Download Treatment of Resistant Hypertension in the Patient With Chronic

CONTINUING EDUCATION
Treatment of Resistant
Hypertension in the Patient
With Chronic Kidney Disease
Harry E. Scher, DNP, APRN, Michelle L. Drew, DNP, FNP, and
Damon B. Cottrell, DNP, FNP
ABSTRACT
The burden of risk and the impact of disease associated with poorly controlled hypertension in the United
States population presents significant challenges to primary care providers, including nurse practitioners. The
lack of blood pressure control leads to a staggering number of premature deaths annually. To reduce risk for
major cardiovascular events, aggressive approaches to treatment of resistant hypertension must be considered.
Hypertension plays a key role in the progression of chronic kidney disease. The goal of treating resistant
hypertension must be directed at reducing cardiovascular risk while preserving renal function.
Keywords: chronic kidney disease, clinical inertia, hypertension, resistant hypertension
Published by Elsevier, Inc.
All authors are affiliated with Texas Woman’s University in Dallas. Harry E. Scher, DNP, APRN, BC, is a student in the College of
Nursing. He can be reached at [email protected]. Michelle L. Drew, DNP, MPH, CNM, FNP-C, is an adjunct clinical
instructor in the College of Nursing. Damon B. Cottrell, DNP, FNP-C, ACNS-BC, CCNS, is an associate clinical professor in the
College of Nursing. In compliance with national ethical guidelines, the authors report no relationships with business or industry that
would pose a conflict of interest.
T
reatment of resistant hypertension (RHTN)
in a patient with chronic kidney disease
(CKD) presents nurse practitioners (NPs)
with unique challenges as they attempt to effectively
treat RHTN while preserving kidney function.
Notwithstanding appropriate treatment, the “uncontrollable” part of hypertension, RHTN, is a
significant threat, because long-standing high levels
of blood pressure along with concomitant debilitating
entities, such as CKD, create a prominent highcardiovascular-risk milieu. Effective individualized
treatment for RHTN requires NPs to recognize that
RHTN and CKD are entangled in a complex and
vicious interaction. The purpose of this study is to
This CE learning activity is designed to augment the knowledge, skills, and attitudes of nurse practitioners and assist in their understanding of the importance of treating
resistant high blood pressure (HBP) in patients with chronic kidney disease (CKD).
At the conclusion of this activity, the participant will be able to:
A. Identify the evidence-based medical treatments for resistant HBP
B. Describe the lifestyle modifications effective in managing resistant HBP in patents with CKD
C. Explain diagnostic studies for several causes of secondary HBP
The authors, reviewers, editors, and nurse planners all report no financial relationships that would pose a conflict of interest.
The authors do not present any off-label or non-FDA-approved recommendations for treatment.
This activity has been awarded 1.0 contact hours for nurses of which 1.0 credit is in the area of pharmacology. The activity is valid for CE credit until July 1, 2017.
Readers may receive the 1.0 CE credit free by reading the article and answering each question online at www.npjournal.org, or they may mail the test answers and
evaluation, along with a processing fee check for $10 made out to Elsevier, to PO Box 1461, American Fork, UT 84003. Required minimum passing score is 70%.
This educational activity is provided by Nurse Practitioner AlternativesÔ.
NPAÔ is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.
Accreditation does not imply endorsement by the provider, Elsevier, or ANCC of recommendations or any commercial products displayed or discussed in conjunction with
the educational activity.
www.npjournal.org
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597
enhance and expand NPs’ understanding of RHTN
with CKD through discussion of evidence-based best
practice. The discussion includes a review of pathophysiologic mechanisms related to RHTN associated
with CKD as well as both pharmacologic and nonpharmacologic treatment. A real-life case study is presented to demonstrate the use of treatment principles.
providers can lead to prevention of renal disease and
decrease risk of cardiovascular disease.
Numerous risk factors contribute to the development of hypertension. Figure 1 includes a
summary of the social determinants as well as the
main behavioral and metabolic risk factors that may
contribute to the development of HTN and
complications.
PROBLEM IDENTIFICATION
Essential hypertension (HTN) is the most prevalent
controllable disease in developed countries, affecting
> 25% of the adult population. The global disease
burden is immense, with 62% of strokes, 49% of heart
disease, and 7.5 million deaths per year attributed
to HTN, which is a major modifiable risk factor
affecting nearly 1 in 3 adults in the United States.
Thus, HTN, as the foremost risk factor for coronary
artery disease and stroke, is responsible for the majority of cardiovascular morbidity and mortality in
the US. Furthermore, HTN is also the leading cause
of congestive heart failure, either directly causing
hypertensive heart disease or indirectly contributing
to ischemic cardiomyopathy.1 Lack of blood pressure
control presents as RHTN, a common clinic problem
encountered by NPs, primary care clinicians, and
specialists. Although the exact prevalence of RHTN
is unknown, clinical trials suggested that it is not rare
and involves perhaps 20%-30% of patients with HTN.2
RHTN has been defined as blood pressure that
remains above goal despite concurrent use of 3
antihypertensive agents of different classes, ideally
including a diuretic, and all at optimal doses.1 An
increased interest in the independent role of RHTN
has evolved from the common observation that
many patients with essential HTN fail to meet their
treatment goal despite polytherapy.
Recent studies have struggled to approximate the
prevalence of RHTN, which may occur in up to
30% of all patients with HTN.3 Other studies focused
on documenting the strength of an association with
chronic diseases such as CKD. In some cases, CKD
was found to be almost 4 times more common in
patients with RHTN.1 It is of paramount importance
that NPs recognize that the increased prevalence of
kidney failure associated with high costs and poor
outcomes of treatment constitute a worldwide public
health threat.4 Aggressive treatment of RHTN by
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OVERVIEW OF RESISTANT HTN IN CKD
RHTN is both a cause and a consequence of CKD.
Failure to effectively treat RHTN increases the risk
of important adverse outcomes, including kidney
failure, early development and accelerated progression of cardiovascular disease, and premature death.5
To achieve effective treatment, the NP utilizes an
understanding of pathophysiology and the importance of blood pressure control in patients with
RHTN and CKD.
Pathophysiology
RHTN plays a key role in progression of CKD.5 A
strong association exists between the 2 conditions,
with a complex reciprocal interaction.1 Renal
dysfunction causes increased sodium and water
retention. Patients with water retention may develop
fluid overload, which in turn makes blood pressure
control difficult. Persistently elevated blood pressure
causes nephrosclerosis, leading to further kidney
damage and perpetuation of the cycle. Adequate
blood pressure control slows the progression of
glomerular filtration rate (GFR) decline in patients
with proteinuria and serves to preserve current
renal function.5
The sympathetic nervous system is known to be a
major contributor to the pathophysiology of RHTN.
Increased renal sympathetic activity leads to a cascade
of actions including: (a) decreased renal blood flow
and decreased glomerular filtration rate by renal
vasoconstriction; and (b), through stimulation of the
release of renin by the juxtaglomerular cells, angiotensin II is produced. The cascade of action is further
amplified by direct activation of renin resulting from
kidney injury secondary to poorly controlled
RHTN. Increases in renal sympathetic nerve activity
also directly increase renal tubular sodium reabsorption.6 The complex cycle that includes activation of
Volume 11, Issue 6, June 2015
Figure 1. Main factors that contribute to the development of high blood pressure and its complications. Reproduced
with the permission of the publisher, from Global Brief on Hypertension, Geneva, World Health Organization, 2013
(Fig. 9, Page 18 http://apps.who.int/iris/bitstream/10665/79059/1/WHO_DCO_WHD_2013.2_eng.pdf? ua¼l.
Accessed 17 November 2014).
renin, renal vasoconstriction, and tubular sodium
reabsorption results in a worsening of CKDrelated RHTN.
Importance of Blood Pressure Control
Blood pressure control is critical in the treatment of
patients with CKD. Multiple landmark studies have
demonstrated unequivocally that lowering blood
pressure in individuals of any age with moderate to
severe hypertension reduces risk of stroke, CKD, and
cardiovascular events.7 With a focus on preserving
current renal function in patients with CKD, clinical
practice may be directed by strong evidence that a
lower blood pressure target has been well
documented in the general population to reduce
cardiovascular risk and, in CKD patients, to reduce
the rate of CKD progression.5 National data suggest
that < 45% of persons with CKD meet target blood
pressure goals, and adequate control often requires 3
or 4 medications.8 Despite widespread dissemination
of the clinical guidelines established by the Eighth
Joint National Committee, achieving blood pressure
targets among patients with CKD remains
challenging.9
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Secondary Causes of HTN
Secondary HTN is elevated blood pressure that results from an underlying, identifiable, often correctable cause. Although only about 5%-10% of HTN
cases are thought to result from secondary causes,
HTN is so common that secondary HTN will likely
be encountered more frequently by the NP.10
Pseudoresistance. The importance of identifying the presence of pseudoresistance cannot be
overstated. Pseudoresistance HTN must be excluded
during the initial evaluation phase of treatment.
Pseudoresistance is identified in those patients who:
(a) lack blood pressure control secondary to an inaccurate suboptimal treatment regimen; (b) have poor
adherence to antihypertensive therapy; (c) have lifestyle and diet issues; and (d) use anti-inflammatory
agents or have “white-coat” hypertension.3,11 In most
patients, home blood pressure monitoring can assist
the NP in identifying white-coat hypertension. Ambulatory blood pressure monitoring can also be useful in
identifying RHTN and hypotensive episodes.5 The
identification of pseudoresistance in patients with CKD
is of paramount importance, as white-coat HTN is not
associated with increased cardiorenal risk.11
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The challenging yet common form of pseudoresistance, medication nonadherence, continues to be a
serious threat to the overall physical, mental, and
economic health of the US population.12 Some large,
randomized, controlled trials indicated nonadherence
is a major problem related to the treatment of HTN,
and was found to be the most common cause of
pseudoresistance, seen in 12% of the population
treated with prescribed medication.13 The correlation
between medication adherence and health literacy is
well documented.14 Once medication nonadherence
is identified, all providers should offer patients
personalized education focused on improving health
literacy and promoting a better understanding of risks
related to poorly controlled HTN.
Another significant issue leading to pseudoresistance involves errors in measurement of blood pressure. One of the most common causes of blood
pressure assessment occurs when using a blood pressure cuff that is either too small or too large for the
patient’s arm. These types of errors, or what may be
considered a poor blood monitoring technique, can
lead to undertreatment of HTN.
Other Causes of Secondary HTN
After aggressively treating HTN with 3 or more
medications, NPs should consider a possible
secondary cause of HTN. The secondary causes may
include such common disorders as obstructive sleep
apnea or chronic renal disease. Examples of rare
secondary causes include coarctation of the aorta and
pheochromocytoma. Table 1 identifies the disorders
that may cause secondary hypertension and includes
diagnostic studies useful in making a diagnosis.
MANAGEMENT OF RESISTANT HTN IN PATIENTS
WITH CKD
Effective treatment of RHTN in patients with CKD
can prevent worsening of renal function and may also
slow progression, reduce complications of decreased
GFR, reduce risk of cardiovascular disease, and
improve survival and quality of life.4 The NP’s
greatest challenge is implementing an individualized
treatment plan leading to successful blood pressure
control and cardiovascular risk reduction.
Lifestyle
Lifestyle modifications in patients with RHTN are
effective in lowering blood pressure. Numerous
outcomes studies support the importance and effectiveness of lifestyle changes encompassing:
Dietary sodium restriction.
Alcohol intake restriction.
Weight loss.
Table 1. Secondary Hypertension Disorders and Associated Diagnostic Studies
Disorder Suspected
Diagnostic Studies
Obstructive sleep apnea
Sleep study
Hypothyroidism
Thyroid-stimulating hormone level
Hyperthyroidism
Thyroid-stimulating hormone level
Hyperparathyroidism
Serum calcium, parathyroid hormone level
Pheochromocytoma
Urinary catecholamine metabolites (vanillylmandelic acid,
metanephrines, normetanephrines)
Cushing’s syndrome
Dexamethasone-suppression test
Aldosteronism
Ratio of plasma aldosterone to plasma renin activity,
computed tomography scan of adrenal glands
Renal parenchymal disease
Creatinine clearance, renal ultrasonography
Renovascular disease
Magnetic resonance angiography, renal arteriography
Coarctation of aorta
Doppler or computed tomography imaging of aorta
Acromegaly
Growth hormone level
Erythropoietin side effect
Off drug trial
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Volume 11, Issue 6, June 2015
High-fiber, low-fat diet.
Physical activity.15
Incorporation of lifestyle changes in concert with
medication management enhances the opportunity
for effective treatment of HTN. Dietary sodium restriction improves blood pressure control in patients
with normal renal function and RHTN. The nonpharmacologic intervention of dietary sodium restriction is pivotal in CKD, because the condition is
characterized by high sodium sensitivity of blood
pressure.11 Numerous trials in the general population
have provided evidence that restricting salt intake
clearly lowers blood pressure. Alcohol consumption
has been shown to produce both acute and chronic
increases in blood pressure, suggesting that restricting
alcohol intake would lower blood pressure. In
patients with RHTN, the importance of achieving or
maintaining a healthy weight, having a high-fiber,
low-fat diet, and increasing physical activity are key
tools in the management of RHTN.5
Medication Management
Medication management for the patient with RHTN
and CKD is complex. Recommendations for treatment of RHTN vary; some investigators have proposed a therapeutic approach of a step-by-step
addition of HTN drug classes in patients with
RHTN. Others suggest what is known as triple therapy, where combining an angiotensin-converting
enzyme inhibitor (ACEI) or angiotensin receptor
blocker (ARB) along with a diuretic and a calciumchannel blocker (CCB) is a reasonable approach to
initial therapy.16 Prescription practice for CKDrelated RHTN should be mindful of the need for
multiple drugs with a minimum of 1 drug being a
properly dosed diuretic. Diuretics remain a mainstay
of therapy for RHTN and for volume overload in
the presence of CKD. Diuretic agents include loop
diuretics, such as furosemide and torsemide, and
thiazide diuretics, such as hydrochlorothiazide and
chlorothalidone. By reducing extracellular fluid volume, diuretics lower blood pressure and thus are
capable of potentiating the effects of other drugs such
as ACEIs, ARBs, and other antihypertensive agents,
including CCBs. NPs should understand that CKD
patients have a 10%-30% increase in extracellular
fluid and blood volume, even in the absence of overt
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edema, and commonly have a salt-sensitive form of
hypertension.17 For patients in CKD stages 1-3 (GFR
> 30 mL/min per 1.73 m2), a thiazide diuretic given
once daily should be considered. Loop diuretics given
once or twice daily are recommended in patients
with GFR < 30 mL/min per 1.73 m2.5
ACEIs and ARBs can be used safely in most patients with CKD.5 These drugs are frequently
administered to patients with CKD and usually given
for the treatment of HTN, due to their cardiorenal
protective effects.17 The most consistent HTN
treatment benefit is noted with use of ACEIs and
ARBs, usually in association with diuretic drugs, in
patients with HTN and high concentrations of
albuminuria.4 Proteinuria is a major risk factor for
cardiovascular disease and CKD progression. In CKD
patients with proteinuria, many randomized,
controlled trials have shown that the use of ARBs or
ACEIs can decrease hard outcomes, such as the
doubling of serum creatinine level, kidney failure, or
death.5 The recently updated Kidney Disease
Improving Global Outcomes clinic practice guideline
on CKD and blood pressure recommends treatment
with ACEI and ARB as first-line therapy in patients
with concomitant HTN and proteinuria, to slow
progression of CKD.18 One recent study showed
that, in non‒dialysis-dependent patients with CKD,
ACEI/ARB administration was associated with
increased survival.19
Although b-blockers are not considered a firstline medication for the treatment RHTN, they are
commonly used in patients with CKD, either for the
treatment of HTN or for their cardioprotective effects. The renoprotective effects of b-blockers in the
CKD population have been established in several
trials where they have been used as adjunctive therapy.17 Commonly prescribed b-blockers known to
be extensively metabolized in the liver, such as
metoprolol and carvedilol, may be utilized safely to
manage HTN in patients with CKD.17
Central a-agonists can be useful in treating CKD
patients with RHTN. As sympathetic activation plays
an important and distinct role in HTN and target
organ damage associated with CKD, clonidine can
provide added treatment value when prescribed to
patients who have not responded well to other classes
of medication. Patients may experience rebound
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HTN with missed clonidine dosing and when discontinuing the medication.17
Mineralocorticoid receptor antagonists (MRAs)
may be prescribed in patients found to have secondary HTN related to primary aldosteronism. In
patients with RHTN, MRAs provide significant
benefit when added to existing multidrug regimens.2
Despite the fact that MRAs are associated with a
significant risk of hyperkalemia, they are
recommended to treat RHTN as they have been
found to reduce proteinuria and blood pressure
among patients in all stages of CKD. Data are still
lacking in relation to how MRAs affect progression
to end-stage renal disease and overall mortality.20
Potent vasodilators, such as hydralazine, are
effective when added to a medication treatment
regimen. However, hydralazine usually requires
concomitant therapy with a diuretic and b-blocker.
Minoxidil is not commonly prescribed to treat
RHTN, as it often causes problematic volume
retention that negates the antihypertensive effects of
other currently prescribed drugs.21
Clinical Inertia
A major contributor to poor blood pressure control is
clinical inertia.22 Clinical inertia is defined as the
failure of medical providers to initiate or intensify
therapy when treatment goals are unmet. NPs are
often managing a large panel of patients, many of
whom have poorly controlled blood pressure.
Progress notes in a patient’s record may often refer to
issues such as white-coat hypertension or nonadherence. However, studies have shown that therapeutic inertia occurs in 75% of consultations for
HTN where treatment change is actually indicated.23
Other studies have indicated that clinical inertia
arises from a combination of medical provider, patient, and office system factors. Addressing these
factors simultaneously is the most effective way to
overcome the problem. Clinical inertia may be present in as many as two thirds of HTN clinic visits.
Recent reviews have identified clinical inertia as a
key intervention target for improving blood pressure control.22
Future success in treating patients with RHTN
and CKD may require increased use of clinical
practice guidelines and sustained patient outreach to
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address unmet blood pressure goals.22 Table 2 lists
factors that may contribute to clinical inertia in the
clinical setting. In the next section, a real-life case
study is presented to demonstrate application of the
treatment principles previously presented.
CASE STUDY
Mr. Jones is in your office for an initial evaluation for
HTN, CKD, and renovascular and hyperparathyroid
disease. He is a 67-year-old Caucasian male with a
history of encapsulated renal cell carcinoma that
resulted in a right nephrectomy in 2001. His current
medications include amlodipine 5 mg, furosemide 40
mg/day, with carvedilol 50 mg twice daily, and hydralazine 100 mg and clonidine 0.1 mg 3 times daily
for treatment of RHTN. He has been referred to an
NP-managed HTN shared medical visit clinic for
evaluation and treatment, which includes a multidisciplinary treatment approach incorporating motivational interviewing, medication management, and
dietary education. His blood pressure is 181/81 mm
Hg with a pulse rate of 64 beats/min. A recent lab
report revealed creatinine of 3.1 mg/dL, estimated
GFR of 20 mL/min, potassium of 4.1 mEq/L, and
parathyroid hormone of 93 pg/ml. Mr. Jones reports
that the recent addition of an ACEI resulted in severe
hyperkalemia and hospitalization. He reports to you
that he feels the lack of care coordination among
previous providers contributed to an acute illness
leading to hospitalization. After consulting with Dr.
M, the patient’s nephrologist, you learn that Mr.
Jones has a diagnosis of renovascular disease, which
can often cause hyperkalemia when ACEIs or ARBs
Table 2. Factors That May Contribute to Clinical Inertia
Lack of provider education
Lack of standardized treatment protocols
Uncertainty regarding which medication change to
recommend
Poor recognition of elevated blood pressure
Measurement of blood pressure using variable office
techniques
Focus on non‒hypertension-related concerns during
office visits
Inability to provide patient outreach when blood
pressure remains elevated
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are prescribed to treat HTN. During the conversation
with Dr. M, you discover that causes of secondary
HTN have been eliminated except for pheochromocytoma. You immediately recognize that Mr.
Jones’s CCB has not been optimized, so his dose of
amlodipine is increased to 10 mg/day. After verification is made that Mr. Jones has not been taking
calcitriol daily as prescribed, a refill order is placed. A
renal sonogram and 24-hour urine for metanephrines
is ordered.
Recognizing that patients with stage 4 CKD have
improved outcomes when evaluated and treated by a
nephrologist, the patient is encouraged to continue
seeking care through his nephrologist. Mr. Jones is
educated regarding the importance of not exceeding
2,000 mg/day of dietary sodium chloride. During the
initial visit with the patient, a comprehensive social
and medical history reveals a current use of cannabis.
Mr. Jones is then informed of the striking relationship
between cardiovascular complications and cannabis
use, especially in high risk patients with poorly
controlled blood pressure.24 During the evaluation of
RHTN, pseudoresistance and white-coat hypertension were excluded.
Mr. Jones returns to the clinic 3 weeks after his
initial visit. His ambulatory blood pressure log reveals
an average systolic blood pressure of 171.2 mm Hg.
The lab report indicates a potassium level of 4.4
mEq/L, creatinine of 2.1 mg/dL, and urinary metanephrines level of 151 mcg/24hrs. The renal sonogram test indicates no hydronephrosis or masses. The
blood pressure reading in the office is 198/91 mm
Hg, which suggests white-coat HTN. Mr. Jones has
been seen by the nephrologist since his previous visit
who recommended an increase in dosage of the loop
diuretic, furosemide, to 40 mg twice daily. Mr. Jones
is noted to have 1þ bilateral pedal edema on physical exam.
Six weeks after his initial visit, Mr. Jones returns for
a third shared medical visit. His average ambulatory
systolic blood pressure is 152.9 mm Hg. The lab
report indicates a PTH of 44 pg/mL, creatinine of
1.8 mg/dL, and estimated GFR of 38 mL/min/1.73 m2.
He is noted to have bilateral trace pedal edema on
physical exam. He denies any problems related to
medical treatment of HTN and CKD. A significant
improvement is noted in blood pressure, pedal edema,
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and renal function and medication adherence.
Lifestyle changes reported by Mr. Jones confirm a
decrease in dietary sodium reduction and an increase
in daily exercise. He also proudly reports having not
used cannabis products in at least 3 weeks. A review of
Mr. Jones’s case study reveals successful treatment of
RHTN as well as improvement in renal function. He
will continue to receive care from his nephrologist and
his primary care provider. In the event Mr. Jones
experiences uncontrolled RHTN, he may return to
the shared medical visit clinic for ongoing treatment.
CONCLUSION
We have presented an overview and treatment
summary related to the management of RHTN in
the patient with CKD. Solutions were discussed with
regard to the unique challenges often experienced by
NPs. Approaches to effectively treat RHTN while
preserving kidney function were emphasized.
HTN is the most common condition seen in
primary care and can lead to RHTN, myocardial
infarction, stroke, renal failure, and death if not
detected early and treated appropriately. HTN and
RHTN play a key role in the progression of CKD. In
addition to controlled blood pressure, antihypertensive therapy affects other key modifiable factors
related to kidney disease progression, including proteinuria, vascular stiffness, and increased activity of
the renin-angiotensin system.5 When treating
RHTN to lower risk for cardiovascular events,
aggressive pharmacologic therapy is needed to lower
both systolic and diastolic blood pressure.
NPs should strive to avoid clinical inertia when
treating patients with RHTN and CKD. Lack of
response to antihypertensive medication should
prompt an evaluation for nonadherence and secondary causes of HTN.
Finally, NPs should understand that blood pressure control is critical in the treatment of patients
with CKD. Goals of therapy, education, and
encouraging medication adherence must be directed
toward reducing cardiovascular risk and slowing
progression of kidney disease.
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1555-4155/15/$ see front matter
Published by Elsevier, Inc.
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Volume 11, Issue 6, June 2015