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QJM Advance Access originally published online on October 13, 2006
QJM 2006 99(11):723-736; doi:10.1093/qjmed/hcl101
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© The Author 2006. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Review

The treatment of coronary artery disease in patients with chronic kidney disease

N.C. Edwards1, R.P. Steeds2, C.J. Ferro3 and J.N. Townend2

From the 1Department of Cardiovascular Medicine, University of Birmingham, 2Department of Cardiology, Queen Elizabeth Hospital and 3Department of Nephrology, Queen Elizabeth Hospital, Birmingham, UK

Address correspondence to Dr Nicola Edwards, Research Fellow in Cardiology, Department of Cardiovascular Medicine, University of Birmingham, Birmingham, B15 2TT, UK. email: N.C.Edwards{at}bham.ac.uk


   Summary
Top
 Summary
Introduction
 Pathology of coronary artery...
 Medical treatment
 Revascularization in CKD
 Conclusion
 References
 
Premature cardiovascular disease is the largest cause of mortality, and a major cause of morbidity, in patients with chronic kidney disease (CKD). Patients with end-stage kidney disease (ESKD) are at extreme risk, but cardiovascular event rates are increased even in early CKD. There is little controlled trial evidence on which to base treatment, as most therapeutic trials have excluded CKD patients. Current treatment strategies are therefore based upon small prospective studies or retrospective analyses of controlled trials and registry data. It is thus unclear whether CKD patients benefit from modern secondary preventive treatments in the same manner as patients with normal renal function. There is a need for randomized trials to identify effective drugs to prevent and treat coronary artery disease in CKD. Revascularization by CABG in CKD has been widely reported in registry data to provide better results than medical treatment or angioplasty. Recent angioplasty data in patients with CKD, however, show improving results, and the risks of CABG in CKD remain high. It is not clear which revascularization technique has a better outcome in patients ‘equally suitable’ on angiographic criteria for either procedure. The high rate of late adverse cardiovascular events after both CABG and angioplasty accentuates the need for effective secondary preventive therapy disease in these high-risk patients.


   Introduction
Top
 Summary
 Introduction
Pathology of coronary artery...
 Medical treatment
 Revascularization in CKD
 Conclusion
 References
 
The prognosis of patients with end-stage kidney disease (ESKD), also called chronic kidney disease (CKD) stage 5, remains poor, with a one-year mortality rate of approximately 20%.1 The biggest single contributor to this high mortality is cardiovascular disease, which accounts for over half of all deaths. Although patients on dialysis are at greatest risk, with age-specific cardiovascular mortality rates of 10–100 times greater than those of the general population, the increased risk also extends to those with milder forms of CKD.2–4 In a large US community study involving over one million people, an independent, graded relationship was observed between estimated glomerular filtration rate (eGFR) and rates of death, cardiovascular events and hospitalization.5 (Figure 1) A similar relationship between eGFR and cardiovascular events was also demonstrated in the VALIANT trial of survivors of acute myocardial infarction complicated by left ventricular dysfunction.6 Below 81 ml/min, each 10 unit reduction in eGFR was associated with a 10% increase in the relative risk of cardiovascular death and non-fatal events.


Figure 1
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  		Figure 1. Adjusted Hazard Ratio for Cardiovascular Events among 1 120 295 adults according to estimated glomerular filtration rate (eGFR). Adapted from Go et al.5 Data adjusted for demographics and co-morbidities. eGFR estimated from serum creatinine by abbreviated Modification of Diet in Renal Disease equation (MDRD). *This group serves as a reference group.

 
Not only is the risk of adverse cardiac events high in CKD, but outcomes after such events are poor. For dialysis patients, myocardial infarction is a catastrophic event. Even in the era of reperfusion therapy, Herzog found that one- and two-year mortality rates were 61% and 74% respectively.7 Chronic kidney disease is also an independent predictor of mortality in acute coronary syndromes (ACS) without ST segment elevation. An increase in mortality and in re-infarction was evident in an analysis of almost 40 000 patients recorded in the databases of four acute coronary syndrome trials.8 An incremental increase in creatinine clearance of 10 ml/min was independently associated with a reduction in the hazard ratio for death at 180 days of 0.79 for ST-elevation MI and 0.81 for non-ST-elevation MI.

In the UK, about 18 000 patients are on dialysis, but the number of patients with mild to moderate CKD is far greater. In the Framingham Heart Study, about 10% of middle-aged men and 30% of the elderly population had biochemical evidence of mild renal dysfunction, with a serum creatinine >136 µmol/l.9 These figures underestimate the prevalence of CKD, as detection of an elevated serum creatinine is a less sensitive method of detecting renal insufficiency than estimates of GFR using the Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formulae.10,11 Thus the economic and healthcare implications of cardiovascular disease associated with CKD are considerable. This review seeks to bring together the available evidence on prevention and treatment of coronary artery disease (CAD) in patients with CKD. Whenever possible, the evidence will be related to the severity of CKD using the 5-stage KDOQI classification (Figure 2).12


Figure 2
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  		Figure 2. The stages of chronic kidney disease (CKD) as defined by the National Kidney Foundation Kidney disease Outcomes Quality Initiative (K/DOQI) Adapted from K/DOQI guidelines of CKD.12 CKD is defined as either (1) kidney damage >=3 months with or without a decrease in eGFR, or (2) eGFR <60 ml/min/1.73 m2 for >=3 months, with or without kidney damage. Kidney damage is defined as damage confirmed by kidney biopsy or markers of kidney damage (proteinuria, abnormal urinary sedimentation, abnormalities on imaging studies).

 

   Pathology of coronary artery disease in CKD
Top
 Summary
 Introduction
 Pathology of coronary artery...
Medical treatment
 Revascularization in CKD
 Conclusion
 References
 
Patients with CKD have a higher than expected cardiovascular death rate even after adjustment for age, diabetes and other traditional cardiovascular risk factors.13–16 Several other ‘non-traditional’ risk factors associated with CKD have also been implicated. They include anaemia,17 abnormalities of calcium phosphate metabolism,18–20 lipid abnormalities other than LDL levels,21,22 altered homeostatic factors,21,23,24 inflammation,25,26 oxidative stress, reduced bioavailability of nitric oxide27–30 and autonomic dysfunction.31,32 It should also not be forgotten that in some patients, CKD may be the result rather than the cause of vascular disease. Ongoing prospective studies may provide a better understanding of this complex field.33,34

The vascular complications in CKD are attributable to two different but associated mechanisms, namely atherosclerosis and arteriosclerosis. Atherosclerosis is an intimal disease that (in the general population) is characterized by fibroatheromatous plaques and occlusive disease.35 In CKD, there are distinct morphological differences comprising increased plaque calcification and increased intimal and medial thickness.36,37 These differences promote chronic myocardial ischaemia (particularly in the small distal coronary arteries) and fibrosis, which may explain the high levels of sudden cardiac death and heart failure in CKD compared with a lower incidence of acute plaque rupture.38,39

The other characteristic feature in CKD is thickening and calcification of the medial arterial layer known as ‘arteriosclerosis’. Increased collagen content, hyperplasia and hypertrophy of the vascular smooth muscle cells results in wall hypertrophy and stiffening of large conduit arteries.40 This disturbs their dampening function (responsible for transforming pulsatile flow and pressure into a steady flow in peripheral tissues) and results in increased systolic and pulse pressures. The consequences of these alterations are: (i) an increased left ventricular afterload with development of left ventricular hypertrophy and increased myocardial oxygen demand; and (ii) altered coronary perfusion and sub-endocardial blood flow distribution. These changes have been described in patients with mild CKD and ESKD,41 and undoubtedly contribute to the high incidence of cardiac failure42 and fibrosis seen in patients with ESKD.43 This is often termed ‘uraemic cardiomyopathy’. The high prevalence of cardiac damage may explain why hypertension is not associated with an increased mortality in dialysis patients, in contrast with the general population.44

Increased arterial stiffness, as determined by pulse pressure or measurements of aortic pulse wave velocity (PWV), is a powerful predictor of cardiovascular mortality, both in the general population45–47 and in patients with ESKD.48,49 ACE inhibitor use is associated with a lower PWV in patients with CKD (creatinine <300 µmol/l), independent of blood pressure and other cardiovascular risk factors.50 In a randomized trial in ESKD patients, cardiovascular mortality was reduced by ACE inhibition only when blood pressure reduction was also associated with a reduction in aortic PWV.51 Studies looking at surrogate markers for cardiovascular mortality in CKD patients should arguably focus on markers of arterial stiffness, rather than relying on brachial blood pressure. This has already been advocated in hypertension studies,52,53 and has been reinforced by a recently published sub-study of ASCOT where, unlike brachial blood pressure, non-invasively measured central aortic pressures and arterial stiffness predicted a survival difference between treatment arms.53


   Medical treatment
Top
 Summary
 Introduction
 Pathology of coronary artery...
 Medical treatment
Revascularization in CKD
 Conclusion
 References
 
The landmark trials which have firmly established anti-platelet therapy, angiotensin-converting-enzyme (ACE) inhibitors, beta-blockers and lipid-lowering agents as effective treatments in the general population with atherosclerotic disease, have systematically excluded patients with moderate and severe CKD. Because the aetiology of premature cardiovascular disease in CKD is complex, and may be different to that in the general population, there is a need to evaluate these drugs in patients with CKD.54 They are underused compared to levels of prescription in the general population, probably due to concerns about limited efficacy and toxic effects when renal clearance is reduced (a concept termed ‘therapeutic nihilism’).55 Patients in the VALIANT trial with a GFR <45 ml/min were at highest risk of death and adverse cardiac events, but had the lowest use of aspirin, statins, beta-blockers and revascularization procedures.6 Similarly, in patients presenting with acute coronary syndromes, not only was the prognosis of patients with CKD stages II and III worse than their counterparts with preserved renal function, but their usage of aspirin, beta blockers, heparin and statins was much lower.56

Anti-platelet therapy
Rates of aspirin use are low in patients with CKD. Despite the poor prognosis of CKD patients after myocardial infarction, the rate of aspirin use was only 61% in dialysis patients and 74% in patients with a GFR of <35 ml/min, compared to 89% in patients with a normal GFR.57 In part this may be due to safety concerns. Uraemia is associated with prolonged bleeding times and impaired platelet function. Bleeding time is further prolonged by aspirin in CKD.58–60 These concerns were only in part assuaged by the results of the UK-HARP study of low-dose aspirin (100 mg modified release) in severe CKD (pre-dialysis, dialysis or functioning transplant) in which there was a three-fold increase (15% vs. 5%) in minor bleeds, but no excess of major bleeds.61 The available information on the efficacy of aspirin in CKD is limited but encouraging. In a study of over 1000 patients with ESKD and 145 000 controls following myocardial infarction, the benefit of aspirin treatment on 30-day mortality was similar to that in patients with normal renal function. The authors suggested that the routine use of aspirin after myocardial infarction in all CKD patients could save one life for every five patients treated.62 There are no controlled data however, on the efficacy of long-term use of aspirin in CKD patients with stable coronary artery disease.

More powerful anti-platelet therapy with parenteral platelet glycoprotein IIb/IIIa inhibitors (GP IIb/IIIa) is an effective treatment in ACS, but these agents continue to be underused in patients with CKD despite their poor cardiovascular outcomes.63,64 Concerns relating to safety and efficacy of GPIIb/IIIa inhibitors do not appear to be warranted, according to the results of two recent retrospective subgroup analyses examining use in patients with a creatinine clearance <60 ml/min.65,66 The ESPIRIT study demonstrated that eptifibatide given during PCI in nearly 300 patients with CKD reduced cardiovascular events and further revascularization procedures over the subsequent 12 months to the same degree as in the non-CKD population, without an excess of bleeding.66 Although the risk of major bleeding was doubled in a further study by Freeman et al., use of GP IIb/IIIa still reduced in-hospital mortality following ACS in 310 patients with CKD (eGFR <60 ml/min).65 The risk of bleeding with the GP IIb/IIIa inhibitor abciximab in patients with CKD has also been analysed retrospectively in over 4000 patients undergoing PCI at the Mayo clinic.63 Although bleeding was more common in CKD patients and increased with abciximab, the relative risk of bleeding with abciximab did not differ according to eGFR. The authors concluded that abciximab is safe for use in patients with CKD of any stage.

Lipid-lowering therapy
In contrast to the situation in patients with normal renal function, there remains substantial uncertainty regarding the beneficial effects of cholesterol reduction with statin therapy in ESKD patients. Lipid profiles in patients with CKD are atherogenic, with a predominance of triglycerides, reduced HDL, elevated oxidized LDL-C and apolipoproteins. Total cholesterol concentration however, tends to be low rather than elevated.67,68 The reasons why the efficacy of lowering cholesterol may be questioned in patients with CKD include: (i) There is no evidence relating cholesterol concentration to cardiovascular risk in CKD. (ii) Although the association between CAD risk and cholesterol concentration is ‘log-linear’ in the general population, the absolute reductions in cholesterol are smaller at lower levels of cholesterol typically found in CKD. Thus the proportional reduction in CAD risk is reduced. (iii) Although statins substantially reduce the risk of death from atheromatous coronary artery and cerebrovascular disease in the general population, the absolute risk of atheromatous arterial disease in CKD is not clear. A large proportion of the cardiovascular disease in CKD patients is non-atheromatous, with both arteriosclerosis and uraemic cardiomyopathy playing important roles.48,69 Although symptoms or signs of coronary artery disease are present in about 25% of dialysis patients, ischaemia can also occur in the absence of atheroma.70

A retrospective analysis of US haemodialysis patients suggested that statins can be used safely in dialysis patients, and were associated with a reduction in cardiovascular death of 36%.71 However, a recently-published prospective study of diabetic patients on dialysis was not supportive. The 4D (Die Deutsche Diabetes Dialyse Studie) randomized haemodialysis patients with diabetes to atorvastatin or placebo.72 Despite an early and sustained reduction in LDL level, there was no significant difference in the cardiovascular event rate or total mortality in the treatment group over a follow-up period of 5 years. The annual incidence of cardiac death (sudden death, myocardial infarction, heart failure) remained high at over 8% per year, representing the highest rate of cardiovascular events in a study cohort in all long-term prospective statin trials.

More information on the effects of statins in ESKD due to other causes should be provided by two ongoing large prospective RCTs. The Study of Heart and Renal Protection (SHARP), is a large multinational randomized controlled trial comparing simvastatin and ezetimibe with placebo in CKD (including dialysis) patients, while AURORA will examine the effect of rosuvastatin in ESKD.73,74

In milder forms of CKD, post hoc analysis of lipid lowering trials suggests that the effects of statins may be comparable with those observed in patients with normal renal function. Retrospective sub-group analysis from the CARE study showed that pravastatin reduced cardiovascular death and non-fatal MI in 1711 patients with mild CKD (creatinine clearance <75 ml/min, mean 61 ml/min) and a previous myocardial infarction who had a cholesterol <6.2 mmol/l. The hazard ratio of 0.72 was similar to that in patients without CKD. The reduction in plasma lipid levels was also similar to that of patients without CKD, with no excess rate of side-effects or discontinuation of treatment.75 Retrospective analysis of three larger pravastatin intervention trials also showed a similar relative risk reduction in patients with CKD (eGFR 30–59 ml/min) to that observed in the overall trial cohorts, including a reduction in total mortality. As the event rate in the CKD patients was about 25% greater than in those with normal kidney function, the absolute benefit was substantially greater. The benefits on cardiovascular end points in CKD occurred irrespective of the presence of overt coronary disease at baseline, and the authors speculated that statins might be effective as a primary preventive measure in CKD.76

Similarly, in the Lescol Intervention Prevention Study (LIPS), CKD patients (eGFR < 55.9 ml/min) undergoing percutaneous coronary intervention (PCI) gained near equal benefit from statin therapy to those seen in patients with normal renal function.77 Despite these retrospective analyses, there is still uncertainty as to the benefit of statin therapy for patients with CKD of any stage. Data from trials such as SHARP will be of great importance in deciding upon the appropriateness of the routine use of statins in CKD.

ACE inhibitors and angiotensin II receptor blockers
There is a large amount of experimental and clinical evidence that pharmacological blockade of the renin-angiotensin system slows progressive renal dysfunction.78 This effect persists even in severe CKD without an increase in major adverse events, including hyperkalaemia and acute renal failure.79 The renoprotective effect of both ACE inhibitors and angiotensin II receptor blockers (ARBs) seems to be due not only to their antihypertensive effect but also to a specific antiproteinuric effect.80–82 This is consistent with the view that proteins act as mediators of fibrosis once they have leaked through the glomerular barrier.83 Given that cardiovascular mortality appears to be directly associated with worsening renal function, it would seem logical that preserving renal function with either an ACE inhibitor or ARB would improve cardiovascular survival of CKD patients as a whole. This view, however, has been challenged by a recent meta-analysis of anti-hypertensive drug therapy in CKD.84

ACE inhibitors decrease cardiovascular mortality in a number of conditions including hypertension,85 type 2 diabetes,86 post-myocardial infarction,87–92 heart failure93,94 and in patients with (or at high risk of) coronary artery disease.95,96 In a post hoc analysis of the HOPE study, treatment with ramipril in 980 patients with CKD (serum creatinine 124 –199 µmol/l) resulted in a near-equal reduction in cardiovascular events to that observed with normal renal function.97 The impact of ACE inhibitor therapy on total mortality, heart failure related hospitalization and cardiovascular mortality was actually greater in patients with CKD than in those without (Figure 3). These beneficial effects were gained without any increased risk of acute renal failure or hyperkalaemia. Whether the decrease in cardiovascular events is independent of blood pressure reduction, remains the subject of debate.84


Figure 3
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  		Figure 3. Clinical outcomes in patients with CKD or normal renal function treated with ramipril (HOPE sub-study). Adapted from Mann et al.97 All patients had objective evidence of vascular disease or diabetes plus another cardiovascular risk factor. CKD was defined as serum creatinine 124–199 µmol/l. Primary outcome, incidence of cardiovascular death, myocardial infarction or stroke; CVD, cardiovascular death.

 
Data in dialysis patients are conflicting. Encouraging survival data were provided by a small non-randomized retrospective study of 126 dialysis patients. Patients treated with an ACE inhibitor had a 52% relative risk reduction for mortality over 5 years (p < 0.0019), with particular benefit in patients under 65 years of age.98 These data were contradicted by the prospective Fosinopril in Dialysis study (FOSIDIAL), comparing 20 mg fosinopril with placebo in 400 haemodialysis patients with documented left ventricular hypertrophy. Over the 2-year follow-up period, there were no differences in cardiovascular deaths or morbidity rates (heart failure hospitalization/non-fatal cardiovascular events).99,100 This study was however underpowered.

ARBs reduce mortality in heart failure101 and in patients with hypertensive left ventricular hypertrophy.102 Two studies have examined the effects of ARBs on patients with diabetic nephropathy.103,104 Both had a secondary composite outcome of cardiovascular morbidity and mortality, and both failed to demonstrate a beneficial effect. To our knowledge, there are no published data on cardiovascular outcomes with ARB treatment in non-diabetic and type I diabetic renal disease.

RAS blockade with both ACE inhibitors and ARB has additional renoprotective benefit when compared to monotherapy in non-diabetic renal disease81 and in incipient diabetic nephropathy,105 which is independent of blood pressure changes. Current evidence suggests that combination treatment is currently best reserved for patients with significant proteinura (>1 g/day) despite optimal blood pressure control on monotherapy with either an ACE inhibitor or ARB.106 Nevertheless, the effect on cardiovascular outcomes of combination treatment remains to be established as does the potential risk of increased hyperkalaemia.

Over recent years, experimental and clinical evidence has been accumulating to suggest that aldosterone may be an important mediator in the progression of renal dysfunction and cardiovascular disease in CKD.107,108 Small short-term studies appear to suggest that the addition of a mineralocorticoid receptor antagonist to conventional therapy with an ACE inhibitor or ARB, decreases proteinuria independently of blood pressure in diabetic and non-diabetic CKD.109,110 Intriguingly, spironolactone appears to lower blood pressure in oligo-anuric haemodialysis patients, suggesting non-renal actions of aldosterone.111 Mineralocorticoid receptors in the heart, vasculature and brain may be relevant. Concerns remain regarding the potential for hyperkalaemia in patients, and prospective randomized controlled trials are needed to establish the safety and efficacy of long-term treatment with mineralcorticoid receptor antagonists in CKD patients. The development of orally active renin inhibitors provides further exciting possibilities for the modulation of the renin-angiotensin system.112

Beta blockers
Beta blockers are used infrequently after ST- elevation myocardial infarction (STEMI) in CKD patients. In 1724 patients admitted to a single coronary care unit in the USA, their use was most frequent in patients with GFR >81.5 ml/min, at 81%, but fell to 52.9% in patients with GFR <46 ml/min, and to 47% in patients on dialysis.113 There was no increase in rates of pulmonary oedema or heart block. Across the range of GFR values, beta blockers and aspirin in combination reduced in-hospital mortality by 78% in patients on dialysis, 64.3% in those with a with GFR <46 ml/min, 69% in those with GFR 46–63 ml/min, and 75% in those with GFR 63–81.5 ml/min. However, the effects of the two drug classes were not examined separately.

In dialysis patients, beta blockers may be associated with a survival benefit after STEMI. Registry data demonstrated a 22% reduction in mortality in over 1000 patients with ESKD after myocardial infarction, a figure not dissimilar to that seen in the control population.62 Retrospective analysis of 2550 dialysis patients from the USRDS also showed a lower risk of new heart failure and cardiac death (adjusted hazard ratio 0.77, p = 0.02) with beta blockers.114 Although these studies have limitations, the benefits appear large, and provide some support for the use of beta blockers in patients with CKD.


   Revascularization in CKD
Top
 Summary
 Introduction
 Pathology of coronary artery...
 Medical treatment
 Revascularization in CKD
Conclusion
 References
 
Percutaneous coronary intervention in CKD
Many studies performed in the pre-stent era reported unfavourable outcomes with balloon angioplasty in CKD. High rates of procedural complications (up to 10%) and restenosis (up to 80%) meant that percutaneous coronary intervention (PCI) was thought to be ineffective in advanced renal disease. Factors thought to contribute to these high rates included small diffusely diseased vessels and extensive intimal and medial coronary calcification.115–119

The introduction of coronary artery stenting appears to have improved both early success rates and long-term outcomes. In an era when stent use was approximately 60% and glycoprotein IIb/IIIa inhibitors were only used in 24% of cases, data from the Mayo Clinic between 1994 and 1999 showed that angiographic success rates were the same in patients with CKD as in ‘mainstream’ patients, although in-hospital mortality and myocardial infarction rates remained elevated in approximate inverse proportion to GFR.120 The in-hospital mortality and myocardial infarction rates were 2.3% and 9%, respectively, in patients with GFR 30–49 ml/min, compared to 0.5% and 5.4% in those with GFR >70 ml/min. At one year, the requirement for target vessel revascularization (TVR) was the same in patients with CKD (including those on dialysis) compared to controls. Studies using higher rates of coronary stenting support these results.121,122 Le Feuvre et al. showed equivalent procedural success (90% vs. 93%), in-hospital mortality (1% vs. 0%), stent thrombosis (0% vs. 0%) and 1-year clinical restenosis rates in dialysis patients compared to those with normal renal function undergoing PCI and stenting. Yet despite the good primary success and low restenosis rates, 1-year mortality and non-fatal MI was increased in patients with CKD, again in approximate inverse proportion to GFR.122 Stent use increased further to 75% in the more recent Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial performed in the late 1990s.123 Analysis of this trial is of particular value in identifying the effect of renal function on outcome, as it was a large prospective randomized trial of over 11 000 patients undergoing mainly single-vessel stenting in which tranilast (the anti-restenotic agent under investigation) proved to be no different from placebo. Serum creatinine >159 µmol/l was an exclusion criterion, yet 1749 patients with eGFR <60 ml/min and 4054 with eGFR 60–89 ml/min were identified. Rates of major adverse cardiac events at 30 days were low (approximately 1.5%) and did not differ by eGFR. Event rates at 9 months were approximately 15%, but again, there was no excess in the groups with lower eGFR. Angiographic restenosis rates did not differ by GFR. Although crude mortality was elevated in the lowest GFR group, this difference was not significant after adjusting for co-morbidity and demographic factors (Figure 4). It appears that the results of PCI in CKD are now comparable to the general population and that subsequent mortality is increased, not as a result of procedural complications or restenosis, but because of the high burden of cardiovascular and other co-morbid disease.123 The impact of drug eluting stents on restenosis and requirement for repeat revascularization has been considerable in patients with intact renal function, but the efficacy of this technology in patients with CKD remains unproven.


Figure 4
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  		Figure 4. Adverse clinical outcomes 9 months after percutaneous coronary intervention (PCI) in patients with CKD and normal renal function (GFR > 90 ml/min). Adapted from Best et al.123 PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; TVR, target vessel revascularisation (defined as repeat PCI or CABG performed to the vessel originally treated); eGFR, estimated glomerular filtration rate. Calculated using the Cockcroft-Gault formula.

 
Surgical revascularization in CKD
There is a lack of prospective trial evidence for the efficacy of coronary bypass graft surgery (CABG) in CKD, but retrospective analysis of data from large US registries has suggested clinical benefit from CABG compared to PCI (see later). A Canadian study examined survival in 750 patients with CKD (creatinine >200 µmol/l, not dialysis-dependent), 652 ESKD patients on dialysis and over 40 000 controls who underwent coronary angiography in Alberta between 1995 and 2001.124 Importantly, this analysis compared patients treated by CABG, PCI and medical therapy. After adjustment for factors including co-morbidity, age, severity of coronary artery disease and left ventricular function, CABG was associated with better survival than medical therapy, in all categories of kidney function. In the reference group and the CKD group, CABG was associated with improved survival compared to PCI, but in the dialysis group, the risk of death was not significantly different between those allocated to PCI and CABG. Both PCI and CABG were associated with improved survival compared to medical therapy.

CABG is associated with high levels of procedural risk and post-operative complications in patients with CKD, and this must be weighed against the long-term benefits on symptoms and mortality.125–129 The increased operative risks of patients with even mild renal disease undergoing first-time CABG were demonstrated in a UK study of 1427 patients. Compared with control patients with creatinine <130 µmol/l, in-hospital mortality was increased three-fold to 7.6% in patients with creatinine 130–149 µmol/l and seven-fold to 18.5% with creatinine >150 µmol/l. A creatinine of >130 µmol/l was also strongly associated with a prolonged requirement for intensive care.127 More recently, in a review of >4000 patients with a baseline creatinine <200 µmol/l undergoing first-time CABG at a single institution, CKD remained an important predictor of in-hospital mortality and morbidity. Operative mortality was 7.1% in patients with patients with eGFR 30–59 ml/min, compared to 1% in patients with eGFR >90 ml/min. The adjusted odds ratio for in-hospital mortality for patients with eGFR <60 ml/min was 1.98 (Figure 5).129


Figure 5
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  		Figure 5. Post-operative complications after CABG in patients with CKD and patients with normal renal function. Adapted from Zakeri et al.129 CKD was defined as pre-operative serum creatinine 131–199 µmol/l. Normal renal function was defined as serum creatinine <=130 µmol/l. LOS, number of patients with a hospital stay >14 days.

 
Outcomes in dialysis-dependent ESKD following CABG are also adverse, although interestingly, the risks are approximately the same as for patients with CKD not requiring dialysis. A retrospective analysis of 15 500 patients undergoing first-time CABG between 1992–1997 in the USA, identified 279 dialysis patients. After adjustment for age and confounding co-morbidities, their in-hospital mortality was 9.6%, vs. 3.1% in reference patients. Post-operative morbidity was also increased with an adjusted stroke rate of 3.7% vs. 1.7% and mediastinitis rate of 3.1% vs. 1.2% in other patients.125

CABG compared to PCI in CKD
The comparative merits of bypass surgery and PCI in CKD are difficult to ascertain, due to the exclusion of patients with established CKD from prospective clinical studies. The evidence base guiding decisions on appropriate revascularization procedures in CKD is almost universally derived from retrospective analyses of large-scale registry data. These studies have consistently reported improved long-term survival and reduced rates of repeat revascularization procedures with CABG compared to PCI.130–132 Interpretation of these comparisons is however complicated by the process of patient selection for each treatment. Factors such as left ventricular function, extent of coronary artery disease and baseline co-morbidities are important indicators of prognosis, yet these are also determinants of the revascularization strategy selected. Many of these studies have used complex statistical modelling to adjust for differences in co-morbidities. Although this approach improves the value of the data, it may not be able to adjust fully for the large differences in the patient populations undergoing each form of revascularization. A clear answer would require a prospective comparison of CABG with PCI in patients with CKD, and at present there is no prospect of such a trial.

The ARTS trial compared CABG with PCI using bare-metal stenting in 1205 patients with multi-vessel CAD disease. CABG and non-drug-eluting stenting led to equivalent mortality and morbidity at 1 year, although the requirement for repeat procedures was significantly higher (21% vs. 4%) in the stent group. Patients with serum creatinine 69 > 15 µmol/l were excluded from the ARTS study, but in a retrospective sub-group analysis, 142 patients were identified with moderate CKD, as defined by eGFR <60 ml/min. There was no significant difference between CABG and PCI in mortality in this group at 5 years (14.5% with PCI vs. 12.3% with CABG) or in the combination of death, stroke and MI (30.4% with PCI vs. 23.3% with CABG). The requirement for repeat revascularization with CKD was more than three-fold greater in the PCI group (29% vs. 9.6%), but this was very similar to the rate in patients with eGFR >60 ml/min (29.7% with PCI vs. 8% with CABG) (Figure 6). However, this was a post hoc analysis: the patents with CKD in this trial were not a pre-specified sub-group and the trial was not powered to detect differences within this group. Despite this caveat and small numbers of patients, this information is of great value, as it was obtained from a randomized trial, thus minimizing the differences between PCI and CABG patients. In addition, all patients were considered to be ‘equally good’ candidates for either therapy, and although drug-eluting stents were not used, in other respects it was a trial of modern cardiological and cardiac surgical practice.


Figure 6
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  		Figure 6. Clinical outcomes among patients with CKD (eGFR <60 ml/min) randomly assigned to CABG or PCI for multi-vessel coronary artery disease at 5-year follow-up. Adapted from Aoki et al.133 MI, myocardial infarction. TRR, total repeated revascularization (defined as a need for further revascularization with either PCI or CABG).

 
Clearly, adverse cardiac events remain depressingly common after revascularization by either technique. Rates of MI, stroke and death in the ARTS patients with CKD were almost double those experienced in patients with normal renal function. In data from Duke University, even after revascularization, outcomes worsened as the severity of CKD increased: with each 10 ml/min decline in GFR below 85 ml/min, there was an increased mortality risk of 14%.131 Advances in secondary preventive strategies in patients with CKD and coronary artery disease following revascularization by either technique are urgently required.


   Conclusion
Top
 Summary
 Introduction
 Pathology of coronary artery...
 Medical treatment
 Revascularization in CKD
 Conclusion
References
 
In contrast to the abundance of information from controlled trials on the treatment of coronary artery disease in the general population, there are few high-quality trial data on which to base such treatment in patients with CKD. Thus decision-making is difficult in symptomatic patients, and becomes more difficult when asymptomatic cases are identified through the now common policy of using screening tests such as perfusion imaging in candidates for renal transplantation.

The limited evidence available would suggest that both medical and interventional strategies are probably effective in treating coronary artery disease in early stage CKD, but for patients with ESKD, treatments including statins may be ineffective in reducing mortality. For patients symptomatic despite medical therapy, decisions on revascularization using CABG or PCI should be made using standard criteria, as both techniques are effective. Patients with multi-vessel disease and impaired left ventricular function will gain symptomatic and probable prognostic benefit from CABG. For such patients, the likelihood of repeat revascularization being required is lower for CABG than for PCI, but an operative risk of up to 10% should be borne in mind. For patients with less extensive disease, PCI is an effective treatment for symptomatic angina, and there is the possibility that results may improve further with the use of drug-eluting stents.

For asymptomatic patients with severe coronary artery disease, the situation is less clear. Results from a study of 26 diabetic CKD patients undergoing assessment for renal transplantation, with ‘silent’ coronary artery disease are often quoted. Patients randomized to a revascularization strategy with either CABG or PCI had a lower risk of adverse coronary events throughout follow-up (24 months) than patients receiving medical treatment.134 It is difficult to relate this data to modern practice, as it predates the widespread use of modern secondary preventative measures; no patients were on statins and only two patients were on aspirin. The in-hospital mortality and morbidity rates for the revascularization group were remarkably low. While there are still no current trial data on which to base decisions in these patients, there is now at least an appreciation of the risks and benefits of both medical and revascularization strategies in CKD.

The need for randomized controlled trials is clear. The effectiveness of current secondary preventive drugs used in the general population requires confirmation in patients with CKD. Identification of patients with early-stage CKD is crucial, as prevention (rather than treatment) of both atheromatous and arteriosclerotic vascular diseases associated with CKD, is likely to be the most successful strategy.


   References
Top
 Summary
 Introduction
 Pathology of coronary artery...
 Medical treatment
 Revascularization in CKD
 Conclusion
 References
 
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