Project ID: 313944
Project Lead: Erin Franceschini
Potential Titles:
 Heart Failure and Comorbid COPD: Prevalence and Impact; Diagnostic and Treatment
Dilemmas; Care Coordination
 Heart Failure and Comorbid COPD: Prevalence and Impact, Therapeutic Dilemmas and
Care Coordination Issues
TARGET AUDIENCE
 Cardiologists
 Primary Care Physicians
PROBLEM STATEMENT
Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death in the United
States, affecting between 12.7 and 14.7 million people, causing severe disability and early
death.1 While the accepted definition of COPD varies and includes chronic bronchitis and
emphysema subgroups, the Global Initiative for Chronic Obstructive Lung Disease2 states that
COPD “is characterized by persistent airflow limitation that is usually progressive and associated
with an enhanced chronic inflammatory response in the airways and the lung to noxious
particles or gases. Exacerbations and comorbidities contribute to the overall severity in
individual patients.”2 Symptoms of COPD include progressive dyspnea, ongoing cough, wheezing
and tightness in the chest. The strongest risk factor for developing COPD in Western countries is
long-term cigarette smoking, though other factors such as second-hand smoke, gas and
particulate exposures, and genetic influences have been well documented.
Heart failure (HF) affects 5.7 million people in the United States, a prevalence 2.4 times lower
than COPD.3 However, nearly 30% of patients with HF have comorbid COPD4 which represents a
higher than expected rate of COPD in patients diagnosed with heart failure based on
background statistics alone.5 Though comorbid COPD in patients with HF has been under
recognized,4 both disease states share common risk factors and underlying systemic
inflammation.5 New pathophysiological interpretations are needed to understand the common
influences of the cardiopulmonary spectrum.5 Patients with comorbid COPD and HF also have
higher all-cause mortality than patients with HF without concomitant COPD6 and physicians
should further recognize that airflow obstruction in COPD is correlated with left ventricular wall
stress.7 These findings should encourage physicians who treat patients with HF to maintain a
high index of suspicion regarding the occurrence of comorbid COPD in order to prevent further
deterioration in cardiac function and to decrease mortality.
While there are well defined treatment regimens for both HF and COPD as individual disease
states, there has been concern about how the use of beta blockers impacts patients with COPD8
and how the use of beta2 agonists impacts patients with HF.5 Maximal bronchodilation has
gained prominence within nationally recognized COPD treatment algorithms, and a relatively
new class of combined long acting muscarinic agonists (LAMAs) and long acting beta agonists
(LABAs) are available and should be known to physicians who treat patients with HF and
1
concomitant COPD to allow understanding of potential effects of these therapeutic agents on
patients with HF. There is also an emerging combined triple therapy class not yet available, but
if approved will offer LAMA/LABA and inhaled corticosteroid (ICS) in the same product for
patients with very severe COPD. Also pending approval is a potentially new delivery method of
an already available therapeutic agent.
HF leads all diagnoses for all-cause rates of hospital readmission within 30 days after discharge
at 23.5 per 100 index stays while COPD is a close second at 20.0 per 100 index stays in 2013.9
However, individualized care coordination and discharge follow up was shown to reduce 30 day
and 6 month hospital readmissions for CMS readmission-penalty diagnoses (heart failure, acute
myocardial infarction, chronic obstructive pulmonary disease, and/or pneumonia).10
Furthermore, an increased level of interspecialty physician communication has demonstrated a
reduction in the likelihood of hospitalization in patients with diabetes, COPD, asthma and HF by
30%.11
STATEMENT OF NEEDS
Clinical Practice Gap #1: Physicians who treat patients with HF under recognize comorbid COPD
in their patients, despite a high prevalence of both conditions in the elderly population.4 Signs
and symptoms as well as risk factors of HF and COPD overlap, making diagnosis of COPD in the
heart failure patient difficult.12,5 Physicians who treat heart failure should have heightened
awareness of the potential for co-occurring COPD in their patients and know when to refer to
pulmonology for further workup and care. Finally, in patients with HF, the presence of COPD is a
reliable risk factor for death and hospitalization.13
Educational Need #1: Physicians who treat patients with heart failure should recognize that a
significant subset have undiagnosed and untreated COPD. Of patients with stable HF (both
preserved ejection fraction and reduced ejection fraction HF), 28% also have COPD, and in 70%
of those cases the COPD is previously unrecognized.4 Cigarette smoking, advanced age, and
systemic inflammation are common risk factors for both conditions therefore the co-occurrence
is not surprising.12 Furthermore, both patient groups share symptoms; dyspnea on exertion,
orthopnea, cough, fatigue, activity intolerance, anxiety, depression, poor sleep, and anorexia are
frequently present in both groups.12,5 Signs on physical exam are nonspecific, as crackles can be
auscultated as small airways open in patients with COPD and wheezing may be present in
patients with HF when airflow is limited in the smaller airways.12 Even chest radiography can be
misleading as pulmonary remodeling can either mask or mimic pulmonary edema.5
Physicians who treat HF need to know when to refer their patients for specialty evaluation and
care if they suspect a diagnosis of COPD. While a high degree of suspicion and clinical acumen is
ultimately required, plasma B-type natriuretic peptide (BNP), echocardiography, and
cardiovascular magnetic resonance imaging (CMR) can be helpful.12 BNP is helpful when very
low (< 100 pg/mL), but there is a large indeterminate zone which bears interpretation for the
patient who has or may have comorbid COPD as right heart failure moderately elevates BNP
measurements.12,13 If echocardiogram is performed and is normal or unchanged from previous,
there is no HF or HF exacerbation and COPD should be considered.12 Finally, while CMR
provides more information about atrial volumes and end diastolic dimensions that is valuable
for patients with COPD, expense and limited availability are disadvantages.12
2
Spirometry measurements are required for COPD diagnosis, but physicians should note that HF
patients must be euvolemic at the time of the measurement.13 Furthermore, FEV1 improves not
only after diuresis but also after patients have been titrated to recommended dosages of HF
medications.12 Therefore, referral and evaluation of potential comorbid COPD should be
delayed until a patient with acute HF is stable from a cardiac standpoint to ensure accurate
testing.
Educational Need #2: Physicians who treat HF should recognize the impact of comorbid COPD
on their patients. Patients with comorbid COPD and HF have similar short-term mortality to
their counterparts with HF without COPD after acute HF hospitalizations, but have a 10%
increase in all-cause mortality at 1 year and a 40% increase at 5 years.6 In a review of 12 studies
specifically examining the prognostic implications of COPD on patients with HF, COPD
“independently predicts mortality in patients with reduced and preserved ejection fraction HF
even following adjustment for beta-blocker utilization.”5 One potential factor that has been
illuminated is that the severity of airway outflow obstruction in patients with COPD correlates
with the severity of left ventricular wall stress.7 It follows that control of the COPD disease state
benefits patients with comorbid heart failure and that patients with both diseases should be
aggressively identified and appropriately treated.
Clinical Practice Gap #2: Physicians who treat patients with HF inadequately prescribe beta
blockers to patients with comorbid COPD,6 despite evidence that cardioselective beta blockers
are well tolerated in patients with COPD.5,12 Physicians may not be aware that beta2 agonists
which are commonly used in COPD treatment have been associated with adverse associations
including increased mortality and HF hospitalization in those with existing HF.5 Physicians who
treat patients with HF may not be aware of several recent medication formulations for patients
with COPD and how those pharmacologic agents could impact patients with HF.
Educational Need #3: Physicians should treat HF following established guidelines in patients
with comorbid COPD. It is well established that treatment with beta-blockers reduces mortality
and improves symptoms in patients with chronic heart failure.14,15,16 Despite evidence that
cardioselective beta blockers are well tolerated by sufferers of COPD, in one large community
based study only 58% of patients with HF and COPD were treated with beta blockers as opposed
to 73% of the patient cohort with HF without concomitant COPD.6 Conversely, beta2 agonists
which are commonly used in the treatment of COPD have been correlated with increased risk of
death and hospitalization in patients with HF.5 While this association could be a result of
clustered variables that denote higher risk for death, concern about the safety of beta2 agonists
in HF patients has prompted randomized controlled trials for further examination.5 While beta2
agonists remain an important tool in relieving acute exacerbations of COPD, long acting
muscarinic antagonists (LAMAs) such as tiotropium which suppress cholinergic activity might be
viewed as safer than long acting beta agonists (LABAs) against prevention of acute
exacerbation.5 Physicians should use caution when treating patients with HF with a beta2
agonist, but should be especially aware of heightened risk during an acute HF exacerbation.17
Physicians who treat heart failure should recognize new and emerging pharmacologic
preparations for the treatment of COPD. The concept of maximal bronchodilation has taken a
prominent role in the management of COPD and a relatively new class of combination LAMAs
and LABAs has been developed.18 In December 2013 the FDA approved umeclidinium/vilenterol
DPI from for once daily dosing for maintenance treatment of COPD. The LAMA/LABA
3
combination was shown to increase FEV1 more than placebo as well as more than either of its
components alone.19 However, subjects with “significant uncontrolled disease (including
cardiovascular-related disease)” were excluded from the study.19 In May, 2015
tiotropium/olodaterol received FDA approval. The MDI was approved in the US for once daily
maintenance therapy in patients with COPD and was also found to improve lung function more
than either component alone.20 However, subjects hospitalized for HF within the last year were
excluded and while adverse events in the subset of patients with cardiac history were
comparable across treatment groups, there was no placebo arm and there was no subgroup
analysis of subjects with HF.20 The most recent approval for LAMA/LABA combination was for
glycopyrrolate/formoterol in April 2016. A twice daily pressurized LAMA/LABA MDI,
glycopyrrolate/formoterol has also been shown to improve lung function more than each
component alone as measured by morning pre-dose FEV1.21 Again, HF was not addressed in
subgroup analysis. Furthermore, in November 2016, furoate/umeclidinium/vilanterol was
submitted for FDA approval as a once daily DPI combination (ICS)/LAMA/LABA. The phase III
FULFIL study findings indicated that when compared to budesonide/formoterol, the closed triple
therapy product showed a “clinically meaningful and statistically significant (P<.001) benefit” in
lung function, measured as mean change from baseline in trough FEV1 as well as health-related
quality of life.22 Also noted was a significant reduction in the annual rate of moderate to severe
exacerbations of COPD using closed triple therapy compared to budesonide/formoterol, with
closed triple therapy showing a 35% reduction versus budesonide/formoterol based on 24 week
data (P=.002).22 Potential subjects with NYHA class 4 HF were excluded from participation.23
In addition to new combination products for patients with COPD, there are new developments
in delivery. In July 2016 the first nebulized LAMA, glycopyrrolate which is delivered via a
patented investigational nebulizer closed system was submitted to the FDA. While
glycopyrrolate does not offer a new therapeutic agent, the GOLDEN-5 trial showed safety and
efficacy of the new delivery system as compared to the LAMA currently available as DPI,
tiotropium.24
Clinical Practice Gap #3: Nearly 25% of patients hospitalized for acute heart failure are
readmitted within 30 days and 20% of patients hospitalized for COPD are readmitted over the
same time period.10
Education Need #4: COPD and HF are both CMS readmission-penalty diagnoses (HF, acute
myocardial infarction, COPD, and/or pneumonia) and have high readmission rates as mentioned
above. Physicians and other care providers should utilize methods at hospital discharge and
after that reduce the rate of hospital readmission for patients with HF and COPD. Care
Transition Solution (CTS) was studied in 14 Texas acute care hospitals and was found to decrease
the rate of readmission of patients with CMS-sensitive conditions by 22% (p = 0.01) relative to
the comparison group.10 CTS encompasses “identification of high readmission–risk patients,
assessment of individual needs, medication reconciliation, discharge planning, care
coordination, and telephonic post discharge follow-up.10 Another comparative review of 47
studies showed that among patients hospitalized for acute heart failure, home-visiting programs
and multidisciplinary HF clinics reduced all-cause 30 day readmission and mortality while
structured telephone support reduced HF-specific readmission and mortality.25 Furthermore,
physicians should communicate with each other regarding their common patients with HF and
COPD. High levels of interspecialty physician communication have demonstrated a reduction in
4
the likelihood of hospitalization in patients with ambulatory sensitive conditions including COPD
and HF by 30%.11
LEARNING OBJECTIVES
Upon completion of this activity, learners will:




Clinical/Practice
Gap
Physicians who
treat patients
with HF under
recognize COPD
in their patients
and may not
know when to
suspect COPD
and refer to a
pulmonologist
Recognize the prevalence of COPD in patients with HF as well as signs and
symptoms which are common to both diseases. Recognize diagnostic methods
helpful to differentiate the 2 disease states
Recognize the impact of comorbid COPD on patients with HF
Prescribe beta blockers to patients with HF and COPD as well as recognize
increased risk of adverse effects of beta2 agonists, particularly during HF
exacerbation; recognize new and emerging pharmacologic therapies that may
be prescribed to patients with COPD and HF and how they may impact the HF
disease state
Identify interventions that show promise in reducing readmission rates in
patients with HF and COPD
Educational
Need
Physicians
should
recognize that
nearly 30% of
patients with HF
have comorbid
COPD; though
the clinical signs
and symptoms
overlap,
physicians need
to develop
testing patterns
that lead to
appropriate
referrals for
COPD
evaluation and
management
Learning
Objective That
Will Address
the Gap and
Need
Recognize the
prevalence of
COPD in
patients with
HF as well as
signs and
symptoms
which are
common to
both diseases.
Recognize
diagnostic
methods
helpful to
differentiate
the 2 disease
states
Result(s) that
will be
measured
Type of Gap
That Will Be
Met
ACGME
Competencies
That Will Be
Met
1) Ability to
meet learning
objectives as
measured by
post-activity
evaluation
2) Changes in
responses to
case vignette
questions
3) Intention to
make practice
changes as
indicated on
post-activity
evaluation
Competence
Medical
Knowledge
Problem
based learning
and
improvement
5
Physicians who
treat patients
with HF
inadequately
prescribe beta
blockers to
patients with
COPD and may
be unaware of
potential
complications
associated with
using beta2
agonists in
patients with HF.
Physicians may
be unaware of
newer
pharmacologic
preparations
prescribed to
patients with
COPD
Nearly 25% of
patients
hospitalized for
acute heart
failure are
readmitted
within 30 days
while 20% of
patients
hospitalized for
COPD are
readmitted over
Physicians
should
recognize the
impact of
comorbid COPD
on patients with
HF
Recognize the
impact of
comorbid
COPD on
patients with
HF
As above
Competence
Physicians
should treat
patients with
heart failure
with beta
blockers even in
the case of
comorbid COPD
as well as
recognize
potential
adverse effects
of beta2
agonists in the
same
population.
Physicians
should be aware
of newer
pharmacologic
preparations
prescribed to
patients with
COPD and how
they may
impact the HF
disease state.
Physicians
should utilize
transitional care
methods that
reduce the rate
of hospital
readmissions for
patients with HF
and COPD.
Physicians
should
communicate
Prescribe beta
blockers to
patients with
HF and COPD
as well as
recognize
increased risk
of adverse
effects of beta2
agonists,
particularly
during HF
exacerbation;
recognize new
and emerging
pharmacologic
therapies
commonly
prescribed to
patients with
COPD and HF
and how they
may impact the
HF disease
state
1) Ability to
meet learning
objectives as
measured by
post-activity
evaluation
2) Changes in
responses to
case vignette
questions
3) Intention to
make practice
changes as
indicated on
post-activity
evaluation
Competence
Identify
interventions
that show
promise in
reducing
readmission
rates in
patients with
HF and COPD
1) Ability to
meet learning
objectives as
measured by
post activity
evaluation
2) Changes in
level of
knowledge as
measured by
pre and postassessment
Competence
Medical
Knowledge
Problem
based learning
and
improvement
Medical
Knowledge
Problem
based learning
and
improvement
Medical
Knowledge
6
the same time
period
with their interspecialty
colleagues
regarding their
common
patients with HF
and COPD
knowledge
based
questions
AGENDA
5 minutes
Activity overview
Pre-activity assessment
5 minutes
Overview of COPD and Co-occurring HF
20 minutes
Comorbid HF and COPD
--Prevalence
--Signs and symptoms
--Differentiating disease states and referral
Impact of COPD in patients with HF
--consistent risk factor for increased mortality
Case study #1:
Mrs. Jones, a 74-year-old woman presents for follow up to her cardiologist for
worsening dyspnea on exertion. She is already diagnosed with reduced ejection
fraction heart failure (last EF = 40%) secondary to ischemic heart disease, HTN,
and HLD. She is a former smoker but quit smoking 30 years ago. She is on
carvedilol 6.25 mg BID, lisinopril 10 mg daily, atorvastatin 40 mg daily, aspirin 81
mg daily, furosemide 20 mg daily, potassium chloride 10 mEq daily, and
nitroglycerin 0.4 mg SL PRN. Her weight is stable, and she does not exhibit
dependent edema. Her vital signs are normal and her oxygen saturation is 92%
on room air. On exam, she has some scattered faint wheezing as well as
crackles in the periphery. Her cardiac exam is unchanged and chest radiography
is unrevealing.


Should you consider COPD as a potential comorbid issue?
What modalities could you use to differentiate her symptoms between
HF and potential COPD?
You perform echocardiography and her EF is stable at 45%. Upon review of the
patient’s laboratory results, you note that her BNP is 246 pg/mL.

What next?
7
10 minutes
Treatment issues in patients with HF and COPD
--Beta-blocker therapy in HF patients with COPD
--Impact of beta2 agonists on the HF disease state
--New and emerging therapies for patients with COPD
Case study #2:
Mr. Smith, an 81-year-old man follows up with his cardiologist for stable
reduced ejection fraction HF (last EF = 35%) secondary to uncontrolled
hypertension. He is also treated for hypertension, hyperlipidemia, and COPD.
He has a 25-pack year smoking history but quit smoking 40 years ago. He is
mildly dyspneic at rest and moderately dyspneic with mild exertion. He is
prescribed aspirin 81 mg daily, carvedilol 6.25 mg BID, lisinopril 10 mg daily,
atorvastatin 40 mg daily, furosemide 40 mg daily, umeclidinium/vilanterol DPI
once daily, and albuterol MDI PRN for wheezing and SOA.
Today the patient’s vital signs are normal and his oxygen saturation on room air
is 91%. His cardiac exam is unchanged and his lung exam reveals crackles in the
bilateral bases. He has 1+ dependent edema. Follow up echocardiography
shows the EF is stable at 30%.

What concerns, if any do you have about the patient’s medication
regimen and it’s potential impact on his HF?
6 weeks later the patient presents to the Emergency Department and is
admitted overnight for acute heart failure with a BNP of 2354 pg/mL and chest
radiography consistent with pulmonary congestion. His cardiac enzymes are
negative and there are no EKG changes. He is diuresed overnight and his home
medications are otherwise restarted. You perform echocardiography the
following day and note that his EF has acutely dropped to 25%.


15 minutes
What concerns, if any do you have about the patient’s medication
regimen and it’s potential impact on his HF?
What potential change(s) will you make to his pulmonary medication
regimen while he is experiencing acute heart failure? Why?
Transitionary care at hospital discharge
--Effective tools to reduce hospital readmission
--Importance if interspecialty physician communication
Expert Roundtable:
Crossing the Specialty Divide:
When Reading the Progress Note Isn’t Enough
5 minutes
Post-activity assessment
8
REFERENCES
1. American Lung Association. March 2013.
http://www.lung.org/assets/documents/research/copd-trend-report.pdf. Accessed
November 23, 2016.
2. Global Initiative for Chronic Obstructive Lung Disease (GOLD), a Guide for Health Care
Professionals. www.goldcopd.org. Updated 2016. Accessed November 23, 2016.
3. Heart failure fact sheet.
https://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_heart_failure.htm Accessed
February 24, 2017.
4. Valk M, Broekhuizen B, Mosterd A, Zuithoff N, Hoes A, Rutten F. COPD in patients with
stable heart failure in the primary care setting. Int J Chron Obstruct Pulm Dis. 2015; 10:
1219-122.
5. Hawkins N, Virani S, Ceconi, C. Heart failure and chronic obstructive pulmonary disease: the
challenges facing physicians and health services. Eur Heart J. 2013;34(36):2795-2807.
6. Fisher KA, Stefan MS, Darling C, Lessard D, Goldberg RJ. Impact of COPD on the mortality
and treatment of patients hospitalized with acute decompensated heart failure: the
Worcester Heart Failure Study. Chest. 2015;147(3):637-645.
7. Alter P, van de Sand K, Nell C, et al. Airflow limitation in COPD is associated with increased
left ventricular wall stress in coincident heart failure. Respiratory Medicine. 2015; 109:
1131-1137.
8. Cooper LB, Mentz RJ. COPD in heart failure: are there long-term implications following acute
heart failure hospitalization? Chest. 2015;147(3):586-588.
9. Fingar K, Washington R. Trends in hospital medicine readmissions for hour high-volume
conditions, 2009-2013. 2015. Healthcare Cost and Utilization Project. Statistical brief #196.
10. Hamar B, Rula EY, Wells AR, Coberley C, Pope JE, Varga D. Impact of a scalable care
transitions program for readmission avoidance. Am J Manag Care. 2016;22(1):28-34.
11. O’Malley A, Reschivsky J, Martinez C. Interspecialty communication supported by health
information technology associated with lower hospitalization rates for ambulatory caresensitive conditions. J Am Board Fam Med. 2015; 28: 404-417.
12. Zeng Q, Jiang S, Update in diagnosis and therapy of coexistent chronic obstructive
pulmonary disease and chronic heart failure. J Thorac Dis. 2012;4(3):310-15.
13. Hawkins N, Petrie M, Jhund P, Chalmers G, Dunn F, McMurray J. Heart failure and chronic
obstructive pulmonary disease: diagnostic pitfalls and epidemiology. Eur J Heart Fail.
2009;11(2):130-9.
14. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in
patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med.
1996;334(21):1349-1355.
15. [No authors listed] Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL
Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet.
1999;353(9169):2001-2007.
16. Packer M, Coats AJS, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart
failure. N Engl J Med. 2001; 344: 1651–1658.
17. Chhabra S, Gupta M. Coexistent chronic obstructive pulmonary disease-heart failure:
mechanisms, diagnostic and therapeutic dilemmas. Indian J Chest Dis Allied Sci.
2010;52(4):225-38.
18. Wilkie M, Finch S, Schembri S. Inhaled Corticosteroids for Chronic Obstructive Pulmonary
Disease--The Shifting Treatment Paradigm. COPD.2015;12(5):582-590
9
19. Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety
of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med.
2013;107(10):1538-1546.
20. Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination
versus mono-components in COPD (GOLD 2–4). Eur Respir J. 2015;45(4):969-979.
21. Radovanovic D, Mantero M, Sferrazza Papa GF, et al. Formoterol fumarate + glycopyrrolate
for the treatment of chronic obstructive pulmonary disease. Expert Rev Respir Med.
2016;10(10):1045-1055.
22. GSK media release. GSK files regulatory submission in US for once-daily closed triple
combination therapy FF/UMEC/VI for patients with COPD http://www.gsk.com/engb/media/press-releases/2016/gsk-files-regulatory-submission-in-us-for-once-daily-closedtriple-combination-therapy-ffumecvi-for-patients-with-copd/ Accessed February 23, 2017.
23. Trial record. Comparative study of fluticasone furoate (FF)/umeclidinium bromide
(UMEC)/vilanterol (VI) closed therapy versus FF/VI plus UMEC open therapy in subjects with
chronic obstructive pulmonary disease (COPD)
https://clinicaltrials.gov/ct2/show/NCT02729051?term=Lung+FUnction+and+quality+of+LiF
e+assessment+in+COPD+with+closed+trIpLe+therapy&rank=1 Accessed February 26, 2017.
24. Sunovion media release. Sunovion announces results of phase 3 long-term safety study
showing SUN-101/eFlow (glycopyrrolate) was well-tolerates in people with moderate-tovery severe chronic obstructive pulmonary disease (COPD)
25. Feltner C, Jones CD, Cené CW, et al. Transitional care interventions to prevent readmissions
for persons with heart failure: a systematic review and meta-analysis. Ann Intern Med.
2014;160(11):774-784.
10