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Nephrology 19 (2014) 3–10
KHA-CARI Guideline
Cardiovascular disease in patients with chronic kidney disease
HELEN PILMORE,1 GURSHARAN DOGRA,2 MATTHEW ROBERTS,3,4 HIDDO J LAMBERS HEERSPINK,6
TOSHIHARU NINOMIYA,7 RACHEL HUXLEY5 and VLADO PERKOVIC5
1
Department of Renal Medicine, Auckland City Hospital and Department of Medicine, Auckland University, Auckland, New Zealand; 2Department of Renal
Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, 3Department of Nephrology, Austin Health, 4Department of Medicine, University of
Melbourne, Melbourne, 5The George Institute for Global Health, The University of Sydney, Sydney, New South Wales, Australia; 6Department of Clinical
Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and 7Department of Nephrology, Hypertension, and
Strokology, Kyushu University Hospital, Kyushu, Japan
Correspondence:
Dr Helen Pilmore, Department of Renal Medicine,
Auckland City Hospital and Department of Medicine,
Auckland University, Auckland, New Zealand.
Email: [email protected]
Accepted for publication 1 August 2013.
Accepted manuscript online 8 August 2013.
doi:10.1111/nep.12148
1. REVASCULARIZATION
Guideline recommendations
a. We recommend that in patients with chronic kidney
disease (CKD), end-stage renal failure (ESRF) and after
kidney transplantation, that guidelines for revascularization
of the general population be adhered to (1D).
Ungraded suggestions for clinical care
• Patients with evidence of coronary artery disease should
be referred to a cardiologist for expert opinion (ungraded).
• Physicians should be aware that revascularization of
coronary arteries with coronary artery bypass graft (CABG)
and percutaneous intervention (PCI) is associated with
greater mortality and morbidity in patients with CKD and
those on dialysis compared with the general population
(ungraded).
Background
Cardiovascular disease is the leading cause of death in
patients with ESRF. The risk of cardiovascular death is significantly reduced in the renal transplant population compared with those on dialysis, but is still significantly greater
than that of the general population.1 In addition, the risk of
cardiac death and major cardiac events is greater in those
with CKD than those with normal renal function.2,3
Revascularization of coronary artery stenoses has been
extensively studied in the general population and guidelines
for the management of both unstable4 and stable5 coronary
artery disease (CAD) have been generated using evidence
from randomized controlled trials (RCTs). However, in most
trials, patients with significant renal impairment have been
excluded.
The aim of this guideline is to review the literature and
assess the benefits and harms of revascularization of CAD in
patients with CKD, including the dialysis and transplant
populations. The revascularization literature was examined
both in unstable and stable CAD.
The data regarding revascularization of patients with
kidney disease are sparse, especially in regards to RCTs. In
contrast there is a large body of data and hence many guidelines in the general population. In the absence of any contrary data, we recommend that guidelines for patients in the
general population be followed. Both the current ACCF/
AHA and European guidelines include special mention of
patients with CKD.
Summary of the evidence
There is limited evidence from RCTs comparing
revascularization with medical therapy specific for patients
with CKD. The available data including ad hoc sub group
analyses of RCTs conducted in the general population does not
currently justify guideline recommendations specific to
people with CKD for either stable or unstable CAD.
In comparison with the general population, patients with
CKD are at increased risk of early and late mortality after
CABG. Patients on dialysis have a greater perioperative mortality than those with normal renal function after CABG and
markedly reduced long-term survival compared with the
general population.
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CKD patients and patients on dialysis treated with PCI
using angioplasty are at greater risk of long-term mortality
and major cardiac events compared with those with normal
renal function.
There are few outcome studies following CABG or PCI that
have included transplant recipients and none of these have
included control groups for comparison.
There are no RCTs comparing outcomes associated with
bare metal stents (BMS) versus drug eluting stents (DES) or
different types of DES. Retrospective data for both CKD and
dialysis patients is inconclusive in relation to the use of DES
compared to BMS and associations with mortality, major
cardiac events and restenosis. There are currently insufficient
data to support guideline recommendations on the use of
DES specific to patients with CKD or those on dialysis. Similarly there has been limited assessment of outcomes following the use of stents in transplant recipients.
REFERENCES
1. McDonald S, Excell L, Livingston B. ANZDATA 2008 Annual Report.
South Australia: Austalia and New Zealand Dialysis and Transplant
Registry, 2008.
2. Anavekar NS, McMurray JJV, Velazquez EJ et al. Relation between
renal dysfunction and cardiovascular outcomes after myocardial
infarction. N. Engl. J. Med. 2004; 351: 1285–95.
3. Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the
risks of death, cardiovascular events, and hospitalization. N. Engl. J.
Med. 2004; 351: 1296–305.
4. Fihn SD, Gardin JM, Abrams J et al. 2012
ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis
and Management of Patients With Stable Ischemic Heart Disease: A
Report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines, and the
American College of Physicians, American Association for Thoracic
Surgery, Preventive Cardiovascular Nurses Association, Society for
Cardiovascular Angiography and Interventions, and Society of
Thoracic Surgeons. Circulation 2012; 126: e354–471.
5. Jneid H, Anderson JL, Wright RS et al. 2012 ACCF/AHA Focused
Update of the Guideline for the Management of Patients With
Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating
the 2007 Guideline and Replacing the 2011 Focused Update): A
Report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines. Circulation
2012; 126: 875–910.
2. MEDICAL MANAGEMENT
Guideline recommendations
Acute coronary syndrome
a. We recommend that all CKD patients, including haemodialysis, peritoneal dialysis and transplant patients, should be
treated as per the general population when presenting with an
acute coronary syndrome (ACS) ST-elevation myocardial
infarction (STEMI) or non-ST-elevation acute coronary syndrome (NSTE-ACS) with regards to reperfusion therapy,
antiplatelet therapy (aspirin and clopidogrel), anticoagulant
therapies (heparin, thrombin and glycoprotein IIb/IIIa inhibitors), beta-blockers and angiotensin-converting enzyme
inhibitors (ACEi) (1C).
b. We recommend that reperfusion therapy give preference
to primary percutaneous coronary intervention over
fibrinolysis (1D).
Chronic stable coronary artery disease
c. We recommend that all CKD patients, including haemodialysis, peritoneal dialysis and transplant patients, should be
treated for chronic stable CAD as the general population with
regards to antiplatelet therapies, beta-blockers, ACEi and
angiotensin receptor blockers (ARB)* (1D).
*For angiotensin-converting enzyme inhibitors and angiotensin receptor blockers refer to The KHA-CARI Guidelines:
‘Cardiovascular effects of blood pressure lowering in patients with
chronic kidney disease.’ (summarized in Section 3 below).
Safety of therapy
d. We recommend that all patients with CKD with an estimated glomerular filtration rate (eGFR) <60 mL/min, and
specifically those with an eGFR <30 mL/min undergoing
antiplatelet or anticoagulant therapy, are considered as
being at increased risk of bleeding. Dose adjustment of
specific antiplatelet and anticoagulant drugs, specifically
enoxaparin, bivalirudin, and glycoprotein IIb/IIIa inhibitors
eptifibatide and tirofiban, is recommended (1A).
e. In CKD patients with an eGFR <30 mL/min we recommend that caution be exercised when using enoxaparin for
ACS, with a preference for (empirical or based on anti-Xa
levels) dose adjustment in an effort to lower bleeding risk
(1B). Caution should also be exercised using glycoprotein
IIb/IIIa inhibitors in CKD patients with ACS because of
increased bleeding risk (1C).
f. We recommend that in CKD patients at risk for, or with
stable cardiovascular disease single antiplatelet agents (lowdose aspirin, dipyridamole, clopidogrel or ticlopidine) can be
used without an increased risk in major bleeding events (1B).
g. We recommend that combination antiplatelet therapy
with high-dose aspirin (325 mg) and clopidogrel or warfarin
not be used in haemodialysis patients because of an increased
risk of significant bleeding requiring hospitalization or transfusion (1B).
Ungraded suggestions for clinical care
• Because of the ease of reversibility, unfractionated
heparin (UFH) may be used in place of low molecular weight
heparin (LMWH) particularly in patients with a eGFR
≤30 mL/min, with standardized monitoring of clotting times
(activated partial thromboplastin time, APPT) (ungraded).
(Note: Data support an increased risk for bleeding with the
use of LMWH or UFH in patients with increasing degrees of
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Cardiovascular disease guidelines
renal dysfunction, and in particular those with a CrCl
≤30 mL/min; however, they do not support an increased risk
of bleeding with the use of LMWH compared with UFH
within subgroups of CKD. The increased risk of bleeding in
patients with eGFR ≤30 mL/min on LMWH is possibly abrogated by the use of anti-Xa adjusted dosing schedules, but
these strategies have not been well tested in patients with
renal insufficiency.)
Background
There is a two- to six-fold increased risk of cardiovascular
events in patients with CKD,1 with approximately 40–50% of
the mortality of patients with stage 5 CKD on renal replacement treatment being attributed to CVD.2 For dialysis
patients, the post-myocardial infarction (MI) 1- and 2-year
mortality rates are 61% and 75%, respectively.3 Furthermore, there is an independent, graded increased risk of death
and cardiovascular (CV) events associated with reduced
eGFR,1 and this relationship is also seen in survivors of acute
MI (AMI) and NSTE-ACS.4–6
Medical management of ACS, which include STEMI and
NSTE-ACS, and chronic stable CAD has been extensively
studied in the general population leading to evidence-based
national clinical practice guidelines.7–9 There are RCTs that
have firmly established roles for reperfusion and primary
PCI, antiplatelet and anticoagulant therapies, beta-blocker
therapy, and ACEi or ARB therapy for ACS in the general
population. In the majority of these trials patients with
moderate-to-severe renal impairment have been excluded,
leading to unanswered concerns about efficacy and safety, and
consequently significant underuse of these therapeutic
options in CKD patients.4,6,10,11
The aim of this guideline is to examine the benefits and
harms of medical management, specifically reperfusion
therapy, antiplatelet and anticoagulant therapies, betablocker therapy, and ACEi/ARB therapy (but excluding lipidlowering therapy), of ACS and chronic stable CAD in
patients with CKD, including the dialysis and transplant
populations. The benefits examined are:
1. The risk of MI and CV death in patients presenting with
ACS, including the risk of coronary restenosis in patients
with an ACS undergoing a PCI and receiving associated
antiplatelet and/or anticoagulant therapy.
2. The risk of MI and CV death in patients with chronic
stable CAD.
The harms examined relate to serious adverse events
reported in the literature in relation to the aforementioned
medical therapies.
Summary of the evidence
There is little high quality evidence regarding the management of ACS or chronic stable CAD in patients with CKD.
The RCT data examining the therapeutic options for the
medical management of ACS or chronic stable CAD are all
taken from post-hoc analyses of RCTs from the general population where patients with CKD were identified based on
serum creatinine and/or eGFR, and outcomes analysed.
These limitations also apply to assessing harms of ACS therapies. Specifically with regards to harm of anticoagulant
therapies, data have been extrapolated from trials using anticoagulants for non-cardiac indications. Prospective and
retrospective registry data or observational cohorts provide a
significant proportion of the evidence for ACS therapies.
The management of ACS in the general population has
been published in the extensive guidelines available.7–9 These
guidelines support the use of PCI in favour of thrombolysis
without specifically including or excluding CKD patients. It is
notable that the latest addendum to the National Heart
Foundation of Australia/Cardiac Society of Australia and
New Zealand Guidelines for the Management of ACS highlights the significance of reduced bleeding risk being associated with improved outcome for patients with ACS in the
general population, and recommends including an eGFR
<60 mL/min when calculating bleeding risk scores to tailor
anticoagulant therapy.9 These Guidelines favour an approach
of improving net clinical outcome by reducing bleeding risk
in patients assessed to be at high risk of bleeding, a marker
for which is renal dysfunction (eGFR < 60 mL/min). There is
a perceived risk of increase bleeding in CKD patients that has
led to other renal guideline groups recommending PCI over
thrombolysis but with ungraded evidence; however, KHACARI have assigned a 1D grading reflecting the general
population guidelines.
REFERENCES
1. Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the
risks of death, cardiovascular events, and hospitalization. N. Engl.
J. Med. 2004; 351: 1296–305.
2. Baigent C, Burbury K, Wheeler D. Premature cardiovascular
disease in chronic renal failure. Lancet 2000; 356: 147–52.
3. Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute
myocardial infarction among patients on long-term dialysis. N.
Engl. J. Med. 1998; 339: 799–805.
4. Wright RS, Reeder GS, Herzog CA et al. Acute myocardial
infarction and renal dysfunction: A high-risk combination. Ann.
Intern. Med. 2002; 137: 563–70.
5. Anavekar NS, McMurray JJV, Velazquez EJ et al. Relation between
renal dysfunction and cardiovascular outcomes after myocardial
infarction. N. Engl. J. Med. 2004; 351: 1285–95.
6. Fox CS, Muntner P, Chen AY et al. Use of evidence-based therapies
in short-term outcomes of ST-segment elevation myocardial
infarction and non-ST-segment elevation myocardial infarction in
patients with chronic kidney disease: A report from the National
Cardiovascular Data Acute Coronary Treatment and Intervention
Outcomes Network registry. Circulation 2010; 121: 357–65.
7. Acute Coronary Syndrome Guidelines Working Group. Guidelines
for the management of acute coronary syndromes 2006. Med. J.
Aust. 2006; 184: S9–29.
© 2013 Asian Pacific Society of Nephrology
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H Pilmore et al.
8. Aylward P, Chew DP, Huang N et al. 2007 addendum to the
national heart foundation of Australia/Cardiac society of australia
and new zealand guidelines for the management of acute coronary
syndromes 2006. Med. J. Aust. 2008; 188: 302–3.
9. Chew DP, Aroney CN, Aylward PE et al. 2011 Addendum to the
National Heart Foundation of Australia/Cardiac Society of
Australia and New Zealand Guidelines for the management of
acute coronary syndromes (ACS) 2006. Heart Lung Circ. 2011; 20:
487–502.
10. Reddan DN, Szczech L, Bhapkar MV et al. Renal function,
concomitant medication use and outcomes following acute
coronary syndromes. Nephrol. Dial. Transplant. 2005; 20:
2105–12.
11. Shlipak MG, Heidenreich PA, Noguchi H et al. Association of renal
insufficiency with treatment and outcomes after myocardial
infarction in elderly patients. Ann. Intern. Med. 2002; 137:
555–62.
prevent cardiovascular or renal events in people with CKD,
as the combination provides no additional proven benefit,
while increasing the risk of adverse outcomes (1B).
Chronic kidney disease requiring dialysis
g. We recommend that blood pressure should be lowered in
individuals with CKD receiving dialysis who have suboptimal blood pressure levels (1C), and in the absence of specific
data, suggest a similar target to the general population where
possible (2D).
h. We suggest that reducing ideal weight be used as the
initial strategy to lower blood pressure in people with CKD
requiring dialysis (2C).
Ungraded suggestions for clinical care
3. CARDIOVASCULAR EFFECTS OF BLOOD
PRESSURE LOWERING IN PATIENTS WITH
CHRONIC KIDNEY DISEASE
Guideline recommendations
Chronic kidney disease not requiring dialysis
a. We recommend that blood pressure targets in people with
CKD should be determined on an individual basis taking into
account a range of patient factors including baseline risk,
albuminuria level, tolerability and starting blood pressure
levels (1C).
b. We suggest that most people with CKD should be treated
to similar targets as the general population, such that most
blood pressure readings are below 140/90 (2D). We suggest
that most blood pressure readings should be below 130/80 in
individuals with CKD and macroalbuminuria (2B).
c. We recommend that lifestyle modification (e.g. weight
loss, salt restriction, and exercise) be incorporated in blood
pressure lowering regimens for all people with CKD (1C)
d. We suggest that:
• Angiotensin-converting enzyme inhibitors or ARB
should be used in most people with CKD who require
blood pressure lowering (particularly those with albuminuria), because of the volume of evidence showing benefits for cardiovascular as well as renal outcomes (2B).
• Diuretics, calcium channel blockers (CCB) and betablockers may also be used to lower blood pressure in
people with CKD requiring treatment (2B).
• Other agents should be used with caution as there are
no trial data demonstrating a benefit in people with CKD
(2D).
e. We suggest that blood pressure lowering agents may also
be used where tolerated in people with CKD who have blood
pressure levels in the normal range and are at high risk of
cardiovascular events (2C).
f. We recommend that a combination of two or more of
ACEi, ARB and renin inhibitors should not be used to
• There is little evidence about the efficacy in preventing
CVD of different combinations of blood pressure (BP)lowering drugs in people with CKD. If BP targets are not met,
the choice of a second agent should be based on individual
patient factors, tolerability, and side-effects (ungraded).
• The choice of blood pressure lowering agent should
be made on the grounds of individual patient variables,
comorbidities, tolerability and side-effect profiles (ungraded).
Background
Individuals with CKD are at significantly increased risk for
cardiovascular events.1 Blood pressure is an important determinant of cardiovascular risk in the general population in
which interventions that lower BP have been clearly shown
to prevent cardiovascular events.2 Blood pressure levels are
commonly elevated in people with CKD raising the possibility that BP lowering may offer significant benefit in this
group.3,4 The objective of this guideline is to evaluate the
evidence of different BP-lowering regimens in preventing
CVD in patients with CKD.
There are three main questions:
1. What is the evidence that BP lowering is effective at
reducing cardiovascular risk in patients with CKD?
2. What is the evidence for different treatment regimens in
terms of their efficacy at reducing CVD risk in patients with
evidence of kidney disease?
3. What BP target should clinicians aim for in treating
patients?
Summary of the evidence
Randomized controlled trials in CKD populations evaluating
the benefit risk ratio of BP-lowering regimens on cardiovascular outcomes are lacking. Recommendations in this guideline are therefore based on a synthesis of the best available
evidence.
© 2013 Asian Pacific Society of Nephrology
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Cardiovascular disease guidelines
• Evidence from large RCTs indicates that BP lowering
in individuals with impaired renal function reduces the
risk of cardiovascular mortality and morbidity and total
death.
• There is limited evidence that lower BP targets in patients
with renal impairment are at reduced risk of CVD. As a result
it would seem reasonable to extrapolate BP targets from
high-risk patients with normal renal function, and to incorporate likely benefits for kidney function, where evidence of
benefit exists for a lower target (namely less than 130/
80 mmHg) in people with albuminuria or proteinuria.
• There is evidence that ACEi are efficacious at reducing BP
and subsequent CVD and all-cause mortality in patients with
mild, moderate and severe renal impairment. There is currently little evidence about the comparative effectiveness of
other agents in preventing cardiovascular mortality and morbidity in this patient population. Post-hoc analyses of ACEi
trials have shown that the treatment effects of ACEi on
cardiovascular outcomes are consistent in patients with and
without CKD. ACEi appear therefore a reasonable first
choice for prevention of CVD in this population.
• The evidence about the cardiovascular protective effects
of ARB in CKD patients is scarce. However, they have been
shown to confer renal protection in patients with diabetic
nephropathy and are therefore a sensible alternative if ACEi
are not tolerated in this population.
• Head to head studies have reported similar cardiovascular outcomes with different classes of agents in people with
CKD, although the power to detect meaningful differences is
limited. ACEi, ARB, CCB and diuretics are therefore all reasonable choices for people with CKD. Renin angiotensin
system blockade with ACEi or ARB is likely to have renal
benefits in people with proteinuria and should therefore be
preferred in this population (see separate guideline).
• There is little evidence about the efficacy in preventing
CVD of different combinations of BP-lowering drugs in
people with CKD. If BP targets are not met, the choice of a
second agent should be based on individual patient factors,
tolerability, and side-effects.
REFERENCES
1. McDonald S, Excell L, Livingston B. ANZDATA 2008 Annual Report.
South Australia: Austalia and New Zealand Dialysis and Transplant
Registry, 2008.
2. Turnbull F. Effects of different blood-pressure-lowering regimens on
major cardiovascular events: Results of prospectively-designed
overviews of randomised trials. Lancet 2003; 362: 1527–35.
3. Heerspink HJL, Ninomiya T, Zoungas S et al. Effect of lowering
blood pressure on cardiovascular events and mortality in patients
on dialysis: A systematic review and meta-analysis of randomised
controlled trials. Lancet 2009; 373: 1009–15.
4. Jafar TH, Stark PC, Schmid CH et al. Progression of chronic kidney
disease: the role of blood pressure control, proteinuria, and
angiotensin-converting enzyme inhibition: A patient-level
meta-analysis. Ann. Intern. Med. 2003; 139: 244–52.
4. HEART FAILURE
Guideline recommendations
Chronic kidney disease and kidney transplant
recipients
a. We recommend that an ACEi or angiotensin receptor
antagonist be prescribed for patients with CKD (or kidney
transplant) and heart failure (1B).
b. We recommend that a beta-blocker be prescribed for
patients with CKD (or kidney transplant) and heart failure
(1B).
c. We suggest that patients with CKD or kidney transplant
recipients who meet the criteria for an implantable
cardioversion/defibrillation device should be considered for
such devices (2C).
Dialysis
d. We suggest that patients receiving dialysis who have heart
failure should be prescribed an ACEi or angiotensin receptor
antagonist (2D).
e. We suggest that patients receiving dialysis who have heart
failure should be prescribed a beta-blocking agent (2C).
f. We suggest that an angiotensin receptor antagonist could
be added to an ACEi and beta-blocker in patients who
continue to experience symptoms because of heart failure
(2C).
Ungraded suggestions for clinical care
Chronic kidney disease and kidney transplant
recipients
• For patients with CKD (or kidney transplant) symptomatic on the recommended agents, the following therapies
could be considered as a third agent (ungraded):
o Aldosterone antagonists have mortality benefit in
people without CKD, but this may be attenuated in CKD
and offset by greater toxicity
o Angiotensin receptor antagonist added to the ACEi
reduces hospitalization but not mortality in people
without CKD, but there are no data in CKD and potential
increased toxicity
o Polyunsaturated fatty acid (PUFA), vasodilators and
digoxin have all been studied in heart failure patients,
but there is insufficient data to recommend for or against
their use in heart failure patients with CKD receiving
ACEi and beta-blocker therapy
• Diuretic therapy should be prescribed as required to
control volume state with careful monitoring of kidney function and electrolytes (ungraded).
• Treatment of anaemia in people with CKD and heart
failure should follow the KHA-CARI Guideline ‘Biochemical
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H Pilmore et al.
and Haematological Targets: Haemoglobin’1 without modification because of the presence of heart failure (ungraded).
Dialysis
• Treatment of anaemia in people requiring dialysis who
have heart failure should follow the KHA-CARI Guideline
‘Biochemical and Haematological Targets: Haemoglobin’1
without modification because of the presence of heart failure
(ungraded).
Background
Chronic kidney disease and chronic heart failure (CHF) frequently coexist. The mechanisms for this,2 and a potential
classification of this ‘cardiorenal syndrome’,3 have been
reviewed in depth by others. Risk factors such as hypertension and diabetes are common to both CKD and CHF. Many
current treatment recommendations for the management of
CHF are based on the highest levels of evidence. However,
most guidelines make no recommendations specific to
patients with CKD. This guideline seeks to fill this gap.
Chronic kidney disease is defined as a glomerular filtration
rate (GFR) less than 60 mL/min, unless otherwise stated.
This is ‘moderate’ (Stage 3 or worse) CKD according to the
National Kidney Foundation Kidney Disease Outcomes
Quality Initiative (NKF KDOQI) Clinical Practice Guidelines
for Chronic Kidney Disease.4 However, not all studies providing evidence for this guideline meet the NKF KDOQI
criteria of having two measures of kidney function at least 3
months apart.
The following definition of CHF stated in the National
Heart Foundation (NHF) of Australia Guideline5,6 is used for
this Guideline:
A complex clinical syndrome with typical symptoms (eg,
dyspnoea, fatigue) that can occur at rest or on effort that is
characterised by objective evidence of an underlying
structural abnormality OR cardiac dysfunction that impairs
the ability of the ventricle to fill with or eject blood
(particularly during exercise).
This guideline does not consider ‘heart failure with
reduced ejection fraction’ and ‘heart failure with preserved
ejection fraction’ separately.
The prevalence of CHF or reduced systolic function is
increased in patients with CKD compared with people with
normal kidney function. In the Chronic Renal Insufficiency
Cohort, a history of CHF was reported by 15% of participants
with a GFR < 30 mL/min, compared with 5% in participants
with GFR > 60 mL/min.7 Likewise, the prevalence of CKD is
very high in CHF patients. In many trial cohorts, this prevalence is over one-third and patients with CHF who also have
CKD have a greater mortality risk than patients with CHF
and normal kidney function.8–11 In fact, reduced creatinine
clearance was a stronger predictor of adverse outcome than
reduced left ventricular ejection fraction (LVEF) in one
study.12
Heart failure is also a significant comorbidity in end-stage
kidney disease (ESKD). The prevalence of CHF has been
reported in between 31 and 40% of patients commencing
dialysis,13,14 and patients receiving dialysis who have
comorbid CHF have a greater mortality than patients with no
CHF.14,15 Heart failure may develop ‘de novo’ after receiving
a kidney transplant. Using United States Medicare Claims
data, the cumulative incidence of de novo CHF was 10.2%
after 12 months and 18.3% after 36 months compared with
12.0% and 32.3%, respectively for patients remaining on
dialysis on the transplant waiting list.16 The cumulative incidence of de novo CHF in patients who survived the first
post-transplant year without CHF has been reported to be
3.6% at 5 years and 12.1% at 10 years.17
The objectives of this guideline are to summarize the available evidence for the treatment of CHF in patients with
CKD defined by a GFR < 60 mL/min not requiring dialysis,
patients receiving dialysis and kidney transplant recipients.
The following treatments have been considered:
• Blockade of the renin-angiotensin system
• Blockade of beta-adrenergic receptors
• Aldosterone antagonists
• Digoxin
• Vasodilators (hydralazine and nitrates)
• Treatment of anaemia
• Strategies to control volume state
• Use of Implantable Devices
• Other therapies
The recommendations for patients with CKD and kidney
transplant are grouped together because these patients are
similar in terms of current actual kidney function, and there
are no trials that specifically enrolled kidney transplant
recipients with CHF to study a heart failure intervention. It is
acknowledged that kidney transplant recipients will differ in
many ways from CKD, including time receiving dialysis,
presence of arteriovenous fistula and immunosuppression.
Summary of the evidence
A number of RCTs have been performed in patients with
CHF that provide a strong evidence base underpinning
many guideline recommendations for the general population.6,18,19 The recommendations for patients with CKD are
based on post-hoc analyses of RCTs of therapies in patients
with heart failure. Although these are post-hoc analyses, a
large proportion of patients in these studies had an eGFR
< 60 mL/min per 1.73 m2 so the results of these trials can be
applied to CKD Stage 3. However, fewer patients in the
trials had an eGFR < 30 mL/min per 1.73 m2 so this should
be borne in mind when applying these guidelines to such
patients. There are no data specifically for kidney transplant
recipients but it is considered reasonable to apply the CKD
recommendations to this group, acknowledging this lack of
© 2013 Asian Pacific Society of Nephrology
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Cardiovascular disease guidelines
specific data. For dialysis patients, there are smaller trials of
lower quality but these data are generally consistent with
the CKD and general population data.
REFERENCES
1. McMahon LP, MacGinley R, Kha C. KHA-CARI guideline:
Biochemical and haematological targets: Haemoglobin
concentrations in patients using erythropoietin-stimulating agents.
Nephrology 2012; 17: 17–19.
2. Schrier RW. Role of diminished renal function in cardiovascular
mortality: Marker or pathogenetic factor? J. Am. Coll. Cardiol. 2006;
47: 1–8.
3. Ronco C, Haapio M, House AA et al. Cardiorenal syndrome. J. Am.
Coll. Cardiol. 2008; 52: 1527–39.
4. National Kidney Foundation K/DOQI Clinical Practice Guidelines
for Chronic Kidney Disease: Evaluation, Classification, and
Stratification. Part 4. Definition and classification of stages of
chronic kidney disease. Am. J. Kidney Dis. 2002; 39: S46–75.
5. National Heart Foundation of Australia and the Cardiac Society of
Australia and New Zealand (Chronic Heart Failure Guidelines
Expert Writing Panel). Guidelines for the prevention, detection
and management of chronic heart failure in Australia. Updated
October 2011. [Cited 21 Dec 2011.] http://www.heartfoundation
.org.au/SiteCollectionDocuments/Chronic_Heart_Failure_
Guidelines_2011.pdf
6. Krum H, Jelinek MV, Stewart S et al. Guidelines for the
prevention, detection and management of people with chronic
heart failure in Australia 2006. Med. J. Aust. 2006; 185: 549–57.
7. Lash JP, Go AS, Appel LJ et al. Chronic Renal Insufficiency Cohort
(CRIC) Study: Baseline characteristics and associations with kidney
function. Clin. J. Am. Soc. Nephrol. 2009; 4: 1302–11.
8. Shlipak MG, Smith GL, Rathore SS et al. Renal function, digoxin
therapy, and heart failure outcomes: Evidence from the digoxin
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*Explanation of grades
The evidence and recommendations in this KHA-CARI
guideline have been evaluated and graded following the
approach detailed by the GRADE working group (http://
www.gradeworkinggroup.org). A description of the grades
and levels assigned to recommendations is provided in
Tables 1 and 2.
**Access to the full text version
For a full text version of the guideline, readers need to go to
the KHA-CARI website (go to the Guidelines section (http://
www.cari.org.au)).
Table 1 Final grade for overall quality of evidence
Overall evidence grade
A
B
C
D
Description
High quality of evidence.
We are confident that the true effect lies close to that of the estimate of the effect.
Moderate quality of evidence.
The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality of evidence.
The true effect may be substantially different from the estimate of the effect.
Very low quality of evidence.
The estimate of effect is very uncertain, and often will be far from the truth.
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H Pilmore et al.
Table 2 Nomenclature and description for grading recommendations
Grade
Implications
Patients
Level 1 ‘We
recommend’
Level 2 ‘We
suggest’
Most people in your situation would want the
recommended course of action and only a
small proportion would not
The majority of people in your situation
would want the recommended course of
action, but many would not
Clinicians
Policy
Most patients should receive the
recommended course of action
The recommendation can be adopted as a
policy in most situations
Different choices will be appropriate for
different patients. Each patient needs help
to arrive at a management decision
consistent with her or his values and
preferences
The recommendation is likely to require
debate and involvement of stakeholders
before policy can be determined
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