Target dose vs highest tolerated dose: Beta blocker …sites.utexas.edu/phr-residencies/files/2015/07/10-7-J...Peterson, Page 1 of 20 Target dose vs highest tolerated dose: Beta blocker

Peterson, Page 1 of 20

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


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


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

D Refractory HF requiring specialized interventions

IV Unable to carry on any physical activity without symptoms of HF

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

0.21.5

6.6

10.6

0.6 1.2

4.8

13.5

02468

10121416

20-39 40-59 60-79 80+

Per

cen

tage

Age (years)

Prevalence of HF by sex and age (National Health and Nutrition Examination Survey 2009-2012)

Male

Female


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


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


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


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 up-

titration 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?


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 Evaluate the associations between BBs and outcomes in older HF patients

Study Design Retrospective cohort study

Inclusion criteria All residents of Alberta, Canada ≥ 65 years old who had at least 1 hospitalization for HF between 1994 and 1999

Exclusion criteria Patients who died during the index hospitalization Patients who had been hospitalized for HF in the 2 years before the index hospitalization

Outcomes All-cause mortality HF hospitalization

Methods 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)

Statistics 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

Results 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)

Author’s Conclusions

The benefits of BBs seen in randomized trials extend to a broader population of elderly patients with HF


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 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

Study Design Retrospective chart review of 2 outpatient HF clinics

Inclusion criteria ≥80 yo LVEF ≤40%

Exclusion criteria

LVEF >40%

Outcomes Primary: All-cause mortality after ≥ 5 years Secondary: 5-year cardiac mortality Hospitalization due to worsening HF

Methods 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%)

Statistics 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


Results 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

Comments 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 To determine the impact of different doses of BBs on survival and admission for HF in elderly patients with reduced ejection fraction (REF)

Study Design Single-center observational study

Inclusion criteria Age ≥ 75yo LVEF ≤ 35%

Exclusion criteria Patients who died or suffered a major cardiovascular event (HF admission requiring intravenous diuretics or sustained ventricular arrhythmia) within this time period

Outcomes Primary Time to all-cause death Secondary Time to first HF admission requiring intravenous diuretics

Methods Between January 2008 to June 2014, 784 patients were assessed for eligibility


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)

Statistics Quantitative datamedian 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

Results 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 non-sudden 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



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

Comments Strengths: Appropriate statistics (i.e. propensity score matching) Representative of elderly population reflection of real- world clinical practice (co-

morbidities, +/- 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


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


XII. References

1. Yancy CW, et al. 2013 ACCF/AHA guideline for the management of heart failure. Circulation. 2013;

128:240-327.

2. Yancy CW, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart

failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure. Circulation.

2016; 134:1-46.

3. Moore, T and Anderson, J. Chapter 2. Heart failure. Pharmacotherapy in Primary Care. Eds. William

D. Linn, et al. New York, NY: McGraw-Hill, 2009.

4. Mann, Douglas L., and Murali Chakinala. "Heart Failure: Pathophysiology and Diagnosis." Harrison's

Principles of Internal Medicine, 19e. Eds. Dennis Kasper, et al. New York, NY: McGraw-Hill, 2015. n.

pag. AccessMedicine. Web. 3 Sep. 2016.

5. McMurray, J., Packer, M., et al. Angiotensin–neprilysin Inhibition versus enalapril in heart failure. N

Eng J Med 371; 11(2014):993-1004.

6. Lexicomp Online®, Pediatric & Neonatal Lexi-Drugs®, Hudson, Ohio: Lexi-Comp, Inc. August 2016.

7. Rich MW. Chapter 78. Heart Failure. In: Halter JB, Ouslander JG, Tinetti ME, Studenski S, High KP,

Asthana S. eds. Hazzard's Geriatric Medicine and Gerontology, 6e. New York, NY: McGraw-Hill; 2009

8. Diez-Villanueva P. and Fernando, A. Heart failure in the elderly. J Ger Card. 2016. 13:115-117.

9. Lien C, Gillespie N, et al. Heart failure in frail elderly patients: diagnostic difficulties, comorbidities,

polypharmacy and treatment dilemmas. Eur J Heart Fail 2002; 4: 91–98.

10. Cacciatore F, Abete P, Mazzella F, et al. Frailty predicts longterm mortality in elderly subjects with

chronic heart failure. Eur J Clin Invest 2005; 35: 723–730.

11. Moser DK, Dracup K, Evangelista LS, et al. Comparison of prevalence of symptoms of depression,

anxiety, and hostility in elderly patients with heart failure, myocardial infarction, and a coronary

artery bypass graft. Heart Lung 2010; 39:378–385.

12. Dobre D., Haaijer-Ruskamp F., et al. B-adrenoreceptor antagonists in elderly patients with heart

failure. Drug Aging. 2007. 24: 1031-44.

13. 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.

14. 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.

15. Gelbrich G., Edelmann F., et al. Is target dose the treatment target? uptitrating beta-blockers for

heart failure in the elderly . Intl J Cardiology 2012. 155:160–166.

16. Gheorghiade M., Colucci W., et al. B-blockers in chronic heart failure. Circulation, 2003; 107:1570-

75.

17. Beta blockers. Micromedex. Truven Health Analytics. August 2016.

18. Malek, Filip. Reaching betablockers target dose in elderly patients with chronic heart failure. Cor Et

Vasa. 2014,56:37-41.

19. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial, Lancet. 1999;353: 9–13.

20. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomize intervention trial in

congestive heart failure (MERIT-HF), Lancet.1999; 353:2001–2007.

21. Packer M., Fowler M., et al. Effect of carvedilol on the morbidity of patients with severe chronic

heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS)

study, Circulation. 2002:106:2194–99.


22. Dungen H., Apostolovic S., et al. On behalf of CIBIS-ELD Investigators. Titration to target dose of

bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBISELD trial, European Journal of

Heart Failure. 2011; 13:670–680.

23. Calvert MJ, Shankar A, McManus RJ, Ryan R, Freemantle N. Evaluation of the management of heart

failure in primary care. Fam Pract 2009;26:145–153.

24. Komajda M, Follath F, Swedberg K, et al. The Euroheart Failure Survey programme—a survey on the

quality of care among patients with heart failure in Europe: Part 2: treatment. Eur Heart J 2003;24:

464–474.

25. Cheng J., et al. A review of heart failure management in the elderly population. Am J Geriatr

Pharmacother. 2009; 7:233–249.

26. Dulin B., et al. Do elderly systolic heart failure patients benefit from beta blockers to the same

extent as the non-elderly? meta-analysis of >12,000 patients in large-scale clinical trials. Am J Cardiol

2005;95:896–898.

27. Word Health Organization. 2016. Accessed on September 25, 2016. Available at:

http://www.who.int/healthinfo/survey/ageingdefnolder/en


Appendix:

Appendix A.

Figure 2 and 3. Pathophysiology of HF3


Appendix B.

Table 10 Guideline Treatment Recommendations1-2

Recommendations for Pharmacological Therapy for Management of Stage C HFrEF


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


Appendix C.

Table 13. Pharmacology of BBs recommended by 2013 ACCF/AHA HF guidelines6,17

Drug Carvedilol Metoprolol Succinate Bisoprolol *

Mechanism of Blockade

Non-selective α1,β1,β2 β1 selective β1 selective

Dosing considerations

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 ER: (Initial dose) 10mg once daily, titrate dose every 2 weeks Maximum dose: 80mg once daily

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

Warning Therapy should not be withdrawn abruptly, but gradually tapered over 1 to 2 weeks to avoid acute tachycardia, hypertension, and/or ischemia

Absorption

Rapid and extensive; delayed with food

Rapid Rapid

Metabolism/ Distribution

Extensively (98%) hepatic via CYP2D6 Vd: 115 L; distributes into extravascular tissues

Extensively hepatic via CYP2D6; Vd: 3.2 to 5.6 L/kg; crosses the blood brain barrier

Extensively hepatic Widely distributed; highest concentrations in heart, liver, lungs, and saliva; crosses blood-brain barrier

Excretion Primarily feces Primarily urine Primarily urine

Half- Life 7 to 10 hours 3 to 4 hours 9 to 12 hours

Absolute Contraindications

Advanced heart block (2nd or 3rd degree), Sick sinus syndrome (without a functional pacemaker), severe bradycardia (<50 bpm), cardiogenic shock, decompensated HF

Relative Contraindications

Caution in HF, COPD, diabetes, and peripheral vascular disease, asymptomatic hypotension, sinus bradycardia (50 to 60 bpm), depression

Most common Drug Interactions

CYP2D6 substrates CYP2D6 substrates CYP3A4 substrates

Most common Adverse Reactions

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%)

Fatigue (dose related; 6% to 8%), diarrhea (dose related; 3% to 4%), upper respiratory infection (5%), rhinitis (3% to 4%)

Pregnancy C C C

Monitoring HR, BP, renal function, liver function, blood glucose in diabetics *Not FDA approved for HF in US


Appendix D.

Table 14. Major Placebo- Controlled Trials of BBs Supporting HF Guideline Recommendations 1-2

Drug Trial Mean follow

-up

N Patient Population

Mean age (yo)

Target dose

% Achieved Target dose

Mortality/ Morbidity

(RRR)

Metoprolol XL

MERIT-HF (1999)

1 yr 3991 NYHA ll-lV; LVEF <40%;

64 200mg daily

64% ↓ 34%/ ↓ 18%

Bisoprolol* CIBIS-II (1999)

1.3 yrs 2647 NYHA class III-IV; LVEF

<35%

61 10mg daily

48% ↓ 34%/ ↓ 20%

Carvedilol COPERNICUS (2002)

10.4 mo

2289 NYHA class lV; LVEF

<25%

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

follow-up

(mo)

N Patient

Population

Mean

age

(yp)

Inclusion

Criteria

(Age, yo)

% ≥70yo Mortality/

Morbidity

(RRR)

Metoprolol XL

MERIT-HF (1999)

12 3991 NYHA ll-lV; LVEF <40%

64 40-80 31% ↓ 34%/ ↓ 18%

Bisoprolol* CIBIS-II (1999)

15.6 2647 NYHA class III-IV; LVEF

<35%

61

18-80 20% ↓ 34%/ ↓ 20%

Carvedilol COPERNICUS (2002)

10.4 2289 NYHA class lV; LVEF

<25%

63

≥18

NR ↓ 35%/ ↓ 20%

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)

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