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bs_bs_banner 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. © 2013 Asian Pacific Society of Nephrology 3 H Pilmore et al. 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 © 2013 Asian Pacific Society of Nephrology 4 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 5 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 6 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 © 2013 Asian Pacific Society of Nephrology 7 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 8 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 intervention group trial. J. Am. Soc. Nephrol. 2004; 15: 2195–203. 9. Hillege HL, Nitsch D, Pfeffer MA et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006; 113: 671–8. 10. Cohen-Solal A, Kotecha D, van Veldhuisen DJ et al. Efficacy and safety of nebivolol in elderly heart failure patients with impaired renal function: Insights from the SENIORS trial. Eur. J. Heart. Fail. 2009; 11: 872–80. 11. 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. 12. Hillege HL, Girbes ARJ, de Kam PJ et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation 2000; 102: 203–10. 13. Levin A, Foley RN. Cardiovascular disease in chronic renal insufficiency. Am. J. Kidney Dis. 2000; 36: S24–30. 14. Harnett JD, Foley RN, Kent GM et al. Congestive heart failure in dialysis patients: Prevalence, incidence, prognosis and risk factors. Kidney Int. 1995; 47: 884–90. 15. Banerjee D, Ma JZ, Collins AJ et al. Long-term survival of incident hemodialysis patients who are hospitalized for congestive heart failure, pulmonary edema, or fluid overload. Clin. J. Am. Soc. Nephrol. 2007; 2: 1186–90. 16. Lentine KL, Schnitzler MA, Abbott KC et al. De novo congestive heart failure after kidney transplantation: A common condition with poor prognostic implications. Am. J. Kidney Dis. 2005; 46: 720–33. 17. Rigatto C, Parfrey P, Foley R et al. Congestive heart failure in renal transplant recipients: Risk factors, outcomes, and relationship with ischemic heart disease. J. Am. Soc. Nephrol. 2002; 13: 1084–90. 18. Hunt SA, Abraham WT, Chin MH et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009; 119: e391–479. 19. Krum. H, Jelinek MV, Stewart S et al. 2011 Update to National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand Guidelines for the prevention, detection and management of chronic heart failure in Australia, 2006. Med. J. Aust. 2011; 194: 405–9. *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. © 2013 Asian Pacific Society of Nephrology 9 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 © 2013 Asian Pacific Society of Nephrology 10