Beta-Blockade in HFpEF: Are They pEFerred?

Sarah Rumbellow, Pharm.D. PGY2 Internal Medicine Resident

South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy

UT Health San Antonio

August 24, 2018

Objectives 1. Describe the epidemiology and classification of heart failure (HF)2. Compare and contrast pathophysiology and treatment options for HF with preserved ejection fraction (HFpEF)

and HF with reduced ejection fraction (HFrEF)3. Apply guideline recommendations to treat patients with HFpEF and HFrEF4. Analyze available data on use of beta-blockers in HFpEF to make a patient-specific treatment recommendation

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Heart Failure Definition 1. Complex clinical syndrome 2. Result of structural or functional impairment1,2 3. Leads to impaired ability to fill and/or eject blood to meet the body’s metabolic needs, elevated intracardiac

pressures1-3

Epidemiology

1. HF1

a. Lifetime risk of 20% for Americans age 40 years b. Incidence of HF increases with age

i. Approximately 20 cases per 1000 people age 65-69 years

ii. More than 80 cases per 1000 people age 85 years c. Higher prevalence of HF in men compared to women and in blacks compared to Caucasians d. Mortality rate of approximately 50% within 5 years of HF diagnosis

2. Economic impact1

a. More than 1 million hospitalizations annually for primary diagnosis of HF b. One-month readmission rate of 25% for HF c. Total cost exceeds $30 billion annually in the United States (US)

Pathophysiology (Appendix A) 1. Risk factors for HF1

a. Hypertension (HTN) b. Diabetes (DM) c. Metabolic syndrome d. Atherosclerotic disease, such as coronary artery disease (CAD), specifically in HFrEF

2. Disease states associated with development of HF1

a. Cardiomyopathy (dilated, familial, obesity, diabetic, peripartum, stress-related)

b. Toxic cardiomyopathy – alcohol, cocaine, chemotherapy

c. Thyroid disease d. Acromegaly and growth hormone deficiency e. Tachycardia

f. Inflammation (e.g. myocarditis, AIDS, Chagas disease)

g. Hypersensitivities h. Rheumatoid disorders i. Iron overload j. Amyloidosis k. Sarcoidosis

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Figure 1: Pathophysiology of HF

3. Compensatory responses4 a. Initial responses are protective and beneficial b. Long-term will lead to detrimental effects and cause HF

Table 1: Compensatory responses in HF4

Compensatory Response Beneficial Effect Detrimental Effects

Sodium and water retention to increase preload

Optimization of stroke volume by Frank-Starling mechanism

Pulmonary and systemic congestion Increased myocardial oxygen demand

Vasoconstriction Maintenance of blood pressure with reduced cardiac output Shunting of blood from nonessential organs to brain and heart

Increased myocardial oxygen demand Increased afterload decreases stroke volume, activates compensatory responses

Sympathetic nervous system (SNS) activation leading to tachycardia and increased contractility

Maintenance of cardiac output Increased myocardial oxygen demand Shortened diastolic filling time Beta-1 receptor downregulation and decreased sensitivity Increased arrhythmia risk Increased myocardial cell death

Ventricular remodeling and hypertrophy

Maintenance of cardiac output Reduction in myocardial wall stress Decreased myocardial oxygen demand

Increased myocardial cell death Increased arrhythmia risk Increased myocardial ischemia Fibrosis

Adapted from DiPiro, et al.4

Clinical presentation Table 2: Signs and symptoms of HF1,2

HFpEF Elevated jugular venous pressure Hepatojugular reflex Third heart sound (gallop rhythm) Laterally displaced apical impulse Dyspnea on exertion Paroxysmal nocturnal dyspnea Orthopnea

Fatigue Pulmonary or splanchnic congestion Reduced exercise tolerance

HFrEF

Peripheral edema

Classification of HF

Figure 2: Comparison of systolic and diastolic dysfunction

1. Based on LVEF 2. Importance1

a. Each LVEF range associated with distinct demographics, comorbidities, prognoses, responses to therapy, and therefore different treatment options

b. Clinical trials often select patients based on LVEF 3. Reason for classification by LVEF2

a. Patients with HFrEF can have evidence of diastolic dysfunction b. Subtle abnormalities common in HFrEF can also occur in HFpEF

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Table 3: HF classification by LVEF1,2

Classification LVEF (%) Description

HFrEF 40% Also called “systolic” dysfunction Guideline definitions of EF for this category vary

HFmrEF (also known as HFbEF)

41% - 49% Characteristics similar to HFpEF, new definition per ESC 2017 guidelines Likely have primarily mild systolic dysfunction with features of diastolic dysfunction Must also have elevated natriuretic peptides and evidence of either structural heart disease or diastolic dysfunction

HFpEF 50% Also called “diastolic” dysfunction, “normal” ejection fraction Must also have elevated natriuretic peptides and either structural heart disease or diastolic dysfunction

HFrEF: heart failure with reduced ejection fraction; HFpEF: heart failure with preserved ejection fraction; HFmrEF: heart failure with mid-range ejection fraction; HFbEF: heart failure with borderline ejection fraction

4. More information in Appendix B

Classification by structural abnormalities and symptoms Table 4: American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) HF stages4

Stage Characteristics

A At high risk of HF but without structural heart disease or symptoms of HF

B Structural heart disease but without signs or symptoms of HF

C Structural heart disease with prior or current symptoms of HF

D Refractory HF requiring specialized interventions

Classification by symptoms and limitations Table 5: New York Heart Association (NYHA) classes of HF4

Class Characteristics

I No limitation on physical activity, ordinary activity does not cause symptoms

II Slight limitation on physical activity, comfortable at rest, ordinary activity results in symptoms

III Marked limitation on physical activity, comfortable at rest, less than normal activity causes symptoms

IV Symptoms occur at rest

Treatment of Heart Failure: Guideline Recommendations European Society of Cardiology (ESC) guideline2 1. Treat comorbidities to prevent HF: HTN, obesity, DM, smoking cessation, statins in CAD, beta-blocker and angiotensin

converting enzyme inhibitor (ACEI) in patients with history of MI

2. Consider empagliflozin in DM to delay or prevent HF (new 2016 recommendation) 3. HF mid-range ejection fraction (HFmrEF) or HFbEF

a. ESC added HFmrEF as a classification of HF in 2016 guideline b. Recommend treatment of HFmrEF based on HFpEF therapy at this time due to lack of data in HFmrEF

ACCF/AHA guideline1,5 1. Treat comorbidities: HTN, lipid disorders, obesity, DM, smoking cessation, statins if history of MI 2. Sodium restriction in patients with congestive symptoms 3. Fluid restriction in stage D HF 4. Education for all HF patients

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Heart Failure with Preserved Ejection Fraction Epidemiology of HFpEF 1. Studies estimate that 40-50% of patients with clinical HF have normal or minimally impaired LVEF1,3,6 2. Prevalence of HFpEF increased from 38% to 54% of all HF from 1987 to 20011,3 3. Lower mortality rate for HFpEF compared to HFrEF3 4. Lower risk of in-hospital mortality for HFpEF compared to HFrEF (2.9% vs. 3.9%; p 0.0001); similar rate of overall

mortality7 5. Survival increased for HFrEF patients, but not for HFpEF patients3 Table 6: Characteristics of patients with HFpEF

Common comorbidities Epidemiology

History of HTN1,3,6,8,9 Non-ischemic etiology of HF7 Lower incidence of CAD compared to HFrEF3,10 Cardiovascular comorbidities common, estimates of incidence vary3 Lower incidence of atrial fibrillation compared to HFrEF8

Generally older1,3,6-9 More commonly women1,3,6,7 May receive less cardiovascular medication than in HFrEF8

Pathophysiology of HFpEF 1. Diverse and heterogenous causes2 2. Most commonly attributed to HTN1,11

a. HTN present in 60-89% of HFpEF cases b. Often due to SNS hyperactivation c. Leads to shorter LV diastolic filling time, increased risk of tachyarrhythmias

3. May see increased LV wall thickness, increased left atrial size2

Diagnosis of HFpEF 1. More difficult than HFrEF2 2. LVEF cutoffs used to define HFpEF vary based on guideline1 3. No validated “gold standard” for diagnosis recognized2 4. Most accurate diagnostic method is invasive measurement of LV filling pressures.3 5. Possible HFpEF diagnostic criteria1-3

a. Clinical signs and symptoms of HF b. Evidence of normal LV systolic function (LVEF ≥ 40%) c. Evidence of impaired LV diastolic function based on echocardiography or cardiac catheterization d. Demonstration of underlying cardiac cause e. Other proposed criteria

i. Elevated levels of natriuretic peptides (e.g. brain natriuretic peptide(BNP)) ii. Objective evidence of other cardiac structural and functional alterations iii. Stress test or measurement of LV filling pressure if uncertain

f. Largely a diagnosis of exclusion Complications and outcomes 1. Prognosis of HFpEF2

a. Various risk scores exist b. Applicability and utility remain uncertain

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2. Hospitalizations in HFpEF a. HF hospitalizations less frequent in the HFpEF population9 b. Hospitalizations and deaths are more likely to be non-cardiovascular for HFpEF and HFmrEF compared to

HFrEF2,9 c. Readmission rates similar to those of HFrEF6

3. Death in HFpEF6,12

a. Most commonly caused by sudden death and HF b. Disparity may be accounted for by structural and functional differences between HFpEF and HFrEF patients c. Preserved systolic function does not equate with better prognosis

Guideline Recommendations: Treatment of HFpEF

1. ESC recommendations for treatment of HFpEF2 c. Diuretics to improve symptoms of volume overload d. Inconsistent evidence for ACEIs and angiotensin receptor blockers (ARBs); lack of evidence for

mineralocorticoid receptor antagonists (MRAs) e. Lack of evidence for beta-blocker benefit f. For patients in sinus rhythm, potential decrease in hospitalizations with use of nebivolol, digoxin,

spironolactone, and candesartan g. No agents have been shown to reduce mortality

2. ACC/AHA recommendations for treatment of stage C HFpEF 5

a. Control systolic and diastolic pressure according to current guidelines (strength I, level B evidence) b. Use diuretics for symptoms of volume overload (strength I, level C evidence) c. Manage CAD and atrial fibrillation based on guidelines (strength IIa, level C evidence) d. Consider ARB to decrease hospitalizations (strength IIb, level B evidence) e. Consider MRAs to decrease hospitalizations if:

i. LVEF > 45% ii. Elevated BNP iii. HF admission in past year

iv. eGFR > 30 ml/min v. Serum creatinine < 2.5 mg/dL vi. Potassium < 5 mEq/L

3. Recognized gaps in evidence

a. Definition of HFpEF, HFmrEF b. Underlying pathophysiology of HFpEF and HFmrEF c. Effective therapies for HFpEF and HFmrEF

Treatment of HF: Beta-Blockade Mechanism of action and proposed benefits in HF 1. Decreased myocardial oxygen demand4

a. Improved blood pressure control b. Improved, or prevention of, myocardial ischemia

2. Reduced heart rate4,13

a. Leads to increased diastolic filling time4,13 b. Improved myocardial perfusion4,13 c. Controlled ventricular rate

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3. Prevention of or reduced arrhythmias and therefore reduced sudden cardiac death13 4. Antihypertensive action13 5. Decreased LV hypertrophy, fibrosis, and progression of LV diastolic dysfunction13,14 6. Improved myocardial function 7. Neurohormonal blockade may improve imbalance in autonomic nervous system and decrease effects of maladaptive

SNS such as cardiac hypertrophy, cardiac fibrosis, apoptosis, arrhythmias 11

Evidence for beta-blockers in HFrEF 1. Most available data on treatment and outcomes is in this group1 2. HF trials mainly enroll patients in this category1 3. Use of beta-blockers causes a 24% relative reduction (4% absolute reduction) in all-cause mortality in HFrEF patients11

Evidence for beta-blockers in HFpEF Explored below in evidence review

Table 7: Guideline recommended beta-blocking agents1,2*

Agent Starting dose Target dose Notes

Bisoprolol 1.25 mg daily 10 mg daily Beta-1 selective

Metoprolol succinate 12.5 mg daily 200 mg daily Beta-1 selective; some beta-2 activity at doses > 100 mg daily

Nebivolol 1.25 mg daily 10 mg daily Beta-1 selective; also produces nitric-oxide dependent vasodilation which decreases vascular resistance

Carvedilol 3.125 mg twice daily 25 mg twice daily Less selective, proposed pleiotropic and antioxidant effects11 *Note: recommended for HFrEF for mortality benefit, not yet proven to decrease mortality in HFpEF

Remaining Questions 1. Trials have shown mixed data regarding renin-aldosterone-angiotensin system (RAAS) inhibitor benefits in HFpEF

a. Irbesartan did not change incidence of all-cause mortality in HFpEF; did not decrease death from any cause or hospitalization for cardiovascular cause in HF patients with LVEF≥ 45% (I-PRESERVE).12,15

b. Candesartan moderately decreased rate of hospital admissions for HF; did not decrease mortality for patients with NYHA functional class II-IV HF and LVEF ≥ 40% in the CHARM-HF trial16

c. Significant decrease in HF hospital and a trend toward lower composite all-cause mortality and hospital

readmission for HF in HFpEF patients age 70 years receiving perindopril compared to placebo17

2. Remaining question: do beta-blockers, which have clearly demonstrated benefit in HFrEF, also have benefit in HFpEF?

3. Must also consider if there is harm associated with beta-blocker use in HFpEF patients

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Clinical Question & Evidence Review

Table 8: SENIORS18

Van Veldhuisen, et al. J Am Coll Cardiol 2009;53(23):2150-58.

Study Aim

Pre-specified analysis of SENIORS trial data examining the effect of nebivolol in patients with LVEF 35% compared to LVEF > 35%; exploration of the interaction of EF with outcome

Methods19

Design Parallel-group, randomized, double-blind, multicenter, international trial

Patient Population

Key inclusion

• Age 70 years

• Clinical history of chronic HF

• At least one of the following: o Documented hospital

admission in prior 12 months with discharge diagnosis of HF

o Documented LVEF 35% in previous 6 months

Key exclusion

• New drug therapy for HF in 6 weeks prior to enrollment

• Change in CV drug therapy in 2 weeks prior to enrollment

• HF due mainly to uncorrected valvular disease

• Current use of, contraindication, or intolerance to beta-blocker

• Significant renal or hepatic dysfunction

• On waiting list for PCI or cardiac surgery

Intervention Nebivolol 1.25 mg daily titrated to maximally tolerated dose (target dose 10 mg daily) or placebo

Outcomes Primary: all-cause mortality or hospital admission for a CV cause (time-to-event analysis) Secondary: all-cause mortality Exploratory: CV hospitalization

Procedures • Baseline LVEF measured by echocardiography following randomization

• Study medication titrated every 2 weeks over a maximum of 16 weeks

• Visits every 1-2 weeks during titration, at 4 months, 6 months, then every 3 months

• 30-day safety follow-up after last drug administration

• Analysis broken into four groups based on LVEF: 30%, 31% to 35%, 36% to 46%, and > 46%

• Intention-to-treat analysis for all outcomes

• Cox proportional hazards model to assess influence of LVEF and other baseline characteristics

Results

Baseline characteristics: patients with LVEF > 35% were more often women, had better NYHA functional class, less CAD, more HTN; similar rate of ACEI, lower ARB, lower MRA use in LVEF > 35% group Mean LVEF: 36% for entire population, about 1/3 with LVEF > 35% Dose achieved: mean 7.6 mg for LVEF > 35%, 68% reached target dose overall Early discontinuation: 27% of patients in nebivolol arm, 25% in placebo arm Primary outcome for all patients: HR 0.86 (95% CI 0.74–0.99, p=0.039) - significant benefit of treatment with nebivolol Secondary outcomes for all patients: all non-significant except CV mortality or CV hospitalization which was lower in nebivolol group (HR 0.84, 95% CI 0.72–0.98, p=0.027) Outcomes based on LVEF

EF 35% EF > 35%

Outcome Nebivolol (n=678), n

(%)

Placebo (n=681), n

(%)

HR (95% CI) Nebivolol (n=380), n

(%)

Placebo (n=372), n

(%)

HR (95% CI), n (%)

p-value*

Primary outcome

218 (32.2) 135 (19.8) 0.86 (0.72-1.04)

110 (29.0) 125 (33.6) 0.81 (0.63-1.04)

0.720

All-cause mortality

115 (17.0) 135 (19.8) 0.84 (0.66-1.08)

52 (13.7) 55 (23.7) 0.91 (0.62-1.33)

0.718

*subgroup interaction

Do beta-blockers decrease morbidity and/or mortality for patients with HF and LVEF > 40%?

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All other secondary outcomes non-significant (p-values > 0.05)

Outcomes for LVEF 40%

Outcome Nebivolol (n=320) Placebo (n=323) HR (95% CI)

Primary outcome 92 (28.8) 108 (33.4) 0.82 (0.62-1.08)

All-cause mortality 44 (13.8) 48 (14.9) 0.92 (0.61-1.36)

All-cause mortality or HF hospitalization

67 (20.9) 75 (23.2) 0.88 (0.63-1.23)

CV mortality 28 (8.8) 35 (10.8) 0.80 (0.49-1.32)

Discussion

Critique Strengths

• Randomized, placebo-controlled design

• One of very few trials including patients with LVEF > 40%

• Measurement of change in LVEF

• Clinically relevant primary outcome

Limitations

• Weak confidence intervals

• Small proportion of patients with LVEF > 35%

• Target dose achieved by small percentage of patients

• Significant percentage of early discontinuations

• Limited power to detect interaction between LVEF and outcomes

• Potential for inclusion of patients in HFpEF group that did not have HF

• Cannot extrapolate results to other beta-blockers

Conclusions Authors: The SENIORS trial shows that nebivolol is well tolerated and effective in reducing mortality and

morbidity in patients age 70 years with HF, regardless of initial ejection fraction. Reviewer: This analysis suggests that nebivolol may decrease mortality and CV hospital admissions in elderly patients with HF and LVEF > 35%-40%. Unlikely that nebivolol benefits elderly patients with LVEF > 40%; however, unclear benefit in any group, results may be skewed.

EF: ejection fraction; LVEF: left-ventricular ejection fraction; CV: cardiovascular; PCI: percutaneous coronary intervention; NYHA: New York Heart Association; LV: left-ventricular; CAD: coronary artery disease; HTN: hypertension; HR: hazard ratio; CI: confidence interval; HF: heart failure; HFpEF: heart failure with preserved ejection fraction

Table 9: J-DHF 20 Yamamoto, et al. Eur J Heart Fail 2013;15:110-118.

Study Aim

Asses the effects of carvedilol in HFpEF patients in Japan

Methods21

Design Multicenter, prospective, randomized, open, blinded-endpoint, controlled trial

Patient Population

Key inclusion

• Age 20 years

• LVEF > 40% upon diagnosis of HF by echocardiography or radionuclide ventriculography

• Clinical diagnosis of HF based on modified Framingham criteria within 12 months before study entry

Key exclusion

• Arrhythmogenic right ventricular cardiomyopathy

• Precapillary pulmonary artery HTN

• Acute MI in 3 months prior to enrollment

• On waiting list for PCI or open-heart surgery or any procedure in last 3 months

• HR < 50 beats/minute, symptomatic hypotension

• Severe renal or hepatic insufficiency

• Change baseline therapy for or symptoms of HF in 1 month prior to study entry

• Contraindication or intolerance to beta-blocker

Intervention Randomized 1:1 to receive either carvedilol 1.25 mg BID (titrated to target dose 10 mg BID) or placebo

Outcomes Primary: composite of CV death and unplanned hospitalization for HF

Secondary: all-cause mortality, worsening of symptoms, increase in BNP by 30% in certain patients, unplanned hospitalization for HF, need for modification of HF treatment Other major outcomes: composite CV death and unplanned hospitalization for CV cause, composite all-cause death and unplanned hospitalization for HF, composite all-cause death and unplanned hospitalization for any CV causes

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Procedures • Stratification by age (< 75 years or 75 years) and LVEF ( 50% or > 50%)

• Standard CV therapy continued in both arms (excluding beta-blockers)

• Dose titration occurred over 8 weeks; maximally tolerated dose continued for duration of study

• Minimum follow-up period of 2 years

• ECG, echocardiography, chest x-ray, and blood sample obtained at study entry, 12 months, and 24 months

• Time-to-first-event analysis and intention-to-treat principle

• Power of 80% based on annual event rate of 30% in placebo arm, estimated risk reduction of 20% with carvedilol, two-sided alpha of 0.05, 3-year mean follow-up period, and total of 800 patients

Results

Patients: 245 patients randomized Follow-up: mean of 3.2 years Baseline characteristics: both arms similar at baseline, average age 72 years, 58% men, 80% with history of HTN, 48% with atrial fibrillation, mean BMI 24.1 kg/m2, mean baseline EF 63% Dose achieved: mean dose 7.5 mg/day, 21.7% of patients reached target dose of 20 mg Outcomes

Outcome Placebo (n=125), no. of patients

Carvedilol (n=120), no. of patients

Relative risk (95% CI) P-value

Primary composite 34 29 0.902 (0.543-1.486) 0.6854

All-cause mortality 21 18 0.990 (0.526-1.864) 0.9747

CV death or unplanned hospitalization for CV causes

52 38 0.768 (0.504-1.169) 0.2187

All-cause death or unplanned hospitalization for HF

39 36 0.990 (0.627-1.564) 0.9655

All-cause death or unplanned hospitalization

56 45 0.846 (0.570-1.255) 0.4054

All other secondary outcomes nonsignificant Subgroup analyses: no significant difference in any subgroup for primary outcome Analysis of carvedilol by dose:

• Carvedilol > 7.5 mg/day: composite CV or all-cause death, unplanned hospitalization for CV causes significantly lower compared to control (HR 0.539, 95% CI 0.303-0.959, p=0.0356)

• Same outcome trended toward significance in subgroup with LVEF 50% (HR 0.555, 95% CI 0.284-1.085, p=0.0646) Safety: carvedilol discontinued in 6 patients

Discussion

Critique Strengths

• Prospective, randomized trial design

• Specifically designed to assess patients with higher LVEF

• Beta-blocker with evidence for benefit in HFrEF

• Background therapy continued

Limitations

• No changes in therapy or symptoms allowed in month preceding enrollment

• Lower number enrolled than planned, rate of primary endpoint only 8% instead of anticipated 30%, underpowered

• Target dose achieved in low percentage of patients; lower than recommended target dose

• Echocardiogram not required for HFpEF diagnosis

• Results may not be applicable to United States population

Conclusions • Overall, carvedilol did not improve prognosis in HFpEF patients

• Trial indicates there may be an association between carvedilol dose and reduction of death or hospitalization for CV cause

• Standard dose carvedilol may decrease risk of death or hospitalization for CV cause

• Larger trials using higher doses of carvedilol are needed to draw firm conclusions about effects in HFpEF HFpEF: heart failure with persevered ejection fraction; LVEF: left-ventricular ejection fraction; HF: heart failure; MI: myocardial infarction; PCI: percutaneous coronary intervention; BID: twice daily; ECG: electrocardiography; CXR: chest x-ray; HTN: hypertension; BMI: body mass index; CI: confidence interval; HR: hazard ratio; HFrEF: heart failure with reduced ejection fraction

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1. Later analysis of risk factors for clinical outcomes in patients with HFpEF and effect on response to standard-dose carvedilol in patients enrolled in the J-DHF study22

a. Decreased LVEF associated with increased composite CV death and unplanned CV hospitalization b. DM, BMI, left atrial dimensions, increasing age, renal dysfunction, elevated serum BNP associated with

increases in poor clinical outcomes c. Benefit of standard dose (≥ 7.5 mg daily) carvedilol higher for patients with larger left atrial diameter d. Higher risk of HF development in obesity, but a better prognosis if elevated BMI; “obesity paradox”

Table 10: Meta-analysis of beta-blockers in HF stratified by LVEF23

Cleland, et al . Eur Heart J 2018;39:26-35.

Study Aim

Investigate the effect of beta-blockers on LVEF and prognosis, stratified according to baseline LVEF and heart rhythm

Methods24,25

Design26 Systematic review and meta-analysis using individual patient data conducted according to PRISMA guidance

Patient population

Inclusion

• Baseline LVEF available

• ECG showing either sinus rhythm, atrial fibrillation, or atrial flutter

Exclusion

• Heart block or paced rhythm at baseline

Intervention Database search for placebo-controlled trials recruiting > 300 patients with > 6 months planned follow-up and explicit reporting of mortality. Following selection of trials, collected individual patient data from each included trial.

Outcomes Primary: all-cause mortality, CV death Secondary: first CV hospitalization, composite of CV death and CV hospitalization

Procedures • Trial conducted by lead investigators from all relevant included trials

• All data cross-checked across various trial databases

• Only small amount of missing data

• Patients classified by heart rhythm and LVEF; separate analyses for sinus rhythm and atrial fibrillation/atrial flutter

• Primary outcome included deaths reported after study censor dates

• All analyses completed by intention-to-treat principle

• Secondary outcomes analyzed using time-to-event analysis

• Data censored at 3.3 years following randomization

• Sensitivity analyses: multivariable adjustment (prespecified), exclusion of patients with reported LVEF = 40% from mid-range group (post hoc)

• 2-tailed p-value of 0.05 considered significant

Results

Trials included: 11 RCTs that represent 95.7% of eligible participants recruited in RCTs, all with low risk of bias

Enrollment by LVEF: 721 patients with LVEF 40-49%, 317 with LVEF 50% Follow-up: mean 1.5 years Baseline characteristics: median age 65 years, 24% women, median LVEF 27%; no significant differences between groups; patients with higher baseline LVEF were older, more commonly women, had lower NYHA class, higher blood pressure, and less likely to have ischemic heart disease Association between LVEF and mortality: lower LVEF associated with decreased all-cause mortality with HR 1.16 for every 5% lower LVEF (95% CI 1.16-1.29 , p<0.0001)

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Outcomes by LVEF and rhythm

Outcome

Sinus rhythm Atrial fibrillation

LVEF 10-49% (n=570) LVEF 50% (n=241) LVEF 10-49% (n=146) LVEF 50% (n=73)

HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value

All-cause mortality 0.59 (0.34-1.03)

0.066 1.79 (0.78-4.10)

0.17 1.30 (0.63-2.67)

0.48 0.86 (0.19-3.94)

0.85

CV death 0.48 (0.24-0.97)

0.040 1.77 (0.61-5.14)

0.29 0.86 (0.36-2.03)

0.73 1.00 (0.10-9.91)

1.00

CV hospitalization 0.95 (0.68-1.32)

0.76 0.66 (0.37-1.18)

0.16 1.15 (0.57-2.32)

0.69 1.33 (0.56-3.16)

0.52

Composite CV death or CV hospitalization

0.83 (0.38-1.15)

0.23 0.66 (0.38-1.15)

0.14 1.06 (0.58-1.94)

0.84 1.17 (0.51-2.71)

0.71

Sensitivity & post hoc analyses: results did not differ from main results

Change in LVEF: larger increase for those in sinus rhythm assigned to beta-blockers (no difference if LVEF 50%) NNT for LVEF 40-49%: 21 to prevent one CV death

Discussion

Critique Strengths

• Analysis of individual patient data

• Inclusion of well-designed, low-bias RCTs

• Inclusion of patients with LVEF > 40%

• Sensitivity analysis to correct for confounding

Limitations

• Majority of included trials limited to patients with

LVEF 35%, limited data available for LVEF > 40%

• Short median follow-up

• Varied design and objectives of included trials

• LVEF 40-49% group weighted toward lower end of the range

Conclusions • In patients with LVEF 10-49%, use of beta-blockers improves LV function and reduces CV morbidity and mortality

• No demonstrated benefit of beta-blocker use in patients with LVEF 50%

• Authors propose possibility that HFmrEF (LVEF 40-49%) will be treated similarly to HFrEF in the future

• More trials needed to confirm outcomes of beta-blocker use for patients with HFpEF LVEF: left ventricular ejection fraction; PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses; AF: atrial fibrillation; CV: cardiovascular; RCT: randomized controlled trial; NYHA: New York Heart Association; IHD: ischemic heart disease; NNT: number needed to treat

Other available data 1. Meta-analyses results (Appendix C)

a. Beta-blockers may decrease mortality risk in HFpEF b. Mixed results regarding effect on hospitalizations

c. Results mainly for patients with LVEF 40% 2. Randomized and observational studies (Appendix D)

a. Mixed results, but several trials suggest benefit of beta-blockers b. Mixed results related to hospitalizations c. Most common benefit was decrease in mortality risk d. Benefits more commonly observed in elderly patients

e. Single trial found no benefit if LVEF 50%27

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Summary 1. HF is caused by long-term activation ang dysregulation of various compensatory mechanisms 2. HF can be broadly divided into three subsets: HFpEF, HFmrEF (or HFbEF), and HFrEF

a. Divisions are based on LVEF b. Each subset has unique epidemiology, risk factors, symptoms, and management strategies

3. Available clinical guidelines provide little direction on how to manage HFpEF due to relative lack of data in this population

4. Current guidelines do not recommend specifically for or against the use of beta-blockers in HFpEF 5. The SENIORS trial weakly suggests that use of nebivolol in elderly patients with HF with LVEF = 35%-40% may decrease

mortality and CV hospital admissions18 6. Results of the J-DHF trial indicate that carvedilol did not improve survival in patients with HFpEF; however, the study

also showed a correlation between carvedilol dose and mortality benefit with greater benefit for higher doses20 7. Most recently, a meta-analysis of RCTs found mortality benefit associated with the use of beta-blockers in patients

with LVEF up to 49%, but did not see the same benefit for those with LVEF ≥ 50% 8. Other meta-analysis and observational studies have mixed results but generally suggest a potential mortality benefit

with the use of beta-blockers in patients with LVEF > 40%

Recommendations 1. For patients with HF and LVEF of 40-49%, consider initiation of a beta-blocker to decrease morbidity and mortality 2. For patients with HF and LVEF ≥ 50%, use a beta-blocker only in the presence of another indication (e.g. atrial

fibrillation) as it does not appear that addition of a beta-blocker provides morbidity or mortality benefit in this group 3. At this time, evidence is not strong enough to give preference for one agent over another; however, providers may

consider using a beta-blocker previously shown to decrease mortality in the HFrEF population 4. If initiated, beta-blockers should be titrated to the highest tolerated dose with the understanding that “target doses”

have not been established in the HFpEF or the HFmrEF (HFbEF) populations 5. It is possible that in the future, HFmrEF will be treated as HFrEF (instead of HFpEF) 6. I propose a new cutoff of HFpEF as LVEF ≥ 50% and < 50% for treatment decisions

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References 1. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810-52. 2. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129-200. 3. Lam CS, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail 2011;13:18-28. 4. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy : a pathophysiologic approach. 9th edition. ed:1 online resource (xxxviii, 2586 pages). 5. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2017;136:e137-e61. 6. Tsutsui H, Tsuchihashi M, Takeshita A. Mortality and readmission of hospitalized patients with congestive heart failure and preserved versus depressed systolic function. Am J Cardiol 2001;88:530-3. 7. Fonarow GC, Abraham WT, Albert NM, et al. Prospective evaluation of beta-blocker use at the time of hospital discharge as a heart failure performance measure: results from OPTIMIZE-HF. J Card Fail 2007;13:722-31. 8. Lenzen MJ, Scholte op Reimer WJ, Boersma E, et al. Differences between patients with a preserved and a depressed left ventricular function: a report from the EuroHeart Failure Survey. Eur Heart J 2004;25:1214-20. 9. Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol 2012;59:998-1005. 10. Sweitzer NK, Lopatin M, Yancy CW, Mills RM, Stevenson LW. Comparison of clinical features and outcomes of patients hospitalized with heart failure and normal ejection fraction (> or =55%) versus those with mildly reduced (40% to 55%) and moderately to severely reduced (<40%) fractions. Am J Cardiol 2008;101:1151-6. 11. von Lueder TG, Kotecha D, Atar D, Hopper I. Neurohormonal Blockade in Heart Failure. Card Fail Rev 2017;3:19-24. 12. Zile MR, Baicu CF, Bonnema DD. Diastolic heart failure: definitions and terminology. Prog Cardiovasc Dis 2005;47:307-13. 13. Dobre D, van Jaarsveld CH, deJongste MJ, Haaijer Ruskamp FM, Ranchor AV. The effect of beta-blocker therapy on quality of life in heart failure patients: a systematic review and meta-analysis. Pharmacoepidemiol Drug Saf 2007;16:152-9. 14. Nishio M, Sakata Y, Mano T, et al. Beneficial effects of bisoprolol on the survival of hypertensive diastolic heart failure model rats. Eur J Heart Fail 2008;10:446-53. 15. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456-67. 16. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003;362:777-81. 17. Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27:2338-45. 18. van Veldhuisen DJ, Cohen-Solal A, Bohm M, et al. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol 2009;53:2150-8. 19. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215-25. 20. Yamamoto K, Origasa H, Hori M, Investigators JD. Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese Diastolic Heart Failure Study (J-DHF). Eur J Heart Fail 2013;15:110-8. 21. Hori M, Kitabatake A, Tsutsui H, et al. Rationale and design of a randomized trial to assess the effects of beta-blocker in diastolic heart failure; Japanese Diastolic Heart Failure Study (J-DHF). J Card Fail 2005;11:542-7. 22. Yamamoto K, Origasa H, Suzuki Y, et al. Relation of risk factors with response to carvedilol in heart failure with preserved ejection fraction - a report from the Japanese Diastolic Heart Failure Study (J-DHF). J Cardiol 2014;63:424-31. 23. Cleland JGF, Bunting KV, Flather MD, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 2018;39:26-35. 24. Kotecha D, Chudasama R, Lane DA, Kirchhof P, Lip GY. Atrial fibrillation and heart failure due to reduced versus preserved ejection fraction: A systematic review and meta-analysis of death and adverse outcomes. Int J Cardiol 2016;203:660-6. 25. Kotecha D, Holmes J, Krum H, et al. Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014;384:2235-43.

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26. Stewart LA, Clarke M, Rovers M, et al. Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. JAMA 2015;313:1657-65. 27. Tehrani F, Phan A, Chien CV, Morrissey RP, Rafique AM, Schwarz ER. Value of medical therapy in patients >80 years of age with heart failure and preserved ejection fraction. Am J Cardiol 2009;103:829-33. 28. Smith DT, Farzaneh-Far R, Ali S, Na B, Whooley MA, Schiller NB. Relation of beta-blocker use with frequency of hospitalization for heart failure in patients with left ventricular diastolic dysfunction (from the Heart and Soul Study). Am J Cardiol 2010;105:223-8. 29. Liu F, Chen Y, Feng X, Teng Z, Yuan Y, Bin J. Effects of beta-blockers on heart failure with preserved ejection fraction: a meta-analysis. PLoS One 2014;9:e90555. 30. Bavishi C, Chatterjee S, Ather S, Patel D, Messerli FH. Beta-blockers in heart failure with preserved ejection fraction: a meta-analysis. Heart Fail Rev 2015;20:193-201. 31. Fukuta H, Goto T, Wakami K, Ohte N. The effect of beta-blockers on mortality in heart failure with preserved ejection fraction: A meta-analysis of observational cohort and randomized controlled studies. Int J Cardiol 2017;228:4-10. 32. Zheng SL, Chan FT, Nabeebaccus AA, et al. Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Heart 2018;104:407-15. 33. Nodari S, Metra M, Dei Cas L. Beta-blocker treatment of patients with diastolic heart failure and arterial hypertension. A prospective, randomized, comparison of the long-term effects of atenolol vs. nebivolol. Eur J Heart Fail 2003;5:621-7. 34. Bergstrom A, Andersson B, Edner M, Nylander E, Persson H, Dahlstrom U. Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart Fail 2004;6:453-61. 35. Lund LH, Benson L, Dahlstrom U, Edner M, Friberg L. Association between use of beta-blockers and outcomes in patients with heart failure and preserved ejection fraction. JAMA 2014;312:2008-18. 36. Aronow WS, Ahn C, Kronzon I. Effect of propranolol versus no propranolol on total mortality plus nonfatal myocardial infarction in older patients with prior myocardial infarction, congestive heart failure, and left ventricular ejection fraction > or = 40% treated with diuretics plus angiotensin-converting enzyme inhibitors. Am J Cardiol 1997;80:207-9. 37. Chan JD, Rea TD, Smith NL, et al. Association of beta-blocker use with mortality among patients with congestive heart failure in the Cardiovascular Health Study (CHS). Am Heart J 2005;150:464-70. 38. Shah R, Wang Y, Foody JM. Effect of statins, angiotensin-converting enzyme inhibitors, and beta blockers on survival in patients >or=65 years of age with heart failure and preserved left ventricular systolic function. Am J Cardiol 2008;101:217-22. 39. Hernandez AF, Hammill BG, O'Connor CM, Schulman KA, Curtis LH, Fonarow GC. Clinical effectiveness of beta-blockers in heart failure: findings from the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) Registry. J Am Coll Cardiol 2009;53:184-92. 40. Gomez-Soto FM, Romero SP, Bernal JA, et al. Mortality and morbidity of newly diagnosed heart failure with preserved systolic function treated with beta-blockers: a propensity-adjusted case-control populational study. Int J Cardiol 2011;146:51-5. 41. Nevzorov R, Porath A, Henkin Y, Kobal SL, Jotkowitz A, Novack V. Effect of beta blocker therapy on survival of patients with heart failure and preserved systolic function following hospitalization with acute decompensated heart failure. Eur J Intern Med 2012;23:374-8. 42. Patel K, Fonarow GC, Ekundayo OJ, et al. Beta-blockers in older patients with heart failure and preserved ejection fraction: class, dosage, and outcomes. Int J Cardiol 2014;173:393-401. 43. Farasat SM, Bolger DT, Shetty V, et al. Effect of Beta-blocker therapy on rehospitalization rates in women versus men with heart failure and preserved ejection fraction. Am J Cardiol 2010;105:229-34.

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Appendix A: HF Pathophysiology

Figure A1: Pathophysiology cycle of HF

Figure A2: Diastolic heart dysfunction

4. Pathophysiology of HFrEF1

a. LV enlargement present in about half of all patients b. Elements of diastolic dysfunction also common c. Major causes and risk factors

a. MI b. CAD

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Appendix B: Characteristics of HF by Classification Systolic HF (“systolic dysfunction”, HFrEF)12 Diastolic HF (“diastolic dysfunction”, HFpEF)12

Systolic LV dysfunction caused by progressive LV dilation Decreased LV stiffness Eccentric remodeling Increased LV diastolic volume and pressure Abnormal contractility Decreased arterial elasticity

Defect in the filling or diastolic phase caused by increased filling pressures2 Functional abnormality in diastolic relaxation, filling, or elasticity of the LV regardless of ejection fraction or symptoms2 Concentric remodeling Slow and delayed LV relaxation Increased passive stiffness Increased LV wall thickness Dilated left atrium Normal LV systolic function, contractility, volume

https://www.cardiologistmidtownnyc.com/conditions/heart-failure-cardiomyopathy-enlarged-heart/

Figure B: Anatomy of systolic versus diastolic HF

Appendix C: Meta-Analyses of Beta-Blockers in HFpEF Author, year

Population Primary Outcome

Results Key Takeaway

Liu, 201429

2 RCTs, 10 observational studies reporting outcomes of mortality and/or hospitalizations for HF with

LVEF 40%

All-cause mortality

9% lower RR for all-cause mortality with beta-blocker use (95% CI 0.87-0.95, p < 0.001); no effect on hospitalization (p = 0.26) or composite mortality and hospitalization (p = 0.88)

Beta-blocker treatment in HF with

LVEF 40% is associated with decreased risk of all-cause mortality but not decreased hospitalizations

Bavishi, 201530

17 RCTs, prospective, or retrospective cohort studies comparing beta-blocker to placebo or no beta-blocker reporting

outcomes for HF with LVEF 40%

All-cause mortality

Observational studies: significantly lower all-cause mortality with beta-blockers (RR 0.81, 95% CI 0.72-0.90), I2 = 71.1% RCTs: no difference (RR 0.94, 95% CI 0.67-1.32), I2= 0%

Beta-blockers may decrease mortality in non-elderly HFpEF patients, but do not decrease hospitalizations; supported only by observational studies

Fukuta, 201731

11 observational cohort studies, 3 RCTs comparing beta-blockers to standard medical care or placebo

in HF with LVEF 40%

All-cause mortality or HHF

Reduced risk of mortality with beta-blockers (RR=0.79, 95% CI 0.71-0.88); result was driven by observational studies

Suggests a mortality benefit of beta-blockers in patients with HF

and LVEF 40%

Zheng, 201732

25 RCTs comparing drug therapies for 18,101 patients with HF and

LVEF 40%

All-cause mortality

Reduced all-cause mortality with beta-blockers (RR: 0.78, 95% CI 0.65-0.94, p=0.008); reduced CV mortality with beta-blockers (RR: 0.75, 95% CI: 0.60 to 0.94, p = 0.01)

Beta-blockers associated with reduction in all-cause mortality and CV hospitalization in HFpEF

RCT: randomized controlled trial; HF: heart failure; LVEF: left ventricular ejection fraction; RR: relative risk; CI: confidence interval; HHF: hospitalization for heart failure; HFpEF: heart failure with preserved ejection fraction; CV: cardiovascular

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Appendix D: Randomized and Observational Studies Randomized and observational studies of beta-blockers for HFpEF

Author, year Design Population Primary Outcome

Results Key Takeaway

Nodari, 200333

Nebivolol compared to atenolol

HFpEF and arterial HTN Resting and exercise hemo-dynamic parameters

Both agents produced significant decrease in heart rate and blood pressure; increase in VO2, stroke volume, decrease in cardiac index, MAP with nebivolol

Nebivolol associated with greater hemodynamic benefit compared to atenolol; equal antihypertensive effects

Bergstrom, 200434

Double-blind, multicenter, randomized trial of carvedilol vs. placebo

113 patients with diastolic dysfunction and preserved LVEF

Change in doppler echocardio-gram readings

No effect of carvedilol on primary endpoint

Suggests benefit of carvedilol in patients with diastolic HF and preserved LVEF

Lund, 201435 Propensity score-matched cohort study, treated vs. untreated with beta-blocker therapy

Review of Swedish HF Registry patients with HFpEF

All-cause mortality

1-year survival 80% vs. 79% and 5-year survival 45% vs. 42% for treated vs. untreated patients (HR 0.93; 95% CI 0.86-0.996, p = .04); no decrease in combination all-cause mortality and HHF

Beta-blockers associated with reduced all-cause mortality but not reduced combined all-cause mortality and HHF in HFpEF

Aronow, 199736

Randomized trial evaluating use of propranolol

153 patients age ≥ 62 years with previous Q-wave MI, NYHA class II-III HF, LVEF ≥ 40%, and treatment with diuretics and ACEIs

Total mortality, total mortality + non-fatal MI

Significantly lower mortality (56% vs. 76%) and mortality plus nonfatal MI (59% vs. 82%) in patients receiving propranolol

Propranolol decreases mortality, mortality plus nonfatal MI in patients with HFpEF and prior MI

Nishio, 200814

Rat model of bisoprolol vs. no medication in HFpEF

Diastolic HF model rats Survival Improved survival, decreased in expression of myocardial,and decreased LV hypertrophy in high-dose group

Beta-blocker use may decrease remodeling and inflammatory markers

Chan, 200537

Longitudinal, population-based study assessing effects of beta-blockers

Adults age 65 years with HF prescribed beta-blockers compared to those not receiving beta-blockers

All-cause mortality

Beta-blocker use associated with decreased rate of all-cause mortality (HR 0.74, 95% CI 0.56-0.98); no difference between

LVEF 40% and LVEF < 40% (interaction p = 0.34)

Suggests association of beta-blocker use with decreased all-cause mortality in elderly patients with HF regardless of LVEF

Dobre, 200713

Prospective observational study comparing beta-blocker to no therapy

Patients in The Netherlands with HF and LVEF ≥ 40% discharged from the hospital with or without beta-blocker (metoprolol, carvedilol, bisoprolol, nebivolol)

All-cause death

Significantly lower rate of all-cause death in beta-blocker group; high dose therapy associated with largest benefit

Potential association between beta-blocker use at discharge and decreased mortality in HFpEF; beta-blocker dose affects outcome

Shah, 200838 Review of the effect of statins, ACEIs, and beta-blocker

National sample of Medicare

registrants age 65 years hospitalized with primary HF diagnosis and documented LVEF > 50%

Mortality Non-significant trend toward decreased mortality (RR 0.93, 95% CI 0.87 to 1.10), significant increase survival at 3 years (RR 0.92%, 95% CI 0.87 to 0.97) in beta-blocker group

Beta-blockers associated with reduced mortality in elderly patients with HFpEF

Hernandez, 200939

Analysis of OPTIMIZE-HF results focused on beta-blocker effects in HFpEF

Patients age 65 years with HFpEF in OPTIMIZE-HF hospitalized for HF and eligible for Medicare benefits at time of discharge

Time to death or re-admission, first re-admission

Beta-blocker use associated with non-significant decrease in mortality (HR 0.94, 95% CI, 0.84–1.07) and non-significant decrease in readmission (HR 0.98, 95% CI, 0.90–1.06)

In elderly patients with HFpEF, beta-blockers did not significantly improve mortality or rehospitalization rates

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Gomez-Soto, 201140

Prospective cohort study of patients started on either bisoprolol or carvedilol

1,085 adults age > 14 years with first-time diagnosis of HF with LVEF ≥ 50% in Spain

Death from any cause, death from CV cause, HHF, visits for any cause

Longer survival (RR 0.37, 95% CI 0.21-0.50), lower CV mortality (RR 0.31, 95% CI 0.18 to 0.45, P < 0.001), lower readmission rate (RR 0.66, CI 95% 0.54 to 0.78, P < 0.001), fewer visits (RR 0.81, 95% CI .75-0.88, p < 0.01) with beta-blockers

Suggests association between beta-blocker use and reduced mortality, readmissions, and visits for patients with HFpEF

Smith, 201028

Prospective cohort study to analyze effects of psychological condition on HF outcomes

Subgroup of patients with HFpEF (13% of total population) and stable CHD

HHF, all-cause mortality

Use of beta-blockers associated with significant decrease in HHF when adjusted for baseline characteristics (HR 0.46, 0.23-0.93; p = 0.03); no significant difference in all-cause mortality

Use of beta-blockers associated with decreased risk of hospitalization for patients with HFpEF and stable CHD

Tehrani, 200927

Observational study of effects of drug therapy in HF

142 patients age > 80 years,

LVEF 50%, and clinical diagnosis of HF

Mortality and rehospitali-zation

Beta-blocker therapy did not significantly affect survival (p=0.89)

No survival benefit with beta-blocker therapy in HF patients age > 80

years and LVEF 50%

Nevzorov, 201241

Retrospective cohort analysis comparing those receiving beta-blockers within 3 months prior to admission to those who did not

345 adult patients with HFpEF hospitalized for HF

2-year all-cause mortality

Protective effect associated with beta-blocker prescription on 2-year survival (HR 0.69, 95% CI 0.47–0.99, p=0.018)

Use of beta-blockers may increase survival for adults with HFpEF

Patel, 201442 Propensity score matched analysis of the OPTIMIZE-HF study linked to Medicare

Medicare patients age 65 years from OPTIMIZE-HF with HF and LVEF ≥ 40% receiving new beta-blockers (carvedilol, bisoprolol, metoprolol succinate) at discharge

Composite all-cause mortality or HHF

No decrease in primary outcome with beta-blocker (HR 1.03; 95% CI 0.94–1.13, p=0.569); significant association with HHF (HR 1.17, 95% CI 1.03–1.34, p=0.014); nonsignificant if LVEF > 45% in beta-blocker use

Beta-blocker use not associated with decreased mortality or HHF for elderly patients with HFpEF; decreased risk of HHF if LVEF 40-45%

Farasat, 200943

Observational comparison of men and women with HFpEF receiving beta-blockers or not

66 patients with HFpEF stratified based on beta-blocker or no beta-blocker received at discharge

HHF in 6 months

Beta-blocker use associated with nonsignificant decrease in rehospitalization rate in men (OR 0.25, 95% CI 0.03 to 1.92, p = 0.18) and increased rehospitalization for women (OR 14, 95% CI 3.09 to 63.51, p < 0.001)

Suggests beta-blocker therapy may be associated with increased hospitalization in women but not in men with HFpEF

LVEF: left ventricular ejection fraction; HR: heart rate; HFpEF: heart failure with preserved ejection fraction; HR: hazard ratio; CI: confidence interval; HHF: hospitalization for heart failure; ACEI: angiotensin converting enzyme inhibitor; MI: myocardial infarction; HF: heart failure; RR: relative risk; CV: cardiovascular