
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Peterson, Page 14 of 20
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http://www.who.int/healthinfo/survey/ageingdefnolder/en
Peterson, Page 15 of 20
Appendix:
Appendix A.
Figure 2 and 3. Pathophysiology of HF3
Peterson, Page 16 of 20
Appendix B.
Table 10 Guideline Treatment Recommendations1-2
Recommendations for Pharmacological Therapy for Management of Stage C HFrEF
Peterson, Page 17 of 20
Table 11. Recommendations for Treatment of HFpEF
Table 12 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for HF: an update of the 2013
ACCF/AHA guideline recommendations
Peterson, Page 18 of 20
Appendix C.
Table 13. Pharmacology of BBs recommended by 2013 ACCF/AHA HF guidelines6,17
Drug
Carvedilol
Metoprolol Succinate
Mechanism of
Blockade
Dosing
considerations
Warning
Absorption
Metabolism/
Distribution
Excretion
Half- Life
Absolute
Contraindications
Relative
Contraindications
Most common
Drug Interactions
Most common
Adverse Reactions
Pregnancy
Monitoring
Bisoprolol *
Non-selective α1,β1,β2
β1 selective
β1 selective
IR: (Initial dose) 3.125mg BID; double
dose every 2 weeks to target dose
Maximum recommended dose:
Mild to moderate HD:
<85 kg: 25 mg BID
>85 kg: 50 mg BID
Severe HF:
25 mg BID
Initial: 25 mg once daily
(reduce to 12.5 mg once
daily in NYHA class higher
than class II); may double
dosage every 2 weeks as
tolerated up to target dose
of 200 mg/day
Initial: 1.25 mg once
daily; may double
dosage every 2 weeks
as tolerated up to
target dose of 10 mg
once daily
ER: (Initial dose) 10mg once daily,
titrate dose every 2 weeks
Maximum dose:
80mg once daily
Therapy should not be withdrawn abruptly, but gradually tapered over 1 to 2 weeks to avoid
acute tachycardia, hypertension, and/or ischemia
Rapid and extensive; delayed with
Rapid
Rapid
food
Extensively (98%) hepatic via CYP2D6 Extensively hepatic via
Extensively hepatic
Vd: 115 L; distributes into
CYP2D6; Vd: 3.2 to 5.6 L/kg;
Widely distributed;
extravascular tissues
crosses the blood brain
highest concentrations
barrier
in heart, liver, lungs,
and saliva; crosses
blood-brain barrier
Primarily feces
Primarily urine
Primarily urine
7 to 10 hours
3 to 4 hours
9 to 12 hours
Advanced heart block (2nd or 3rd degree), Sick sinus syndrome (without a functional
pacemaker), severe bradycardia (<50 bpm), cardiogenic shock, decompensated HF
Caution in HF, COPD, diabetes, and peripheral vascular disease, asymptomatic hypotension,
sinus bradycardia (50 to 60 bpm), depression
CYP2D6 substrates
CYP2D6 substrates
CYP3A4 substrates
Hypotension (9% to 20%), dizziness
(2% to 32%), fatigue (4% to 24%),
hyperglycemia (5% to 12%), weight
gain (10% to 12%), diarrhea (1% to
12%)
Hypotension (1% to 27%),
bradycardia (2% to 16%),
dizziness (2% to 10%),
fatigue (1% to 10%),
depression (>2% to 5%)
C
C
HR, BP, renal function, liver function, blood glucose in diabetics
Fatigue (dose related;
6% to 8%), diarrhea
(dose related; 3% to
4%), upper respiratory
infection (5%), rhinitis
(3% to 4%)
C
*Not FDA approved for HF in US
Peterson, Page 19 of 20
Appendix D.
Table 14. Major Placebo- Controlled Trials of BBs Supporting HF Guideline Recommendations 1-2
Drug
Trial
Mean
N
Patient
Mean
Target
% Achieved
follow
Population
age
dose
Target dose
-up
(yo)
Metoprolol
MERIT-HF
1 yr
3991 NYHA ll-lV;
64
200mg
64%
XL
(1999)
LVEF <40%;
daily
Bisoprolol*
CIBIS-II
(1999)
1.3 yrs
2647
Carvedilol
COPERNICUS
(2002)
10.4
mo
2289
NYHA class
III-IV; LVEF
<35%
NYHA class
lV; LVEF
<25%
Mortality/
Morbidity
(RRR)
↓ 34%/ ↓ 18%
61
10mg
daily
48%
↓ 34%/ ↓ 20%
63
25mg BID
65%
↓ 35%/ ↓ 20%
*Not FDA approved for HF in US
CIBIS-II (Cardiac Insufficiency Bisoprolol Study II)
MERIT-HF (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure)
COPERICUS (Carvedilol Prospective Randomized Cumulative Survival)
APPENDIX E.
Table 16. BB Clinical Trials Included in Meta-analysis26
Drug
Trial
Mean
N
Patient
follow-up
Population
(mo)
Metoprolol
MERIT-HF
12
3991
NYHA ll-lV;
XL
(1999)
LVEF <40%
Mean
age
(yp)
64
Inclusion
Criteria
(Age, yo)
40-80
% ≥70yo
31%
Mortality/
Morbidity
(RRR)
↓ 34%/ ↓ 18%
NYHA class
III-IV; LVEF
<35%
NYHA class
lV; LVEF
<25%
61
18-80
20%
↓ 34%/ ↓ 20%
63
≥18
NR
↓ 35%/ ↓ 20%
Bisoprolol*
CIBIS-II
(1999)
15.6
2647
Carvedilol
COPERNICUS
(2002)
10.4
2289
Carvedilol
Carvedilol U.S.
Trials (1996)
6.5
1094
NYHA ll-lV;
LVEF <35%
59
≥18
NR
↓ 65%/ ↓ 27%
Bucindolol*
BEST (2001)
24
2708
NYHA llI-lV;
LVEF <35%
60
>18
28%
NS/ ↓ 8%
NS= non-significant, NR= Not reported
*Not FDA approved for HF in US
BEST (Beta-Blocker Evaluation of Survival Trial)
Peterson, Page 20 of 20