ORIGINAL ARTICLE

Adoption of Sacubitril/Valsartan
for the Management of Patients
With Heart Failure

See Editorial by Colaco and Kazi Lindsey R.

Sangaralingham, MPH
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018

BACKGROUND: The US Food and Drug Administration approved the use S. Jeson Sangaralingham,
of sacubitril/valsartan in patients with heart failure with reduced ejection MS, PhD
fraction in July 2015. We aimed to assess the adoption and prescription Nilay D. Shah, PhD
Xiaoxi Yao, PhD
drug costs of sacubitril/valsartan in its first 18 months after Food and
Shannon M. Dunlay, MD,
Drug Administration approval.
MS
METHODS AND RESULTS: Using a large US insurance database, we
identified privately insured and Medicare Advantage beneficiaries who
filled a first prescription for sacubitril/valsartan between July 1, 2015,
and December 31, 2016. We compared them to patients treated with
an angiotensin-converting enzyme inhibitor or angiotensin receptor
blocker. Outcomes included adoption, prescription drug costs, and 180-
day adherence, defined as a proportion of days covered ≥80%. A total of
2244 patients initiated sacubitril/valsartan. Although the number of users
increased over time, the proportion of heart failure with reduced ejection
fraction patients taking sacubitril/valsartan remained low (<3%). Patients
prescribed sacubitril/valsartan were younger, more often male, with
less comorbidity than those taking an angiotensin-converting enzyme
inhibitor/angiotensin receptor blocker. Although a majority of prescription
costs were covered by the health plan (mean, $328.37; median, $362.44
per 30-day prescription), out-of-pocket costs were still high (mean,
$71.16; median, $40.27). By comparison, median out-of-pocket costs
were $2 to $3 for lisinopril, losartan, carvedilol, and spironolactone.
Overall, 59.1% of patients were adherent to sacubitril/valsartan. Refill
patterns suggested that nearly half of nonadherent patients discontinued
sacubitril/valsartan within 180 days of starting.
CONCLUSIONS: Adoption of sacubitril/valsartan after Food and Drug
Administration approval has been slow and may be associated with the
Correspondence to: Shannon M.
high cost. Dunlay, MD, MS, Mayo Clinic, 200
First St SW, Rochester, MN 55905.
E-mail dunlay.shannon@mayo.edu

Key Words: adoption ◼ drug

costs ◼ heart failure ◼ sacubitril
◼ valsartan
© 2018 American Heart
Association, Inc.

Circ Heart Fail. 2018;11:e004302. DOI: 10.1161/CIRCHEARTFAILURE.117.004302 February 2018 1

 Sangaralingham et al; Adoption of Sacubitril/Valsartan in Heart Failure
WHAT IS NEW?
• In this claims-based cohort study, adoption of
sacubitril/valsartan was slow after Food and Drug
Administration approval.
• Sacubitril/valsartan was more often prescribed in
patients with heart failure with reduced ejection
fraction who were younger, male, and had less
comorbidity.
• Out-of-pocket and insurer-paid prescription drug
costs were much higher than other guideline-
directed heart failure therapies.
• In total, 40.9% of patients were nonadherent/dis-
continued sacubitril/valsartan in the first 6 months
after initiation. Nonadherence and discontinuation
were more common in Black patients and patients
who had not previously been taking an angioten-
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018
sin-converting enzyme inhibitor or angiotensin
receptor blocker.
WHAT ARE THE CLINICAL
IMPLICATIONS?
• Slow adoption of sacubitril/valsartan may be asso-
ciated with the high cost.
• Factors contributing to the high rates of nonadher-
ence/discontinuation observed in this study require
further exploration.
H
eart failure (HF) is complex pathophysiological
and clinical syndrome that continues to be a
leading cause of morbidity, hospitalization, and
mortality.1,2 Although significant improvement in HF
survival has been observed over the last few decades,3
largely because of the identification and increased use
of pharmacological therapies that improve outcomes
such as those targeting the renin–angiotensin–aldoste-
rone system,4 the 5-year mortality and rates of hospital-
ization remain unacceptably high.1 Because of this, the
discovery and development of novel pharmacothera-
pies remain paramount to improving outcomes in HF.
In 2014, a major breakthrough in HF therapeutics
occurred with the publication of the results of the PAR-
ADIGM-HF trial (Prospective Comparison of Angiotensin
II Receptor Blocker Neprilysin Inhibitor With Angiotensin-
Converting Enzyme Inhibitor [ACEi] to Determine Impact
on Global Mortality and Morbidity in HF) which was
stopped after a median follow-up of 27 months because
of a significant reduction in morbidity and mortality in
participants receiving AngII receptor blocker neprilysin
inhibitor.5 Specifically, McMurray et al5 reported that
LCZ696, a first in class small molecule that delivers simul-
taneous angiotensin receptor blockade via valsartan and
neprilysin inhibition via sacubitril, significantly reduced
all-cause mortality, cardiovascular mortality, and HF hos-
pitalization compared with enalapril in patients with
Circ Heart Fail. 2018;11:e004302. DOI: 10.1161/CIRCHEARTFAILURE.117.004302
HF with reduced ejection fraction (HFrEF). Given these
results from a single, multicenter, international, double-
blind, randomized trial, the US Food and Drug Admin-
istration (FDA) approved sacubitril/valsartan (Entresto,
Novartis) for use in patients with chronic HFrEF and New
York Heart Association functional classes II to IV symp-
toms in July 2015. Approval by the European Commis-
sion then followed in November 2015. Less than a year
later, sacubitril/valsartan received a class I recommenda-
tion for use in chronic symptomatic HFrEF in both the US
and European HF clinical practice guidelines.6,7
Since approval and the incorporation of sacubitril/
valsartan into the HF guidelines, the adoption of sacu-
bitril/valsartan into real-world clinical practice in the US
has yet to be described. Thus, the goal of this study was
aimed to assess the adoption, continuation, and pre-
scription cost of sacubitril/valsartan in its first year after
FDA approval in individuals enrolled in US commercial
and Medicare Advantage health plans.
METHODS
Data Source
We conducted a retrospective analysis using the OptumLabs
Data Warehouse, a large database including over 100 mil-
lion individuals with private and Medicare Advantage health
plans.8,9 The database comprises of medical and pharmacy
claims for individuals in all 50 states and of all ages and eth-
nic and racial groups. Medical claims include claims for pro-
fessional (eg, physician), facility (eg, hospital), and outpatient
prescription medication services. Pharmacy claims include
fill date, strength, days supply, prescriber specialty, generic/
brand names, and paid amounts (out-of-pocket [OOP] and
health plan paid amounts). The data, analytic methods, and
study materials will not be made available to other research-
ers for purposes of reproducing the results or replicating the
procedure, as access to the data requires a partnership with
OptumLabs. Pursuant to the Health Insurance Portability and
Accountability Act, the use of deidentified data does not
require Institutional Review Board approval.
Study Populations
First, we identified all individuals 18 years or older who filled
a prescription for sacubitril/valsartan between July 1, 2015,
and December 31, 2016 (sacubitril/valsartan cohort). For each
individual, we defined the index initiation date as the date of
first fill date of sacubitril/valsartan.
To contextualize and understand which patients with
HFrEF were initiated on sacubitril/valsartan, we also identi-
fied all patients with systolic HF (HFrEF cohort). We relied
on billing codes for systolic HF, an approach which has been
demonstrated to be 97.7% specific for identifying individuals
with HF and an EF <45%.10 We included those with a single
inpatient claim or at least 2 outpatient claims on different
dates (International Classification of Diseases, 9th Edition/
International Classification of Diseases, 10th Edition 428.2X
or I50.2X in any position on the claim) from July 1, 2015, to
December 31, 2016, a method similar to that used by Curtis
February 2018 2
 Sangaralingham et al; Adoption of Sacubitril/Valsartan in Heart Failure
et al.11 We defined the index date as the date of first billing
code for systolic HF during the study period.
Finally, as we were interested in identifying differences in
characteristics of patients initiated on sacubitril/valsartan with
those who were eligible for initiation, we identified the sub-
set of patients with HFrEF who were treated with an ACEi
or angiotensin receptor blocker (ARB) and did not receive
sacubitril/valsartan during the study period (HFrEF ACEi/ARB
cohort). We selected those adults with a billing code for sys-
tolic HF that filled a prescription for an ACEi or ARB. The index
date was the date of first fill of an ACEi or ARB during the
study period.
We required all patients to have continuous enrollment
in a medical and prescription drug plan for at least 6 months
before their index date.
Independent Variables
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018
Independent variables of interest at index included age, sex,
race/ethnicity, residence region, health plan coverage, comor-
bidities, prescription medications, and prescriber specialty.
Comorbidities were captured by International Classification
of Diseases, 9th Edition and International Classification of
Diseases, 10th Edition codes in any position on claims in
the 6 months before the index date.12 Comorbidity burden
was assessed using the Charlson comorbidity index.12 For
each patient in the sacubitril/valsartan and HFrEF ACEi/ARB
cohorts, we assessed prescriber specialty, categorizing as car-
diologist, primary care (family medicine, internal medicine), or
other. Use of other HF medications in the 90 days before index
date was determined based on pharmacy claims. Monthly
OOP and health plan (insurer) costs of sacubitril/valsartan
and other commonly used HF medications were determined
based on the pharmacy claims. Total number of medications
(other than ACEi/ARB and sacubitril/valsartan) at index date
was assessed by therapeutic class using pharmacy claims. The
total OOP cost of all medications (other than ACEi/ARB and
sacubitril/valsartan) at index date was calculated. For those
filling prescriptions for other than 30 days supply, a 30-day
supply cost was calculated.
Sacubitril/Valsartan Adherence and Dose  (58.6%), with fewer initially filling 49/51 mg (32%) and
Titration
We obtained pharmacy fills for the 180-day period after ini-
tiation of sacubitril/valsartan. Pharmacy claims are complete
with a 3-month lag in the OptumLabs Data Warehouse.
Patients who ended coverage within 180 days of first fill were
excluded from analysis. Medication adherence/continuation
was calculated by the proportion of days covered. The numer-
ator was the number of days supply in the first 180 days after
initiation, and the denominator was 180. As medications
are provided to patients in the hospital, days hospitalized
were added to the numerator. Nonadherence was defined
as a proportion of days covered <80%.13 We recognize that
patients may choose to stop taking a prescription medication
for several reasons, such as cost and intolerance, and may
make the decision in conjunction with their physician or on
their own. Although we cannot fully distinguish these reasons
using pharmacy claims, we hypothesized that patients who
stopped after discussion with their physician would often
Circ Heart Fail. 2018;11:e004302. DOI: 10.1161/CIRCHEARTFAILURE.117.004302
resume treatment with an ACEi or ARB. As such, we exam-
ined the proportion of patients that failed to refill sacubitril/
valsartan that filled an ACEi or ARB in the follow-up period.
Titration of sacubitril/valsartan in the 180 days after initiation
was determined based on the doses of initial and subsequent
fills. Available doses include 24 mg sacubitril/26 mg valsartan,
49/51 mg, and 97/103 mg.
Statistical Analysis
Baseline characteristics of the sacubitril/valsartan and HFrEF
ACEi/ARB cohorts are reported as frequencies with percent-
ages for categorical data and means with SDs for continuous
variables. Differences in baseline characteristics in patients in
the 2 cohorts were compared using χ2 tests for categorical
variables and t tests for continuous variables. Logistic regres-
sion was used to assess predictors of use of sacubitril/valsar-
tan versus ACEi/ARB with results presented as odds ratios and
95% confidence intervals.
The proportion of beneficiaries with HFrEF (denomina-
tor) who were taking sacubitril/valsartan (numerator) in each
month of the study period was calculated. Univariate and
multivariate logistic regression were used to assess predictors
of adherence (proportion of days covered ≥80%) to sacubitril/
valsartan in the 180 days after initiation with data presented
as odds ratios and 95% confidence interval. All analyses were
conducted using SAS 9.4 (SAS Institute Inc, Cary, NC).
RESULTS
Population Characteristics
The baseline characteristics of patients taking sacubitril/
valsartan and those with HFrEF taking an ACEi/ARB in the
study period are shown in Table  1. A total of 102 247
patients had HFrEF, of whom 39 598 were taking an ACEi/
ARB but not sacubitril/valsartan in the study period. A
total of 2244 patients filled a new prescription for sacubi-
tril/valsartan in the 18 months after FDA approval, which
was predominantly prescribed by a cardiologist (82%). A
majority of patients were initiated on the 24/26 mg dose
97/103 mg (9.4%). Many patients (43.9%) initiated on
sacubitril/valsartan were not taking an ACEi or ARB in the
90 days before initiation. Only a small proportion filled
their first prescription for sacubitril/valsartan within 7 days
(3%) and 30 days (9%) of discharge after a hospitaliza-
tion, suggesting that the vast majority of patients are
initiated on sacubitril/valsartan in the outpatient setting.
Compared with patients taking ACEi/ARB, those taking
sacubitril/valsartan were younger (mean age, 67.6 versus
70.3 years), more often male (68.2% versus 58.5%), and
had fewer comorbidities. Patients filling sacubitril/valsar-
tan were also more likely to be using other commonly
prescribed HF medications at baseline, but were taking
fewer total medications (Table 1). Adjusting for potential
confounders, use of other HF medications was associ-
ated with greater odds of receiving sacubitril/valsartan,
whereas older age, female sex, chronic obstructive pul-
February 2018 3
 Sangaralingham et al; Adoption of Sacubitril/Valsartan in Heart Failure

Table 1.  Baseline Characteristics of Patients With Table 1. Continued

HFrEF Taking an ACEi/ARB and Initiators of Sacubitril/
Sacubitril/
Valsartan HFrEF ACEi/ARB Valsartan P
(n=39 598) (n=2244) Value
Sacubitril/
HFrEF ACEi/ARB Valsartan P Medication use (prior 90 days)
(n=39 598) (n=2244) Value
 ACEi/ARB … 1260 (56.1%) …
Age, y 70.3 (12.1) 67.6 (12.0) <0.001
 β-blockers 26 727 (67.5%) 1942 (86.5%) <0.001
Age category, y <0.001
 Aldosterone
6891 (17.4%) 899 (40.1%) <0.001
 18–64 11 438 (28.9%) 806 (35.9%) antagonist
 65–74 12 431 (31.4%) 747 (33.3%)  Digoxin 3845 (9.7%) 371 (16.5%) <0.001
 75+ 15 729 (39.7%) 691 (30.8%)  Loop diuretics 20 629 (52.1%) 1430 (63.7%) <0.001
Female 16 424 (41.5%) 713 (31.8%) <0.001 OOP cost of sacubitril/valsartan or ACEi/ARB (per 30-day supply) <0.001
Race/ethnicity <0.001  Mean (SD) $3.07 ($8.15) $71.16 ($119.36)

 Asian 632 (1.6%) 49 (2.2%)  Median (IQR) $40.27

$2.00 ($0.65–$2.66)
($3.60–$60.00)
 Black 6855 (17.3%) 388 (17.3%)
Other medication use* <0.001
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018

 Hispanic 2707 (6.8%) 202 (9.0%)

 Mean (SD)
 Unknown 7475 (18.9%) 331 (14.8%) therapeutic 15.6 (10.3) 13.5 (8.4)
 White 21 929 (55.4%) 1274 (56.8%) classes

Census region <0.001  Median (IQR)

therapeutic 13 (9–20) 12 (8–17)
 Missing 40 (0.1%) 1 (<0.1%) classes
 Midwest 11 534 (29.2%) 475 (21.2%) Other medication OOP* (per 30-day supply)
 Northeast 5874 (14.8%) 344 (15.3%)  Mean (SD) $112.91 ($293.5) $80.17 ($151.7) <0.001
 South 18 805 (47.5%) 1290 (57.5%)  Median (IQR) $44.96 $39.04
($12.80–$120.54) ($8.56–$98.92)
 West 3345 (8.5%) 134 (6.0%)

Charlson Comorbidity Index <0.001 ACEi/ARB indicates angiotensin-converting enzyme inhibitor/angiotensin

receptor blocker; HFrEF, heart failure with reduced ejection fraction; IQR,
 Mean (SD) 4.0 (2.4) 3.6 (2.3) interquartile range; and OOP, out-of-pocket.
 Median (IQR) 3.0 (2.0–5.0) 3.0 (2.0–5.0) *At time of initiation of sacubitril/valsartan or date of first fill of ACEi/ARB
in the study period.
Chronic conditions (6 mo baseline)

 Myocardial monary disease, cerebrovascular disease, dementia, and

8473 (21.4%) 442 (19.7%) 0.06
infarction
use of a greater total number of prescription medications
 Diabetes mellitus 18 482 (46.7%) 1009 (45.0%) 0.11
were associated with lower odds of receiving sacubitril/
 Chronic renal
10 957 (27.7%) 553 (24.6%) 0.002 valsartan. Differences by region and race/ethnicity were
disease
also observed (Figure 1)
 Chronic
pulmonary 14 769 (37.3%) 613 (27.3%) <0.001
disease
Monthly Trends in Initiation of Sacubitril/
 Cerebrovascular
disease
6987 (17.6%) 268 (11.9%) <0.001 Valsartan
 Dementia 2925 (7.4%) 42 (1.9%) <0.001 The number of patients initiating sacubitril/valsartan
 Hypertension 33 554 (84.7%) 1842 (82.1%) <0.001 steadily increased after its market debut in July 2015
(Figure 2A). However, the overall proportion of patients
 Atrial fibrillation 15 654 (39.5%) 854 (38.1%) 0.164
with HFrEF taking sacubitril/valsartan remained low
Health plan coverage <0.001
(maximum 2.3%) throughout the study period (Fig-
 Privately insured 7154 (18.1%) 541 (24.1%) ure 2B).
 Medicare
32 444 (81.9%) 1703 (75.9%)
Advantage

Prescribing provider Monthly Costs

 Cardiologist 10 933 (36.0%) 1480 (82.0%) <0.001 The average monthly costs incurred by patients and
 Primary Care 15 998 (52.7%) 174 (9.6%) insurers for sacubitril/valsartan and other common
 Other 3422 (11.3%) 151 (8.4%)
HF medications are shown in Figure 3. Both OOP and
insurer costs for sacubitril/valsartan were substantially
(Continued )
higher than costs for other guideline-directed HFrEF
medications including lisinopril, losartan, carvedilol,

Circ Heart Fail. 2018;11:e004302. DOI: 10.1161/CIRCHEARTFAILURE.117.004302 February 2018 4

 Sangaralingham et al; Adoption of Sacubitril/Valsartan in Heart Failure
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018
Figure 1. Predictors of use of sacubitril/valsartan.
The adjusted odds ratios (95% CI) of receiving sacubitril/
valsartan rather than angiotensin-converting enzyme inhibi-
tor (ACEi)/angiotensin receptor blocker (ARB) associated
with selected baseline patient characteristics are shown. All
variables shown were included in the model. COPD indicates
chronic obstructive pulmonary disease; MI, myocardial infarc-
tion; and ref, referent group.
and spironolactone. A majority of prescription costs
for sacubitril/valsartan were covered by the insurer
(mean, $328.37; median, $362.44; interquartile range,
$315.41–$396.06). Monthly OOP costs varied widely
(mean, $71.16; median, $40.27; interquartile range,
$3.60–$60.00). Costs were similar in beneficiaries
enrolled in commercial and Medicare Advantage health
plans early after FDA approval; in more recent months,
OOP costs were lower in patients with commercial
plans. In contrast, median OOP costs were $2 to $3 for
lisinopril, losartan, carvedilol, and spironolactone.
Sacubitril/Valsartan Adherence/
Continuation
Overall, 1161 of the 1964 (59.1%) patients were
adherent to sacubitril/valsartan in the 180 days after ini-
tiation. Of those who were nonadherent (n=803), 393
(48.9%) did not refill a prescription for sacubitril/val-
sartan for >30 days after their supply ended, suggest-
ing that they discontinued sacubitril/valsartan. Of those
who were nonadherent/discontinued sacubitril/valsar-
tan (n=803), 160 (20%) switched to an ACEi/ARB. The
univariate and multivariate predictors of 180-day medi-
cation adherence/continuation are shown in Table  2.
Adjusting for potential confounders, higher rates of
Circ Heart Fail. 2018;11:e004302. DOI: 10.1161/CIRCHEARTFAILURE.117.004302
nonadherence observed in Black patients, those with
chronic obstructive pulmonary disease, and patients
residing in the South. Better adherence was observed
in patients previously on an ACEi/ARB, those taking a
higher number of total medications, and those initiated
on the 97/103 mg dose. We found no association of
OOP costs of sacubitril/valsartan with adherence/con-
tinuation (odds ratio for adherence per $10 increase,
0.999; 95% confidence interval, 0.992–1.006; P=0.76).
Sacubitril/Valsartan Dose Titration
Of the 1161 patients who continued sacubitril/valsartan
for 180 days after initiation, 355 (30.6%) had a dose
titration (Figure 4). A majority of patients were started
on the 24/26 mg dose, 26% of whom titrated up in
the 180 days after initiation. A similar proportion of
those initiated on 49/51 mg were titrated up to 97/103
mg after initiation (29%), whereas a small proportion
was titrated down to 24/26 mg (5%). A small number
of patients were initiated on 97/103 mg, very few of
whom titrated down during follow-up (3%). In total,
285 (24.5%) patients were taking 97/103 mg of sacu-
bitril/valsartan by the end of the study period.
DISCUSSION
There are several important findings from this study.
In this large population of individuals with HF enrolled
in US private and Medicare Advantage health plans,
adoption of sacubitril/valsartan was slow in the first
18 months after FDA approval. There were system-
atic differences in the characteristics of individuals
initiated on sacubitril/valsartan compared with oth-
ers with HFrEF, in that they were younger, more often
male, and had fewer comorbidities. In addition, the
observed OOP costs for sacubitril/valsartan were much
higher than other guideline-directed medical therapies
for HFrEF and may represent an important barrier to
initiation and continuation. Finally, many patients ini-
tiated on sacubitril/valsartan discontinued use in the
first 180 days.
Sacubitril/valsartan is a new drug class that simul-
taneously blocks the renin–angiotensin–aldosterone
system and inhibits neprilysin, the enzyme responsible
for the degradation of the natriuretic peptides and oth-
er peptides.14,15 Despite a class I recommendation for
use of sacubitril/valsartan in the 2016 HF guidelines,7
the adoption after FDA approval in this HFrEF popula-
tion was slow. While use slowly increased over time,
18 months after FDA approval only 2.3% of patients
with HFrEF were taking sacubitril/valsartan. These find-
ings can be compared with a recent report from the
Get With The Guidelines (GWTG) HF registry. Among
patients hospitalized with HFrEF at GWTG-participating
February 2018 5
 Sangaralingham et al; Adoption of Sacubitril/Valsartan in Heart Failure
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018

Figure 2. Use of sacubitril/valsartan in the first 18 months after Food and Drug Administration (FDA) approval.
A, The number of patients filling a first-time prescription for sacubitril/valsartan by month in the first 18 months after FDA
approval. The release of the American College of Cardiology/American Heart Association Heart Failure guideline update on
May 20, 2016, is depicted by the arrow. B, The proportion of patients with heart failure with reduced ejection fraction (HFrEF)
taking sacubitril/valsartan by month after approval.

hospitals from July 2015 to June 2016, the authors
examined how often sacubitril/valsartan was listed as a
discharge medication. Similar to our report, they found
that sacubitril/valsartan was documented in only 2% of
patients and that older individuals and those with more
comorbid conditions were less likely to be taking sacu-
bitril/valsartan.16 However, unlike the GWTG report,
our study captured actual prescription fills by patients,
rather than documentation of sacubitril/valsartan on
a discharge medication list. Our findings suggest that
the vast majority of patients are initiated on sacubitril/
valsartan in the outpatient setting, as only 9% filled a
new prescription within 30 days of hospital discharge.
As such, the GWTG analysis may have been detecting
prevalent users. Alternatively, patients who were pre-
scribed sacubitril/valsartan at discharge may have never
filled the prescription because of cost or other factors,
underscoring the importance of inclusion of pharmacy
data in our analysis. The access to pharmacy data also
enabled us to provide novel information about adher-

Circ Heart Fail. 2018;11:e004302. DOI: 10.1161/CIRCHEARTFAILURE.117.004302 February 2018 6

 Sangaralingham et al; Adoption of Sacubitril/Valsartan in Heart Failure
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018

Figure 3. Monthly costs of heart failure medications.

The mean out-of-pocket costs (A) and insurer-paid costs (B) for sacubitril/valsartan and other common medications used to
treat patients with heart failure with reduced ejection fraction are shown.

ence, continuation, and cost of sacubitril/valsartan,
which was not possible in GWTG.
It is important to contextualize the early adoption of
sacubitril/valsartan compared with other pharmacologi-
cal therapies for patients with a chronic condition. After
publication of the results of the RALES trial (Randomized
Aldactone Evaluation Study) of spironolactone versus
placebo in HFrEF in 1999,17 the rate of spironolactone
use in Medicare beneficiaries with HFrEF tripled over the
next 18 months.18 However, spironolactone had already
been in use in clinical practice for other indications such
as hypertension, and as such, many physicians may have
been more willing to adopt the medication for use in
HFrEF when compared with a newly developed medica-
tion like sacubitril/valsartan. By comparison, after FDA
approval of the first novel oral anticoagulant, dabi-
gatran, for use in nonvalvular atrial fibrillation, it was
prescribed to ≈10% of patients with nonvalvular atrial
fibrillation, constituting ≈20% of all oral anticoagulant
prescriptions, over the next 18 months.19 However,
dabigatran offered a large convenience advantage to
patients over warfarin, as it did not require international
normalized ratio monitoring and may have contributed
to its strong early adoption. Finally, many novel medica-
tions to treat the chronic serious illness hepatitis C have
been FDA approved since 2011. These medications offer
shorter treatment periods and are more effective and
tolerable than older regimens (interferon alfa and riba-
virin), but are also more expensive. In one claims-based
study, although only 10% of patients with hepatitis C
received any treatment, by the end of 2014, essentially
all patients treated were receiving the newer medica-
tions.20 Thus, compared with other selected examples of
novel treatments in chronic serious illness, adoption of
sacubitril/valsartan has been slow.
Cost is an important potential barrier to use of sacu-
bitril/valsartan. Both the insurer-paid and OOP costs for
sacubitril/valsartan were several orders of magnitude
higher than other guideline-based HFrEF medications.
These high costs can contribute to multi-level barriers
to initiation and continuation. Insurers often impose
strict coverage criteria, prior authorizations, and tiered
OOP coverage to deter unnecessary use. UnitedHealth-
care, the largest insurer represented in this data source,
has instituted both prior authorization and the highest
tier prescription coverage (tier 3) for sacubitril/valsartan,
such that patients are required to pay a higher cost to
fill. While intended to promote appropriate drug use,
time-consuming prior authorizations can be a deterrent
to clinician prescribing.21 Finally, higher OOP costs not

Circ Heart Fail. 2018;11:e004302. DOI: 10.1161/CIRCHEARTFAILURE.117.004302 February 2018 7

 Sangaralingham et al; Adoption of Sacubitril/Valsartan in Heart Failure

Table 2.  Factors Association with Sacubitril/Valsartan if effective at improving outcomes. Insurer coverage of
Adherence sacubitril/valsartan may change after results of addi-
Univariate OR Multivariable OR tional clinical trials that are underway, and the manu-
Factors (95% CI) (95% CI) facturer (Novartis) now offers financial assistance such
Age, y as a free 30-day trial and reduced copay cards to help
 18–64 ref ref individuals afford the OOP costs.
 65–74 1.253 (1.006–1.561)* 1.096 (0.960–1.252)
Some would argue that the clear demonstration of
efficacy of sacubitril/valsartan in the PARADIGM-HF trial
 75+ 1.118 (0.896–1.395) 1.018 (0.887–1.168)
is sufficient to warrant widespread adoption in patients
Female 0.878 (0.724–1.065) 0.956 (0.863–1.059)
with chronic symptomatic HFrEF.24 However, in an era
Race/ethnicity where HF care already accounts for >18 billion dollars
 White ref ref annually in the United States,25 considering cost in addi-
 Asian 0.48 (0.375–0.614)† 1.301 (0.759–2.230) tion to efficacy is important in determining value of a
 Black 0.674 (0.49–0.928)* 0.694 (0.545–0.885)†
new treatment. In several analyses using data from PAR-
ADIGM-HF,26–29 the incremental cost-effectiveness ratio
 Hispanic 0.917 (0.478–1.759) 0.843 (0.628–1.131)
ranged from $45 017 to $50 959 per quality-adjusted life
 Unknown 0.662 (0.508–0.862)† 0.927 (0.722–1.189)
year over a lifetime, a level relatively consistent with other
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018

Census region accepted invasive cardiovascular interventions.30 By com-

 Midwest ref ref parison, the cost-effectiveness of other HFrEF pharmaco-
 Northeast 0.848 (0.627–1.147) 0.890 (0.714–1.109) logical therapies, such as ACEi, β-blockers, and aldoste-
 South 0.785 (0.624–0.988) * 0.834 (0.707–0.984)* rone antagonists, is much more favorable (<$10 000 per
 West 1.275 (0.811–2.004) 1.337 (0.960–1.863)
quality-adjusted life year).31 However, higher costs are
expected with newly released medications, and medica-
Charlson Comorbidity
Index
0.985 (0.948–1.025) tions with higher associated costs may have value if there
is a significant gain in quality-adjusted life year. The exist-
Chronic conditions
ing cost-effectiveness analyses for sacubitril/valsartan are
 Myocardial infarction 0.966 (0.769–1.214) 0.965 (0.854–1.089)
limited to data obtained from a single clinical trial, and
 Diabetes mellitus 1.031 (0.861–1.236) 0.927 (0.837–1.028) real-world outcomes data are needed to determine true
 Chronic renal disease 0.935 (0.759–1.151) 0.954 (0.849–1.071) effectiveness. In our study, patients taking sacubitril/val-
 Chronic pulmonary
0.811 (0.664–0.991)* 0.849 (0.761–0.947)†
sartan were older (mean, 68 versus 64 years), more often
disease female (32% versus 21%), Black (17% versus 5%), and
 Cerebrovascular disease 1.009 (0.763–1.334) 1.009 (0.869–1.172) had higher prevalence of comorbidities such as diabe-
 Hypertension 1.039 (0.822–1.313) 1.084 (0.951–1.235) tes mellitus (45% versus 35%) than patients enrolled in
 Atrial fibrillation 1.034 (0.859–1.244) 0.935 (0.846–1.034) the PARADIGM-HF trial.5 The effectiveness and impact
Prior ACEi/ARB use 1.402 (1.17–1.681)† 1.146 (1.042–1.262)†
on outcomes of sacubitril/valsartan in patients who were
not well represented in PARADIGM-HF may differ.
Total number other
medications
1.047 (1.034–1.06)† 1.056 (1.042–1.070) † Even if we decide that sacubitril/valsartan is a high-
value treatment in HFrEF, patients may still struggle to
Initial sacubitril/valsartan dose
afford to continue to fill and take the medication as
 24–26 mg ref ref
prescribed. We found that over one third of patients
 49–51 mg 1.005 (0.825–1.224) 0.880 (0.751–1.031) initiated on sacubitril/valsartan were nonadherent
 97–103 mg 1.369 (0.988–1.897) 1.320 (1.055–1.652)* over the next 180 days. The refill patterns suggest
Factors associated with adherence/continuation (defined as proportion of that almost half of nonadherent patients discontinued
days covered ≥80%) in the 180 days after initiating sacubitril/valsartan are sacubitril/valsartan completely. Whether this occurred
shown. An OR >1 indicated a greater likelihood of a patient being adherent
because of cost, hemodynamic, renal, or other intol-
during the first 180 days. ACEi/ARB indicates angiotensin-converting enzyme
inhibitor/angiotensin receptor blocker; CI, confidence interval; and OR, odds erance would be of interest to investigate in future
ratio. studies. Our analyses revealed 2 factors that may have
*P<0.05.
contributed. Sacubitril/valsartan was tested in the
†P<0.01.
PARADIGM-HF trial in patients with chronic symptom-
atic HFrEF who were able to tolerate an ACEi or ARB.5
only deter patient initiation of a medication but can also However, we found that many patients initiated on
negatively impact adherence and outcomes.22,23 Most sacubitril/valsartan had not filled a prescription for an
patients with HF are taking numerous daily medications ACEi/ARB in the 3 months prior. Patients who were not
and, in the absence of unlimited financial resources, are previously on an ACEi or ARB were more likely to be
often faced with important decisions about what they nonadherent/discontinue therapy. In the PARADIGM-HF
can afford to allocate toward a single medication, even trial, almost 20% of patients had to discontinue the

Circ Heart Fail. 2018;11:e004302. DOI: 10.1161/CIRCHEARTFAILURE.117.004302 February 2018 8

 Sangaralingham et al; Adoption of Sacubitril/Valsartan in Heart Failure
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018
study during either the enalapril or sacubitril/valsar-
tan run-in phase, primarily because of adverse events
or abnormal laboratory values.5 Our findings suggest
that patients who are not taking an ACEi/ARB before
starting sacubitril/valsartan may be less likely to tolerate
it, leading to discontinuation. It is possible that other
patients were prescribed sacubitril/valsartan outside of
the recommended route or indication (eg, New York
Heart Association functional class I, administered with-
out 36-hour ACEi washout period), and this may have
also adversely impacted real-world tolerability. Further-
more, we found that Black patients were more often
nonadherent. Although the reasons for nonadherence/
discontinuation are unknown, Blacks may have a strong
vasoactive response, possibly because of the preven-
tion of natriuretic peptide breakdown via neprilysin
inhibition as they are relatively deficient in natriuretic
peptides.32,33 Further work is needed to understand tol-
erability of sacubitril/valsartan in Black individuals. As
previously mentioned, enrollment of Black participants
in PARADIGM-HF was low (5% of total participants),5
compared with 17% of those initiating sacubitril/valsar-
tan in our study, underscoring the importance of exami-
nation of real-world data such as these to determine
effectiveness of new therapies.
Limitations
There are important limitations to acknowledge to aid
in interpretation of these findings. First, the data source
includes patients enrolled in private and Medicare Advan-
tage health plans with pharmacy benefits, and findings
in other populations may differ. Second, we used billing
codes to identify patients with HFrEF. Though a billing
code for systolic HF has a high positive predictive value
Circ Heart Fail. 2018;11:e004302. DOI: 10.1161/CIRCHEARTFAILURE.117.004302
Figure 4. Titration of
sacubitril/valsartan in the
first 180 days after initia-
tion.
Among those who were
adherent (proportion of days
covered ≥80%) to sacubitril/
valsartan, the proportion that
changed dose during the 180
days after initiation by starting
dose are shown.
and is specific for a reduced EF, it not very sensitive.10
This could result in an underestimation of the number
of patients with HFrEF on an ACEi/ARB. However, many
patients may be taking an ACEi/ARB in the presence of a
reduced EF, but have no HF symptoms, and would there-
fore not be eligible to switch to sacubitril/valsartan. As
such, the true denominator of patients eligible for sacu-
bitril/valsartan is likely to be smaller than the number of
individuals with HFrEF taking an ACEi/ARB in this study.
Conclusions
Despite FDA approval and a strong recommendation
for use in the HF guidelines, the adoption of sacubi-
tril/valsartan in clinical practice has been slow. High
insurer-paid and patient OOP costs represent an
important potential barrier to use and continuation.
Additional real-world data are needed to determine
the effectiveness and impact on outcomes of sacu-
bitril/valsartan in patients who were not well repre-
sented in PARADIGM-HF.
ACKNOWLEDGMENTS
All authors made substantial contribution to the conception or
design of the work. L.R. Sangaralingham analyzed the data.
L.R. Sangaralingham and Dr Dunlay drafted the article, and
Drs Sangaralingham, Shah, and Yao critically revised it for con-
tent. All authors gave final approval of the version submitted.
SOURCES OF FUNDING
This analysis was funded by the Mayo Robert D. and Patricia
E. Kern Center for the Science of Healthcare Delivery. Dr Dun-
lay's time is funded by the National Institutes of Health (NIH;
February 2018 9
 Sangaralingham et al; Adoption of Sacubitril/Valsartan in Heart Failure
K23 HL116643), and Dr Sangaralingham is supported by the
NIH (R01 HL132854).
DISCLOSURES
None.
AFFILIATIONS
From the Robert D. and Patricia E. Kern Center for the Science
of Healthcare Delivery (L.R.S., N.D.S., X.Y.), Department of
Cardiovascular Medicine (S.J.S., S.M.D.), and Department of
Health Sciences Research (N.D.S., X.Y., S.M.D.), Mayo Clinic,
Rochester, MN; and OptumLabs, Cambridge, MA (N.D.S.).
FOOTNOTES
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018
Received June 7, 2017; accepted December 22, 2017.
Circ Heart Fail is available at http://circheartfailure.
ahajournals.org.
REFERENCES
1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Fer-
ranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan
LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT,
Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neu-
mar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey
M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao
CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger
HM, Wong SS, Muntner P; American Heart Association Statistics Commit-
tee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statis-
tics-2017 Update: a report from the American Heart Association. Circula-
tion. 2017;135:e146–e603. doi: 10.1161/CIR.0000000000000485.
2. Dunlay SM, Roger VL. Understanding the epidemic of heart failure: past,
present, and future. Curr Heart Fail Rep. 2014;11:404–415. doi: 10.1007/
s11897-014-0220-x.
3. Roger VL, Weston SA, Redfield MM, Hellermann-Homan JP, Killian J,
Yawn BP, Jacobsen SJ. Trends in heart failure incidence and survival in a
community-based population. JAMA. 2004;292:344–350. doi: 10.1001/
jama.292.3.344.
4. Kaye DM, Krum H. Drug discovery for heart failure: a new era or the end
of the pipeline? Nat Rev Drug Discov. 2007;6:127–139. doi: 10.1038/
nrd2219.
5. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR,
Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF
Investigators and Committees. Angiotensin-neprilysin inhibition ver-
sus enalapril in heart failure. N Engl J Med. 2014;371:993–1004. doi:
10.1056/NEJMoa1409077.
6. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk
V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C,
Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope
LM, Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Mem-
bers. 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 Asso-
ciation (HFA) of the ESC. Eur Heart J. 2016;37:2129–2200. doi: 10.1093/
eurheartj/ehw128.
7. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner
MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld
J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 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 Cardiol-
ogy/American Heart Association Task Force on Clinical Practice Guidelines
and the Heart Failure Society of America. Circulation. 2017;136:e137–
e161. doi: 10.1161/CIR.0000000000000509.
Circ Heart Fail. 2018;11:e004302. DOI: 10.1161/CIRCHEARTFAILURE.117.004302
8. Sangaralingham LR, Shah ND, Yao X, Roger VL, Dunlay SM. Incidence
and early outcomes of heart failure in commercially insured and Medi-
care advantage patients, 2006 to 2014. Circ Cardiovasc Qual Outcomes.
2016;9:332–337. doi: 10.1161/CIRCOUTCOMES.116.002653.
9. Wallace PJ, Shah ND, Dennen T, Bleicher PA, Bleicher PD, Crown WH. Op-
tum Labs: building a novel node in the learning health care system. Health
Aff (Millwood). 2014;33:1187–1194. doi: 10.1377/hlthaff.2014.0038.
10. Li Q, Glynn RJ, Dreyer NA, Liu J, Mogun H, Setoguchi S. Validity of claims-
based definitions of left ventricular systolic dysfunction in Medicare patients.
Pharmacoepidemiol Drug Saf. 2011;20:700–708. doi: 10.1002/pds.2146.
11. Curtis LH, Whellan DJ, Hammill BG, Hernandez AF, Anstrom KJ, Shea
AM, Schulman KA. Incidence and prevalence of heart failure in el-
derly persons, 1994-2003. Arch Intern Med. 2008;168:418–424. doi:
10.1001/archinternmed.2007.80.
12. Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, Saun-
ders LD, Beck CA, Feasby TE, Ghali WA. Coding algorithms for defining
comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care.
2005;43:1130–1139.
13. Hess LM, Raebel MA, Conner DA, Malone DC. Measurement of adher-
ence in pharmacy administrative databases: a proposal for standard defi-
nitions and preferred measures. Ann Pharmacother. 2006;40:1280–1288.
doi: 10.1345/aph.1H018.
14. Hubers SA, Brown NJ. Combined angiotensin receptor antagonism and
neprilysin inhibition. Circulation. 2016;133:1115–1124. doi: 10.1161/
CIRCULATIONAHA.115.018622.
15. von Lueder TG, Sangaralingham SJ, Wang BH, Kompa AR, Atar D,
Burnett JC Jr, Krum H. Renin-angiotensin blockade combined with
natriuretic peptide system augmentation: novel therapeutic con-
cepts to combat heart failure. Circ Heart Fail. 2013;6:594–605. doi:
10.1161/CIRCHEARTFAILURE.112.000289.
16. Luo N, Fonarow GC, Lippmann SJ, Mi X, Heidenreich PA, Yancy CW,
Greiner MA, Hammill BG, Hardy NC, Turner SJ, Laskey WK, Curtis LH,
Hernandez AF, Mentz RJ, O’Brien EC. Early adoption of sacubitril/valsar-
tan for patients with heart failure with reduced ejection fraction: insights
from Get With the Guidelines-Heart Failure (GWTG-HF). JACC Heart Fail.
2017;5:305–309. doi: 10.1016/j.jchf.2016.12.018.
17. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes
J. The effect of spironolactone on morbidity and mortality in patients with
severe heart failure. Randomized Aldactone Evaluation Study Investigators. N
Engl J Med. 1999;341:709–717. doi: 10.1056/NEJM199909023411001.
18. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A,
Redelmeier DA. Rates of hyperkalemia after publication of the Random-
ized Aldactone Evaluation Study. N Engl J Med. 2004;351:543–551. doi:
10.1056/NEJMoa040135.
19. Marzec LN, Wang J, Shah ND, Chan PS, Ting HH, Gosch KL, Hsu JC, Mad-
dox TM. Influence of direct oral anticoagulants on rates of oral anticoagu-
lation for atrial fibrillation. J Am Coll Cardiol. 2017;69:2475–2484. doi:
10.1016/j.jacc.2017.03.540.
20. Yao X, Sangaralingham LR, Ross JS, Shah ND, Talwalkar JA. Adoption of
new agents and changes in treatment patterns for hepatitis C: 2010-
2014. Am J Manag Care. 2016;22:e224–e232.
21. Fischer MA, Schneeweiss S, Avorn J, Solomon DH. Medicaid prior-autho-
rization programs and the use of cyclooxygenase-2 inhibitors. N Engl J
Med. 2004;351:2187–2194. doi: 10.1056/NEJMsa042770.
22. Eaddy MT, Cook CL, O’Day K, Burch SP, Cantrell CR. How patient cost-
sharing trends affect adherence and outcomes: a literature review. P T.
2012;37:45–55.
23. Gourzoulidis G, Kourlaba G, Stafylas P, Giamouzis G, Parissis J, Maniadakis
N. Association between copayment, medication adherence and outcomes
in the management of patients with diabetes and heart failure. Health
Policy. 2017;121:363–377. doi: 10.1016/j.healthpol.2017.02.008.
24. Packer M. Angiotensin neprilysin inhibition for patients with heart failure:
what if sacubitril/valsartan were a treatment for cancer? JAMA Cardiol.
2016;1:971–972. doi: 10.1001/jamacardio.2016.3053.
25. International R. Cardiovascular disease: a costly burden for America. pro-
jections through 2035. http://www.heart.org/idc/groups/heart-public/@
wcm/@adv/documents/downloadable/ucm_491543.pdf. Accessed Janu-
ary 23, 2018.
26. Gaziano TA, Fonarow GC, Claggett B, Chan WW, Deschaseaux-Voinet C,
Turner SJ, Rouleau JL, Zile MR, McMurray JJ, Solomon SD. Cost-effective-
ness analysis of sacubitril/valsartan vs enalapril in patients with heart fail-
ure and reduced ejection fraction. JAMA Cardiol. 2016;1:666–672. doi:
10.1001/jamacardio.2016.1747.
27. King JB, Shah RU, Bress AP, Nelson RE, Bellows BK. Cost-effectiveness of
sacubitril-valsartan combination therapy compared with enalapril for the
February 2018 10
 Sangaralingham et al; Adoption of Sacubitril/Valsartan in Heart Failure
treatment of heart failure with reduced ejection fraction. JACC Heart Fail.
2016;4:392–402. doi: 10.1016/j.jchf.2016.02.007.
28. Ollendorf DA, Sandhu AT, Pearson SD. Sacubitril-valsartan for the treat-
ment of heart failure: effectiveness and value. JAMA Intern Med.
2016;176:249–250. doi: 10.1001/jamainternmed.2015.7661.
29. Sandhu AT, Ollendorf DA, Chapman RH, Pearson SD, Heidenreich PA.
Cost-effectiveness of sacubitril-valsartan in patients with heart failure
with reduced ejection fraction. Ann Intern Med. 2016;165:681–689. doi:
10.7326/M16-0057.
30. Sanders GD, Hlatky MA, Owens DK. Cost-effectiveness of implantable
cardioverter-defibrillators. N Engl J Med. 2005;353:1471–1480. doi:
10.1056/NEJMsa051989.
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018
Circ Heart Fail. 2018;11:e004302. DOI: 10.1161/CIRCHEARTFAILURE.117.004302
31. Banka G, Heidenreich PA, Fonarow GC. Incremental cost-effectiveness of
guideline-directed medical therapies for heart failure. J Am Coll Cardiol.
2013;61:1440–1446. doi: 10.1016/j.jacc.2012.12.022.
32. Gupta DK, Claggett B, Wells Q, Cheng S, Li M, Maruthur N, Selvin E,
Coresh J, Konety S, Butler KR, Mosley T, Boerwinkle E, Hoogeveen R,
Ballantyne CM, Solomon SD. Racial differences in circulating natriuretic
peptide levels: the atherosclerosis risk in communities study. J Am Heart
Assoc. 2015;4:e001831. doi: 10.1161/JAHA.115.001831.
33. Gupta DK, de Lemos JA, Ayers CR, Berry JD, Wang TJ. Racial differenc-
es in natriuretic peptide levels: the Dallas Heart Study. JACC Heart Fail.
2015;3:513–519. doi: 10.1016/j.jchf.2015.02.008.
February 2018 11
 Adoption of Sacubitril/Valsartan for the Management of Patients With Heart Failure
Lindsey R. Sangaralingham, S. Jeson Sangaralingham, Nilay D. Shah, Xiaoxi Yao and Shannon
M. Dunlay
Downloaded from http://circheartfailure.ahajournals.org/ by guest on February 16, 2018

Circ Heart Fail. 2018;11:

doi: 10.1161/CIRCHEARTFAILURE.117.004302
Circulation: Heart Failure is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX
75231
Copyright © 2018 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-3289. Online ISSN: 1941-3297

The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circheartfailure.ahajournals.org/content/11/2/e004302

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation: Heart Failure can be obtained via RightsLink, a service of the Copyright Clearance Center, not
the Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further information
about this process is available in the Permissions and Rights Question and Answer document.

Reprints: Information about reprints can be found online at:

http://www.lww.com/reprints

Subscriptions: Information about subscribing to Circulation: Heart Failure is online at:

http://circheartfailure.ahajournals.org//subscriptions/