Download focus on heart failure

Therapeutic
TherapeuticOptions
Options
FOCUS
FOCUS
ONON
HEART
HEART
FAILURE
FAILURE
HeartHeart
failure
failure
(HF) is(HF)
a common
is a common
condition,
condition,
affecting
affecting
1–2% 1–2%
of theof the
adultadult
population
population
in developed
in developed
1
1
countries.
countries.
Among
Among
thosethose
aged aged
70 70
yearsyears
or older,
or older,
the prevalence
the prevalence
of of
1
1
HF is HF
≥10%.
is ≥10%.
Despite
Despite
advances
advances
in
in
detection
detection
and therapy,
and therapy,
HF remains
HF remains
a significant
a significant
causecause
of morbidity
of morbidity
2,3
2,3
and mortality.
and mortality.
In Canada,
In Canada,
HF is HF
reported
is reported
to beto
the
bemost
the most
common
common
causecause
of hospitalization
of hospitalization
in patients
in patients
over 65
over
years
65 years
of age,
of age,
as well
as as
well
theascause
the cause
of 9%ofof9%
allof all
4
4
deaths
deaths
nationwide.
nationwide.
Obviously,
Obviously,
therethere
is an urgent
is an urgent
need need
for for
aggressive
aggressive
measures
measures
to reduce
to reduce
the burden
the burden
of illness
of illness
associated
associated
4
4
with this
withclinical
this clinical
syndrome.
syndrome.
In theInpresence
the presence
of LV of
systolic
LV systolic
dysfunction
dysfunction
(the most
(the most
common
common
causecause
of HF),
ofthe
HF),body
the body
activates
activates
several
several
neurohumoral
neurohumoral
pathways
pathways
to increase
to increase
circulating
circulating
bloodblood
volume
volume
in an in
attempt
an attempt
to maintain
to maintain
6
adequate
adequate
cardiac
cardiac
output.
output.
Two6key
Two key
neurohumoral
neurohumoral
systems
systems
activated
activated
are the
arerenin–angiotensin–
the renin–angiotensin–
aldosterone
aldosterone
system
system
and the
and the
1
1
sympathetic
sympathetic
nervous
nervous
system.
system.
Initially,
Initially,
activation
activation
of these
of these
pathways
pathways
is compensatory
is compensatory
and and
beneficial,
beneficial,
but itbut
eventually
it eventually
leadsleads
to detrimental
to detrimental
effects,
effects,
including
including
pathologic
pathologic
LV remodelling
LV remodelling
with dilation,
with dilation,
hypertrophy,
hypertrophy,
and and
1,6
1,6
impaired
impaired
contractility.
contractility.
7
classification
classification
system
system
(see7 Table
(see Table
1).
1).
Additionally,
Additionally,
patients
patients
may be
may be
classified
classified
basedbased
on whether
on whether
LV LV
ejection
ejection
fraction
fraction
(EF) is(EF)
reduced
is reduced
(HF with
(HF reduced
with reduced
EF [HF-REF])
EF [HF-REF])
or preserved
or preserved
(HF with
(HF preserved
with preserved
EF [HF-PEF])
EF [HF-PEF])
(see Table
(see Table
2). 2).
The hallmark
The hallmark
manifestations
manifestations
of HFof
are
HFdyspnea
are dyspnea
(shortness
(shortness
of breath),
of breath),
fatigue,
fatigue,
and edema
and edema
1,2,5,7
1,2,5,7
(fluid(fluid
retention).
retention).
Other
Other
typical
typical
symptoms
symptoms
include
include
orthopnea,
orthopnea,
paroxysmal
paroxysmal
nocturnal
nocturnal
dyspnea,
dyspnea,
and and
1
reduced
reduced
exercise
exercise
tolerance.
tolerance.
Less1 Less
typically,
typically,
patients
patients
may complain
may complain
of nocturnal
of nocturnal
cough,
cough,
wheezing,
wheezing,
weight
weight
gain, anorexia,
gain, anorexia,
palpitations,
palpitations,
and confusion
and confusion
(the latter
(the latter
is most
is most
1
1
in theinelderly).
the elderly).
ETIOLOGY
ETIOLOGY
AND PATHOPHYSIOLOGY
AND PATHOPHYSIOLOGY CLASSIFICATION
CLASSIFICATION
AND SYMPTOMS
AND SYMPTOMS likelylikely
It is notable
It is notable
that symptom
that symptom
severity
severity
can vary
can vary
substantially
substantially
during
during
the course
the course
of of
ThereThere
are many
are many
known
known
etiologies
etiologies
HeartHeart
failure
failure
is often
is often
classified
classified
the disease
the disease
and may
and not
maycorrelate
not correlate
of HF,ofand
HF,several
and several
risk factors
risk factors
according
according
to thetoNew
the York
New Heart
York Heart
1,2
1,2
with changes
with changes
in underlying
in underlying
have have
been been
identified.
identified.
Association
Association
(NYHA)
(NYHA)
functional
functional
Coronary
Coronary
arteryartery
disease
disease
is cited
is cited
to beto be
1,2
1,2
TableTable
1 – New
1 – York
New Heart
York Heart
Association
Association
functional
functional
classification
classification
responsible
responsible
for roughly
for roughly
two- two1
thirdsthirds
of systolic
of systolic
HF cases
HF cases
(see1 (see
NYHANYHA
class*class*
Description
Description
TableTable
2, below,
2, below,
for descriptions
for descriptions
of systolic
of systolic
and diastolic
and diastolic
HF). HF).
No limitation
No limitation
of physical
of physical
activity;
activity;
ordinary
ordinary
physical
physical
Hypertension
Hypertension
is also
is aalso
major
a major
I
I
activity
activity
does does
not cause
not cause
HF symptoms
HF symptoms
2
2
risk factor
risk factor
in HF in
development.
HF development.
SomeSome
otherother
risk factors
risk factors
include
include
SlightSlight
limitation
limitation
of physical
of physical
activity;
activity;
comfortable
comfortable
at rest,
at rest,
II
II
valvular
valvular
heartheart
disease,
disease,
diabetes
diabetes
but ordinary
but ordinary
physical
physical
activity
activity
results
results
in HF in
symptoms
HF symptoms
mellitus,
mellitus,
hyperlipidemia,
hyperlipidemia,
Marked
Marked
limitation
limitation
of physical
of physical
activity;
activity;
comfortable
comfortable
at rest,
at rest,
excessive
excessive
alcohol
alcohol
intake,
intake,
use use
III
III
but less
butthan
less ordinary
than ordinary
activity
activity
causes
causes
HF symptoms
HF symptoms
of certain
of certain
chemotherapy
chemotherapy
drugsdrugs
(e.g., doxorubicin
(e.g., doxorubicin
or trastuzumab),
or trastuzumab),
Unable
Unable
to carry
to carry
on any
onphysical
any physical
activity
activity
without
without
1,2
1,2
IV IV
physical
physical
inactivity,
inactivity,
and smoking.
and smoking.
HF symptoms
HF symptoms
or symptoms
or symptoms
of HFof
atHF
rest
at rest
Most Most
patients
patients
with HF
with
have
HF have
symptoms
symptoms
due to
due
lefttoventricular
left ventricular
5
5
(LV) myocardial
(LV) myocardial
dysfunction.
dysfunction.
HF = heart
HF =failure;
heart failure;
NYHA =NYHA
New York
= New
Heart
YorkAssociation
Heart Association
1
1
* Patients
* Patients
in NYHAinclasses
NYHA II,
classes
III, andII,IVIII,are
and
sometimes
IV are sometimes
said to have
said mild,
to have
moderate,
mild, moderate,
and severe
andsymptoms,
severe symptoms,
respectively.
respectively.
THERAPEUTIC
THERAPEUTIC
OPTIONS
OPTIONS
APRIL/MAY/JUNE
APRIL/MAY/JUNE
2014 2014
I
I
cardiac function.2 Importantly,
any deterioration in symptoms
indicates a heightened risk of
hospitalization and death, and
warrants prompt medical attention.1
MANAGEMENT
The main goals of treatment in
patients with HF are to improve/
relieve symptoms and signs,
reduce morbidity (including
hospital admissions), and improve
survival.1 Recommendations for
managing patients with HF-REF
and HF-PEF are summarized
below. In addition to the specific
therapies discussed, comorbidities
should be appropriately treated,
particularly those that are major
risk factors for HF and those that
directly impact HF symptoms and/
or progression (e.g., hypertension,
atrial fibrillation, anemia).1,2,5 A
thorough discussion of such
holistic management is beyond
the scope of this review; however,
recommendations are provided in
guidelines available online1,2,5 (see
References, below, for URLs).
Pharmacotherapy for HF-REF
There is general consensus among
recent guidelines1,5,7 that the
foundation of treatment for most
patients with HF-REF should be a
multidrug regimen consisting of
an angiotensin-converting enzyme
(ACE) inhibitor (or an angiotensin
receptor blocker [ARB]) and a
beta-blocker. A mineralocorticoid
receptor antagonist (MRA) is
considered standard additional
therapy for individuals who
continue to meet NYHA class II–IV
criteria despite optimized treatment
with an ACE inhibitor (or ARB)
and a beta-blocker.1,5,7 Each of the
aforementioned drug classes has
been shown to improve survival
in trials involving patients with
HF-REF.1,5,7 These core therapies
are generally used in conjunction
with diuretics to relieve congestive
symptoms/fluid retention.1,5,7
Adjunctive or alternative therapies
such as digoxin, isosorbide
dinitrate plus hydralazine, and
omega-3 polyunsaturated fatty
acids may also be beneficial
in certain scenarios.1,5,7
Evidence-based dosing strategies
for disease-modifying therapies
are summarized in Table 3;
recommendations and practical tips
regarding these agents are provided
in Box 1. Recommendations and
II
Table 2 – Classification based on left ventricular ejection fraction1,5
Classification*
LVEF
Heart failure with
reduced ejection
fraction (HF-REF)
≤40%
Heart failure with
preserved ejection
fraction (HF-PEF)
≥50 %
Comments
• Also referred to as “systolic HF”†
• Best understood type of HF in terms of
pathophysiology and treatment; RCTs
proving therapies to be efficacious in HF
have primarily enrolled patients with HF-REF
• Also referred to as “diastolic HF”‡
• To date, efficacious therapies for patients
with HF-PEF have not been identified
HF = heart failure; LVEF = left ventricular ejection fraction; RCTs = randomized controlled trials
* Classifications in addition to those listed have been described: (1) HF-PEF, borderline: LVEF
41–49% (overall patient characteristics, treatment patterns, and outcomes appear similar to
those of patients with HF-PEF); and (2) HF-PEF, improved: LVEF >40% (a subset of patients who
previously had HF-REF; further research is necessary to better characterize these patients).5
† In systolic HF, cardiac contractility is reduced.6
‡ In diastolic HF, cardiac relaxation is impaired and ventricular filling is abnormal.6
Table 3 – Doses of disease-modifying medications for HF-REF1,5,7,8
Dosage
Drug
Initial*
Target†
Angiotensin-converting enzyme inhibitors
Captopril
6.25 mg tid
50 mg tid
Enalapril
1.25–2.5 mg bid
10 mg bid
Lisinopril
2.5–5 mg od
20–35 mg od
Perindopril
2 mg od
4–8 mg od
Ramipril
1.25–2.5 mg od
5 mg bid
Trandolapril
0.5–1 mg od
4 mg od
Bisoprolol
1.25 mg od
10 mg od
Carvedilol
3.125 mg bid
25 mg bid‡
Metoprolol CR/XL§
12.5–25 mg od
200 mg od
Beta-blockers
Angiotensin receptor blockers
Candesartan
4 mg od
Valsartan
40 mg bid
32 mg od
160 mg bid
Mineralocorticoid receptor antagonists
¶
Eplerenone
25 mg od
50 mg od
Spironolactone
12.5 mg od
25–50 mg od
Hydralazine
37.5 mg tid
75 mg tid
Isosorbide dinitrate
20 mg tid
40 mg tid
Vasodilators
bid = twice daily; HF-REF = heart failure with reduced ejection fraction; od = once daily; tid = three times daily
* In instances where initial recommended doses varied among guidelines consulted, lower doses have
been listed.
† If target doses cannot be reached, use maximum tolerated doses.
‡ 50 mg bid if weight >85 kg.
§ The metoprolol CR/XL (succinate) formulations are not commercially available in Canada.
¶ Also referred to as aldosterone antagonists.
THERAPEUTIC OPTIONS APRIL/MAY/JUNE 2014
Box 1 – Recommendations* and practical tips† for disease-modifying medications for HF-REF 1,5,7,9
Angiotensin-converting
enzyme inhibitors
Recommended use:
• All symptomatic (and previously
symptomatic) patients with EF ≤40%
(in addition to a beta-blocker)
Tips/comments:
• When initiating therapy, double
the dose at intervals of no less
than 2 weeks in the community;
quicker up-titration may occur in
hospital or in other settings where
patients are closely monitored
• An increase in serum creatinine
is expected upon initiating
therapy; there is no immediate
need to lower the dose if the
increase stabilizes at ≤30%
• Symptom improvement occurs
within a few weeks to a few
months after starting treatment
• Abrupt withdrawal can lead
to clinical deterioration
and should be avoided
• The combination of an ACE
inhibitor and ARB increases the
risk of hypotension, hyperkalemia,
and renal dysfunction, and
should be used with caution
Beta-blockers
Recommended use:
• All symptomatic (and previously
symptomatic) patients with EF ≤40%
(in addition to an ACE inhibitor)
Tips/comments:
• When initiating therapy, double
the dose at intervals of no
less than 2 weeks (slower
up-titration may be necessary)
• Therapy should generally be
initiated in stable patients (e.g., not
during or within 4 weeks of a HF
exacerbation); attempts should be
made to relieve congestion/fluid
retention prior to starting therapy
• Major dose reduction or abrupt
withdrawal can lead to clinical
deterioration and should be avoided
• Symptom improvement may
occur slowly after starting
treatment, sometimes taking
3–6 months or longer
Angiotensin receptor blockers
Recommended uses:‡
• As an alternative to an ACE
inhibitor in patients who: (1)
cannot tolerate ACE inhibitor
therapy,§ or (2) are already taking
an ARB for another indication
• In combination with an ACE inhibitor
and beta-blocker for persistently
symptomatic patients when a
MRA is not tolerated (see tips/
comments for ACE inhibitors, above,
for statement regarding combined
use of an ACE inhibitor and ARB)
Tips/comments:
• Tips/comments for ACE inhibitors
(see above) apply to ARBs
Mineralocorticoid receptor
antagonists¶
Recommended uses:**
• All patients with persistent
symptoms (NYHA Class
II-IV††) and an EF ≤35% despite
treatment with an ACE inhibitor
(or ARB) and beta-blocker
• Following an acute MI in patients
with: (1) symptoms of HF and an
EF ≤40%, or (2) an EF ≤40% and
a history of diabetes mellitus
Tips/comments:
• Consider dose up-titration 4–8
weeks after initiation of therapy
• Symptom improvement occurs
within a few weeks to a few
months after starting treatment
• Hyperkalemia is the main concern
with MRA therapy, and risk is
increased when therapy is combined
with an ACE inhibitor or ARB; vigilant
monitoring of serum potassium
and renal function is essential‡‡
• Interruption of therapy may
be necessary during periods
of worsening renal function
and/or dehydration
Vasodilators
Recommended use:
• The combination of isosorbide
dinitrate and hydralazine may be
considered: (1) for black patients
with persistent symptoms despite
standard therapy with an ACE
inhibitor (or ARB) and beta-blocker
(and MRA as appropriate), and (2)
as an alternative to an ACE inhibitor
or ARB in any patient unable to
use/tolerate these therapies
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; EF = ejection fraction; HF = heart failure; HF-REF = heart failure with
reduced ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association
* Recommendations provided were summarized/synthesized from guidelines consulted; refer to complete online documents1,5,7 for details
of recommendations made in individual guidelines, including grade/level of evidence (see References, below, for URLs).
† Many useful tips and comments in addition to those listed (including ones related to contraindications, precautions, drug interactions,
monitoring, and management of adverse effects) are made in the full guidelines; refer to complete online documents1,5,7,9 for details
(see References, below, for URLs). Web tables 11, 12, 13, and 15 from the European guidelines9 are particularly helpful.
‡ In addition to the listed uses, Canadian guidelines7 propose ARBs be considered “as adjunctive therapy to ACE inhibitors
when β-blockers are either contraindicated or not tolerated after careful attempts at initiation.”
§ Intolerable ACE inhibitor-induced cough is the primary indication for ARB therapy; caution is advised in patients who developed angioedema with an ACE inhibitor.5
¶ Also referred to as aldosterone antagonists.
** Recommendations from Canadian guidelines7 are more restrictive (based on EF) than those from US5 or European1 guidelines; Canadian
guidelines7 also make differential recommendations for eplerenone and spironolactone, whereas US5 and European1 guidelines do not.
†† According to US guidelines,5 patients with NYHA class II HF should have a history of prior cardiovascular
hospitalization, or elevated plasma natriuretic peptide levels, to be considered for MRA therapy.
‡‡ Refer to online guidelines1,5,7 for detailed recommendations (see References, below, for URLs).
tips for use of adjunctive therapies
are summarized in Box 2.
In instances where a drug with
proven mortality or morbidity
benefits (i.e., those listed in Table
3) seems to be poorly tolerated
(e.g., low blood pressure, low
heart rate, renal dysfunction),
concomitant drugs that have
less proven benefit should be
re-evaluated to determine if their
dose can be reduced (or the drug
discontinued) to allow better
tolerance of the proven drug.7
Medications that are not specifically
used to treat HF-REF per se, but
THERAPEUTIC OPTIONS APRIL/MAY/JUNE 2014
which may be used in patients
with other indications for
therapy include platelet inhibitors,
anticoagulants, and statins.1,5,7 Drugs
that should generally be avoided
based on risk of HF exacerbation
include thiazolidinediones
(“glitazones”), traditional nonsteroidal anti-inflammatory drugs,
III
Box 2 – Recommendations* and practical tips† for adjunctive therapies for HF-REF1,5,7,9
Diuretics
Recommended use:
• Patients with signs and symptoms
of fluid retention/congestion
(e.g., dyspnea, edema)
Tips/comments:
• Loop diuretics (e.g., furosemide) are
preferred for most patients; once
acute congestion resolves, use
the lowest dose‡ that maintains
stable signs and symptoms
(continuous treatment may not
be necessary for all patients)
• When volume overload persists
despite optimal medical therapy
(including increased loop diuretic
doses), cautious addition of a
second diuretic (e.g., a thiazide
or low-dose metolazone)
may be considered, with close
monitoring of daily weight, renal
function, and serum potassium
• Symptoms improve quickly, usually
within days of starting treatment
in the range of 0.6–1.1 nmol/L [0.5–
0.9 ng/mL] have been suggested
based on limited evidence)
Digoxin
Recommended use:
• Digoxin may be considered for:
(1) patients in sinus rhythm who
continue to have moderate to
severe symptoms despite optimized
therapy, and (2) patients with chronic
atrial fibrillation and poor ventricular
rate control despite optimal
beta-blocker therapy (or when a
beta-blocker cannot be used)
Tips/comments:
• Therapy is typically initiated and
maintained at a dose of 0.125–0.25
mg daily, although lower doses may
be appropriate for some patients
(target plasma drug concentrations
Omega-3 polyunsaturated fatty acids
Recommended use:
• An n-3 PUFA preparation may
be considered as adjunctive
therapy in patients with persistent
symptoms to reduce the risk of
death and CV hospitalizations
Tips/comments:
• In the main study supporting the
recommended use, patients received
a dose of 1 g n-3 PUFA§ daily
• The small treatment effect in the
main study was only detected
after covariate adjustment
in the statistical analysis
CV = cardiovascular; HF-REF = heart failure with reduced ejection fraction; n-3 PUFA = omega-3 polyunsaturated fatty acid
* Recommendations provided were summarized/synthesized from guidelines consulted; refer to complete online documents1,5,7 for details
of recommendations made in individual guidelines, including grade/level of evidence (see References, below, for URLs).
† Many useful tips and comments in addition to those listed (including ones related to contraindications, precautions, drug interactions, monitoring, and
management of adverse effects) are made in the full guidelines; refer to complete online documents1,5,7,9 for details (see References, below, for URLs).
‡ Detailed diuretic dosing recommendations are provided in Table 14 of the online US guidelines5 (see References, below, for URL).
§ Including 850–882 mg eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as ethyl esters in the average ratio of EPA/DHA 1:1.2.
cyclooxygenase-2 inhibitors,
nondihydropyridine calcium
channel blockers (amlodipine and
felodipine may be used if otherwise
clinically indicated), and nonamiodarone antiarrhythmics.1,5,7
The routine combined use of ACE
inhibitor + ARB + MRA should also
be avoided due to risk of renal
dysfunction and hyperkalemia.1,5,7
Pharmacotherapy for HF-PEF
No treatment has been shown
to definitively reduce morbidity
and mortality in patients with
HF-PEF.1 As a result, the main
treatment approach is to control
potentially etiologic risk factors
such as hypertension and
myocardial ischemia.1,7 Control of
ventricular rate in patients with
atrial fibrillation is also considered
important.1 Where appropriate for
the aforementioned indications,
ACE inhibitors, ARBs, and betablockers are reasonable choices.5,7
Diuretics are used to relieve
dyspnea and edema.1,5,7 In contrast
to HF-REF, nondihydropyridine
calcium channel blockers
may be used if indicated.1,7
www.chfn.ca/clinic-resource-manual/
rationale-for-hf-clinics
Nonpharmacological Interventions
Various lifestyle interventions
and device-related or surgical
procedures may be indicated for
patients with HF. A full review of
these interventions is beyond the
scope of this review; however,
recommendations are provided
in guidelines available online1,2,5,7
(see References, below, for URLs).
5. Yancy CW, et al. Circulation. 2013
Oct 15;128(16):e240-319. Available
from: http://circ.ahajournals.org/
content/128/16/e240.full.pdf+html
6. Hobbs R, Boyle A. Heart failure. Available
from: http://www.clevelandclinicmeded.
com/medicalpubs/diseasemanagement/
cardiology/heart-failure/
7. McKelvie RS, et al. Can J Cardiol. 2013
Feb;29(2):168-81. Available from: http://
download.journals.elsevierhealth.
com/pdfs/journals/0828-282X/
References
PIIS0828282X12013797.pdf
8. McKelvie RS, et al. Can J Cardiol. 2013
1.
Feb;29(2). [supplemental material]
McMurray JJ, et al. Eur Heart J. 2012
Jul;33(14):1787-847. Available from:
Available from: http://download.journals.
http://eurheartj.oxfordjournals.org/
elsevierhealth.com/mmcs/journals/0828282X/PIIS0828282X12013797.mmc1.pdf
content/33/14/1787.full.pdf
9. McMurray JJ, et al. Eur Heart J. 2012
2. Heart Failure Society of America. J Card
Fail. 2010 Jun;16(6):475-539. Available from:
Jul;33(14). [supplemental material]
http://download.journals.elsevierhealth.
Available from: http://www.escardio.
com/pdfs/journals/1071-9164/
org/guidelines-surveys/esc-guidelines/
PIIS1071916410001740.pdf
GuidelinesDocuments/GuidelinesHeart-Failure-Web-Tables.pdf
3. Shearer F, et al. Clin Pharmacol
Ther. 2013 Oct;94(4):459-67.
4. Canadian Heart Failure Network. Rational
for HF clinics. Available from: http://
Disclaimer: The Drug Information and Resource Centre (DIRC) of the Ontario Pharmacists Association provides this material to health professionals for informational
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responsibility of the health professional to use professional judgment in evaluating this material in light of any relevant clinical or situational data.
IV
THERAPEUTIC OPTIONS APRIL/MAY/JUNE 2014