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Q J Med 2006; 99:723–736

doi:10.1093/qjmed/hcl101

Review

The treatment of coronary artery disease in


patients with chronic kidney disease

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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

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

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

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@bham.ac.uk
! 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
724 N.C. Edwards et al.

Adjusted hazard ratio for


3.5

cardiovascular events
3
2.5 3.4
2
2.8
1.5
1 2
1.4
0.5 1
0
>60* 45 – 49 30 – 44 15 – 29 <15
Estimated GFR (ml/min/1.73m2)

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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 >90


120
high in CKD, but outcomes after such events are
1
poor. For dialysis patients, myocardial infarction 100 60-89
is a catastrophic event. Even in the era of reperfusion
therapy, Herzog found that one- and two-year GFR (ml/min/1.73m2) 80
2
mortality rates were 61% and 74% respectively.7 30-59
60
Chronic kidney disease is also an independent
predictor of mortality in acute coronary syndromes 3 15-29
40
(ACS) without ST segment elevation. An increase in
4 <15
mortality and in re-infarction was evident in an 20

analysis of almost 40 000 patients recorded in the 5


0
databases of four acute coronary syndrome trials.8 Kidney Kidney Moderately Severely Kidney
damage with damage with decreased decreased failure
An incremental increase in creatinine clearance normal or mildly GFR GFR
of 10 ml/min was independently associated with increased decreased
GFR GFR
a reduction in the hazard ratio for death at 180 days
of 0.79 for ST-elevation MI and 0.81 for non-ST- 1 2 3 4 5

elevation MI. Stages of CKD


In the UK, about 18 000 patients are on dialysis,
Figure 2. The stages of chronic kidney disease (CKD) as
but the number of patients with mild to moderate defined by the National Kidney Foundation Kidney
CKD is far greater. In the Framingham Heart Study, disease Outcomes Quality Initiative (K/DOQI) Adapted
about 10% of middle-aged men and 30% of the from K/DOQI guidelines of CKD.12 CKD is defined as
elderly population had biochemical evidence of either (1) kidney damage 53 months with or without a
mild renal dysfunction, with a serum creatinine decrease in eGFR, or (2) eGFR <60 ml/min/1.73 m2 for 53
4136 mmol/l.9 These figures underestimate the months, with or without kidney damage. Kidney damage
prevalence of CKD, as detection of an elevated is defined as damage confirmed by kidney biopsy or
serum creatinine is a less sensitive method of markers of kidney damage (proteinuria, abnormal urinary
sedimentation, abnormalities on imaging studies).
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 cardio- Pathology of coronary artery
vascular disease associated with CKD are consider-
able. This review seeks to bring together the
disease in CKD
available evidence on prevention and treatment of Patients with CKD have a higher than expected
coronary artery disease (CAD) in patients with CKD. cardiovascular death rate even after adjustment for
Whenever possible, the evidence will be related to age, diabetes and other traditional cardiovascular risk
the severity of CKD using the 5-stage KDOQI factors.13–16 Several other ‘non-traditional’ risk factors
classification (Figure 2).12 associated with CKD have also been implicated.
CAD in patients with CKD 725

They include anaemia,17 abnormalities of calcium cardiovascular mortality was reduced by ACE inhibi-
phosphate metabolism,18–20 lipid abnormalities other tion only when blood pressure reduction was also
than LDL levels,21,22 altered homeostatic fac- associated with a reduction in aortic PWV.51 Studies
tors,21,23,24 inflammation,25,26 oxidative stress, looking at surrogate markers for cardiovascular
reduced bioavailability of nitric oxide27–30 and mortality in CKD patients should arguably focus on
autonomic dysfunction.31,32 It should also not be markers of arterial stiffness, rather than relying
forgotten that in some patients, CKD may be the result on brachial blood pressure. This has already been
rather than the cause of vascular disease. Ongoing advocated in hypertension studies,52,53 and has been
prospective studies may provide a better understand- reinforced by a recently published sub-study of
ing of this complex field.33,34 ASCOT where, unlike brachial blood pressure,
The vascular complications in CKD are attributable non-invasively measured central aortic pressures

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to two different but associated mechanisms, namely and arterial stiffness predicted a survival difference
atherosclerosis and arteriosclerosis. Atherosclerosis is between treatment arms.53
an intimal disease that (in the general population) is
characterized by fibroatheromatous plaques and
occlusive disease.35 In CKD, there are distinct Medical treatment
morphological differences comprising increased
The landmark trials which have firmly established
plaque calcification and increased intimal and
anti-platelet therapy, angiotensin-converting-enzyme
medial thickness.36,37 These differences promote
(ACE) inhibitors, beta-blockers and lipid-lowering
chronic myocardial ischaemia (particularly in the
agents as effective treatments in the general popula-
small distal coronary arteries) and fibrosis, which may
tion with atherosclerotic disease, have systematically
explain the high levels of sudden cardiac death and
excluded patients with moderate and severe CKD.
heart failure in CKD compared with a lower incidence
Because the aetiology of premature cardiovascular
of acute plaque rupture.38,39
disease in CKD is complex, and may be different to
The other characteristic feature in CKD is
that in the general population, there is a need to
thickening and calcification of the medial arterial
evaluate these drugs in patients with CKD.54 They are
layer known as ‘arteriosclerosis’. Increased
underused compared to levels of prescription in the
collagen content, hyperplasia and hypertrophy of
general population, probably due to concerns about
the vascular smooth muscle cells results in
limited efficacy and toxic effects when renal clearance
wall hypertrophy and stiffening of large conduit
is reduced (a concept termed ‘therapeutic nihilism’).55
arteries.40 This disturbs their dampening function
Patients in the VALIANT trial with a GFR <45 ml/min
(responsible for transforming pulsatile flow and
were at highest risk of death and adverse cardiac
pressure into a steady flow in peripheral tissues) and
events, but had the lowest use of aspirin, statins, beta-
results in increased systolic and pulse pressures. The
blockers and revascularization procedures.6 Similarly,
consequences of these alterations are: (i) an increased
in patients presenting with acute coronary syndromes,
left ventricular afterload with development of left
not only was the prognosis of patients with CKD stages
ventricular hypertrophy and increased myocardial
II and III worse than their counterparts with preserved
oxygen demand; and (ii) altered coronary perfusion
renal function, but their usage of aspirin, beta
and sub-endocardial blood flow distribution. These
blockers, heparin and statins was much lower.56
changes have been described in patients with mild
CKD and ESKD,41 and undoubtedly contribute to the
Anti-platelet therapy
high incidence of cardiac failure42 and fibrosis seen in
patients with ESKD.43 This is often termed ‘uraemic Rates of aspirin use are low in patients with CKD.
cardiomyopathy’. The high prevalence of cardiac Despite the poor prognosis of CKD patients after
damage may explain why hypertension is not myocardial infarction, the rate of aspirin use was
associated with an increased mortality in dialysis only 61% in dialysis patients and 74% in patients
patients, in contrast with the general population.44 with a GFR of <35 ml/min, compared to 89% in
Increased arterial stiffness, as determined by patients with a normal GFR.57 In part this may be
pulse pressure or measurements of aortic pulse due to safety concerns. Uraemia is associated
wave velocity (PWV), is a powerful predictor of with prolonged bleeding times and impaired platelet
cardiovascular mortality, both in the general function. Bleeding time is further prolonged by
population45–47 and in patients with ESKD.48,49 ACE aspirin in CKD.58–60 These concerns were only in
inhibitor use is associated with a lower PWV in part assuaged by the results of the UK-HARP study
patients with CKD (creatinine <300 mmol/l), indepen- of low-dose aspirin (100 mg modified release) in
dent of blood pressure and other cardiovascular risk severe CKD (pre-dialysis, dialysis or functioning
factors.50 In a randomized trial in ESKD patients, transplant) in which there was a three-fold increase
726 N.C. Edwards et al.

(15% vs. 5%) in minor bleeds, but no excess in patients with CKD include: (i) There is no
of major bleeds.61 The available information on evidence relating cholesterol concentration to
the efficacy of aspirin in CKD is limited but cardiovascular risk in CKD. (ii) Although the
encouraging. In a study of over 1000 patients with association between CAD risk and cholesterol
ESKD and 145 000 controls following myocardial concentration is ‘log-linear’ in the general popula-
infarction, the benefit of aspirin treatment on 30-day tion, the absolute reductions in cholesterol are
mortality was similar to that in patients with normal smaller at lower levels of cholesterol typically
renal function. The authors suggested that the found in CKD. Thus the proportional reduction in
routine use of aspirin after myocardial infarction in CAD risk is reduced. (iii) Although statins
all CKD patients could save one life for every five substantially reduce the risk of death from
patients treated.62 There are no controlled data atheromatous coronary artery and cerebrovascular

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however, on the efficacy of long-term use of aspirin disease in the general population, the absolute
in CKD patients with stable coronary artery disease. risk of atheromatous arterial disease in CKD is not
More powerful anti-platelet therapy with clear. A large proportion of the cardiovascular
parenteral platelet glycoprotein IIb/IIIa inhibitors disease in CKD patients is non-atheromatous, with
(GP IIb/IIIa) is an effective treatment in ACS, but both arteriosclerosis and uraemic cardiomyopathy
these agents continue to be underused in patients playing important roles.48,69 Although symptoms or
with CKD despite their poor cardiovascular signs of coronary artery disease are present in
outcomes.63,64 Concerns relating to safety and about 25% of dialysis patients, ischaemia can also
efficacy of GPIIb/IIIa inhibitors do not appear to occur in the absence of atheroma.70
be warranted, according to the results of two recent A retrospective analysis of US haemodialysis
retrospective subgroup analyses examining use patients suggested that statins can be used safely
in patients with a creatinine clearance in dialysis patients, and were associated with a
<60 ml/min.65,66 The ESPIRIT study demonstrated reduction in cardiovascular death of 36%.71
that eptifibatide given during PCI in nearly 300 However, a recently-published prospective study
patients with CKD reduced cardiovascular events of diabetic patients on dialysis was not supportive.
and further revascularization procedures over the The 4D (Die Deutsche Diabetes Dialyse Studie)
subsequent 12 months to the same degree as in randomized haemodialysis patients with diabetes
the non-CKD population, without an excess of to atorvastatin or placebo.72 Despite an early and
bleeding.66 Although the risk of major bleeding sustained reduction in LDL level, there was no
was doubled in a further study by Freeman et al., significant difference in the cardiovascular event
use of GP IIb/IIIa still reduced in-hospital mortality rate or total mortality in the treatment group over a
following ACS in 310 patients with CKD (eGFR follow-up period of 5 years. The annual incidence
<60 ml/min).65 The risk of bleeding with the GP of cardiac death (sudden death, myocardial
IIb/IIIa inhibitor abciximab in patients with CKD has infarction, heart failure) remained high at over 8%
also been analysed retrospectively in over 4000 per year, representing the highest rate of cardio-
patients undergoing PCI at the Mayo clinic.63 vascular events in a study cohort in all long-term
Although bleeding was more common in CKD prospective statin trials.
patients and increased with abciximab, the relative More information on the effects of statins in ESKD
risk of bleeding with abciximab did not differ due to other causes should be provided by
according to eGFR. The authors concluded that two ongoing large prospective RCTs. The Study of
abciximab is safe for use in patients with CKD of Heart and Renal Protection (SHARP), is a large
any stage. multinational randomized controlled trial compar-
ing simvastatin and ezetimibe with placebo in CKD
(including dialysis) patients, while AURORA will
Lipid-lowering therapy
examine the effect of rosuvastatin in ESKD.73,74
In contrast to the situation in patients with normal In milder forms of CKD, post hoc analysis of lipid
renal function, there remains substantial uncertainty lowering trials suggests that the effects of statins
regarding the beneficial effects of cholesterol may be comparable with those observed in patients
reduction with statin therapy in ESKD patients. with normal renal function. Retrospective sub-
Lipid profiles in patients with CKD are atherogenic, group analysis from the CARE study showed that
with a predominance of triglycerides, reduced HDL, pravastatin reduced cardiovascular death and
elevated oxidized LDL-C and apolipoproteins. Total non-fatal MI in 1711 patients with mild CKD
cholesterol concentration however, tends to be (creatinine clearance <75 ml/min, mean 61 ml/min)
low rather than elevated.67,68 The reasons why the and a previous myocardial infarction who had a
efficacy of lowering cholesterol may be questioned cholesterol <6.2 mmol/l. The hazard ratio of 0.72
CAD in patients with CKD 727

was similar to that in patients without CKD. The dysfunction.78 This effect persists even in severe
reduction in plasma lipid levels was also similar CKD without an increase in major adverse events,
to that of patients without CKD, with no excess rate including hyperkalaemia and acute renal failure.79
of side-effects or discontinuation of treatment.75 The renoprotective effect of both ACE inhibitors
Retrospective analysis of three larger pravastatin and angiotensin II receptor blockers (ARBs) seems to
intervention trials also showed a similar relative be due not only to their antihypertensive effect
risk reduction in patients with CKD (eGFR but also to a specific antiproteinuric effect.80–82 This
30–59 ml/min) to that observed in the overall trial is consistent with the view that proteins act
cohorts, including a reduction in total mortality. as mediators of fibrosis once they have leaked
As the event rate in the CKD patients was about through the glomerular barrier.83 Given that cardi-
25% greater than in those with normal kidney ovascular mortality appears to be directly associated

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function, the absolute benefit was substantially with worsening renal function, it would seem logical
greater. The benefits on cardiovascular end points that preserving renal function with either an ACE
in CKD occurred irrespective of the presence of inhibitor or ARB would improve cardiovascular
overt coronary disease at baseline, and the authors survival of CKD patients as a whole. This view,
speculated that statins might be effective as a however, has been challenged by a recent meta-
primary preventive measure in CKD.76 analysis of anti-hypertensive drug therapy in CKD.84
Similarly, in the Lescol Intervention Prevention ACE inhibitors decrease cardiovascular mortality
Study (LIPS), CKD patients (eGFR < 55.9 ml/min) in a number of conditions including hypertension,85
undergoing percutaneous coronary intervention type 2 diabetes,86 post-myocardial infarction,87–92
(PCI) gained near equal benefit from statin heart failure93,94 and in patients with (or at high
therapy to those seen in patients with normal risk of) coronary artery disease.95,96 In a post hoc
renal function.77 Despite these retrospective ana-
analysis of the HOPE study, treatment with ramipril
lyses, there is still uncertainty as to the benefit of
in 980 patients with CKD (serum creatinine
statin therapy for patients with CKD of any stage.
124 –199 mmol/l) resulted in a near-equal reduction
Data from trials such as SHARP will be of great
in cardiovascular events to that observed with
importance in deciding upon the appropriateness of
normal renal function.97 The impact of ACE
the routine use of statins in CKD.
inhibitor therapy on total mortality, heart failure
related hospitalization and cardiovascular mortality
ACE inhibitors and angiotensin II
was actually greater in patients with CKD than in
receptor blockers those without (Figure 3). These beneficial effects
There is a large amount of experimental and clinical were gained without any increased risk of acute
evidence that pharmacological blockade of the renal failure or hyperkalaemia. Whether the
renin-angiotensin system slows progressive renal decrease in cardiovascular events is independent

30
Incidence of outcome in patients

25
with and without CKD (%)

20
CKD + Placebo

15 CKD + ACE
Inhibitor
10 Normal renal
function + Placebo
Normal renal function + ACE
5 Inhibitor

0
Primary CVD All death
outcome
Outcomes in patients with and without CKD

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 mmol/l. Primary outcome, incidence of cardiovascular death, myocardial
infarction or stroke; CVD, cardiovascular death.
728 N.C. Edwards et al.

of blood pressure reduction, remains the subject of regarding the potential for hyperkalaemia in
debate.84 patients, and prospective randomized controlled
Data in dialysis patients are conflicting. trials are needed to establish the safety and efficacy
Encouraging survival data were provided by a of long-term treatment with mineralcorticoid recep-
small non-randomized retrospective study of 126 tor antagonists in CKD patients. The development of
dialysis patients. Patients treated with an ACE orally active renin inhibitors provides further excit-
inhibitor had a 52% relative risk reduction for ing possibilities for the modulation of the renin-
mortality over 5 years (p < 0.0019), with particular angiotensin system.112
benefit in patients under 65 years of age.98 These
data were contradicted by the prospective Fosinopril Beta blockers
in Dialysis study (FOSIDIAL), comparing 20 mg
Beta blockers are used infrequently after ST-

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fosinopril with placebo in 400 haemodialysis
elevation myocardial infarction (STEMI) in CKD
patients with documented left ventricular hypertro-
patients. In 1724 patients admitted to a single
phy. Over the 2-year follow-up period, there were
coronary care unit in the USA, their use was most
no differences in cardiovascular deaths or morbidity
frequent in patients with GFR481.5 ml/min, at 81%,
rates (heart failure hospitalization/non-fatal cardio-
but fell to 52.9% in patients with GFR <46 ml/min,
vascular events).99,100 This study was however
and to 47% in patients on dialysis.113 There was no
underpowered.
increase in rates of pulmonary oedema or heart
ARBs reduce mortality in heart failure101 and in
block. Across the range of GFR values, beta blockers
patients with hypertensive left ventricular hypertro-
and aspirin in combination reduced in-hospital
phy.102 Two studies have examined the effects of
mortality by 78% in patients on dialysis, 64.3% in
ARBs on patients with diabetic nephropathy.103,104
those with a with GFR <46 ml/min, 69% in
Both had a secondary composite outcome of
those with GFR 46–63 ml/min, and 75% in those
cardiovascular morbidity and mortality, and both
with GFR 63–81.5 ml/min. However, the effects
failed to demonstrate a beneficial effect. To our
of the two drug classes were not examined
knowledge, there are no published data on cardio-
separately.
vascular outcomes with ARB treatment in non-
In dialysis patients, beta blockers may be associ-
diabetic and type I diabetic renal disease.
ated with a survival benefit after STEMI. Registry
RAS blockade with both ACE inhibitors and
data demonstrated a 22% reduction in mortality in
ARB has additional renoprotective benefit when
over 1000 patients with ESKD after myocardial
compared to monotherapy in non-diabetic renal
infarction, a figure not dissimilar to that seen in the
disease81 and in incipient diabetic nephropathy,105
control population.62 Retrospective analysis of 2550
which is independent of blood pressure changes.
dialysis patients from the USRDS also showed a
Current evidence suggests that combination treat-
lower risk of new heart failure and cardiac death
ment is currently best reserved for patients with
(adjusted hazard ratio 0.77, p ¼ 0.02) with beta
significant proteinura (41 g/day) despite optimal
blood pressure control on monotherapy with either blockers.114 Although these studies have
an ACE inhibitor or ARB.106 Nevertheless, the effect limitations, the benefits appear large, and provide
on cardiovascular outcomes of combination treat- some support for the use of beta blockers in patients
ment remains to be established as does the potential with CKD.
risk of increased hyperkalaemia.
Over recent years, experimental and clinical
evidence has been accumulating to suggest that Revascularization in CKD
aldosterone may be an important mediator in the Percutaneous coronary intervention
progression of renal dysfunction and cardiovascular
in CKD
disease in CKD.107,108 Small short-term studies
appear to suggest that the addition of a mineralo- Many studies performed in the pre-stent era reported
corticoid receptor antagonist to conventional unfavourable outcomes with balloon angioplasty
therapy with an ACE inhibitor or ARB, decreases in CKD. High rates of procedural complications
proteinuria independently of blood pressure in (up to 10%) and restenosis (up to 80%) meant
diabetic and non-diabetic CKD.109,110 Intriguingly, that percutaneous coronary intervention (PCI)
spironolactone appears to lower blood pressure in was thought to be ineffective in advanced renal
oligo-anuric haemodialysis patients, suggesting disease. Factors thought to contribute to these
non-renal actions of aldosterone.111 high rates included small diffusely diseased
Mineralocorticoid receptors in the heart, vasculature vessels and extensive intimal and medial coronary
and brain may be relevant. Concerns remain calcification.115–119
CAD in patients with CKD 729

The introduction of coronary artery stenting 18

adverse clincal outcomes (%)


Incidence of subsequent
appears to have improved both early success rates 16
14
and long-term outcomes. In an era when stent use
12
was approximately 60% and glycoprotein IIb/IIIa 10
inhibitors were only used in 24% of cases, data from 8
the Mayo Clinic between 1994 and 1999 showed 6
that angiographic success rates were the same 4
in patients with CKD as in ‘mainstream’ patients, 2
0
although in-hospital mortality and myocardial PCI CABG TVR Death
infarction rates remained elevated in approximate <60 60–89 >90
eGFR (ml/min)
inverse proportion to GFR.120 The in-hospital

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mortality and myocardial infarction rates were Figure 4. Adverse clinical outcomes 9 months after
2.3% and 9%, respectively, in patients with GFR percutaneous coronary intervention (PCI) in patients
30–49 ml/min, compared to 0.5% and 5.4% in those with CKD and normal renal function (GFR >90 ml/min).
with GFR 470 ml/min. At one year, the requirement Adapted from Best et al.123 PCI, percutaneous coronary
for target vessel revascularization (TVR) was the intervention; CABG, coronary artery bypass grafting; TVR,
same in patients with CKD (including those on target vessel revascularisation (defined as repeat PCI or
CABG performed to the vessel originally treated); eGFR,
dialysis) compared to controls. Studies using
estimated glomerular filtration rate. Calculated using the
higher rates of coronary stenting support these
Cockcroft-Gault formula.
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 eluting stents on restenosis and requirement for
patients compared to those with normal renal repeat revascularization has been considerable in
function undergoing PCI and stenting. Yet despite patients with intact renal function, but the efficacy
the good primary success and low restenosis rates, of this technology in patients with CKD remains
1-year mortality and non-fatal MI was increased in unproven.
patients with CKD, again in approximate inverse
proportion to GFR.122 Stent use increased further to Surgical revascularization in CKD
75% in the more recent Prevention of REStenosis
with Tranilast and its Outcomes (PRESTO) trial There is a lack of prospective trial evidence for the
performed in the late 1990s.123 Analysis of this efficacy of coronary bypass graft surgery (CABG) in
trial is of particular value in identifying the effect of CKD, but retrospective analysis of data from large
renal function on outcome, as it was a large US registries has suggested clinical benefit from
prospective randomized trial of over 11 000 patients CABG compared to PCI (see later). A Canadian
undergoing mainly single-vessel stenting in study examined survival in 750 patients with CKD
which tranilast (the anti-restenotic agent under (creatinine 4200 mmol/l, not dialysis-dependent),
investigation) proved to be no different from 652 ESKD patients on dialysis and over 40 000
placebo. Serum creatinine 4159 mmol/l was an controls who underwent coronary angiography in
exclusion criterion, yet 1749 patients with eGFR Alberta between 1995 and 2001.124 Importantly,
<60 ml/min and 4054 with eGFR 60–89 ml/min this analysis compared patients treated by CABG,
were identified. Rates of major adverse cardiac PCI and medical therapy. After adjustment for
events at 30 days were low (approximately 1.5%) factors including co-morbidity, age, severity of
and did not differ by eGFR. Event rates at 9 months coronary artery disease and left ventricular function,
were approximately 15%, but again, there was no CABG was associated with better survival than
excess in the groups with lower eGFR. Angiographic medical therapy, in all categories of kidney function.
restenosis rates did not differ by GFR. Although In the reference group and the CKD group, CABG
crude mortality was elevated in the lowest GFR was associated with improved survival compared to
group, this difference was not significant after PCI, but in the dialysis group, the risk of death was
adjusting for co-morbidity and demographic factors not significantly different between those allocated
(Figure 4). It appears that the results of PCI in CKD to PCI and CABG. Both PCI and CABG were
are now comparable to the general population associated with improved survival compared to
and that subsequent mortality is increased, not as medical therapy.
a result of procedural complications or restenosis, CABG is associated with high levels of procedural
but because of the high burden of cardiovascular risk and post-operative complications in patients
and other co-morbid disease.123 The impact of drug with CKD, and this must be weighed against
730 N.C. Edwards et al.

20
18
16 Normal renal
14 function (n = 3945)

Events (%)
12
10 CKD
8 (n = 458)
6
4
2
0
Post-op Stroke Dialysis LOS
death

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Complications

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 mmol/l. Normal renal function was defined
as serum creatinine 4130 mmol/l. LOS, number of patients with a hospital stay 414 days.

the long-term benefits on symptoms and clinical studies. The evidence base guiding
mortality.125–129 The increased operative risks of decisions on appropriate revascularization proce-
patients with even mild renal disease undergoing dures in CKD is almost universally derived from
first-time CABG were demonstrated in a UK study retrospective analyses of large-scale registry data.
of 1427 patients. Compared with control patients These studies have consistently reported improved
with creatinine <130 mmol/l, in-hospital mortality long-term survival and reduced rates of repeat
was increased three-fold to 7.6% in patients with revascularization procedures with CABG compared
creatinine 130–149 mmol/l and seven-fold to 18.5% to PCI.130–132 Interpretation of these comparisons
with creatinine 4150 mmol/l. A creatinine of is however complicated by the process of patient
4130 mmol/l was also strongly associated with a selection for each treatment. Factors such as left
prolonged requirement for intensive care.127 More ventricular function, extent of coronary artery
recently, in a review of 44000 patients with a disease and baseline co-morbidities are important
baseline creatinine <200 mmol/l undergoing first- indicators of prognosis, yet these are also determi-
time CABG at a single institution, CKD remained an nants of the revascularization strategy selected.
important predictor of in-hospital mortality and Many of these studies have used complex statistical
morbidity. Operative mortality was 7.1% in patients modelling to adjust for differences in co-morbidities.
with patients with eGFR 30–59 ml/min, compared to Although this approach improves the value of
1% in patients with eGFR 490 ml/min. The adjusted the data, it may not be able to adjust fully for the
odds ratio for in-hospital mortality for patients with large differences in the patient populations under-
eGFR <60 ml/min was 1.98 (Figure 5).129 going each form of revascularization. A clear answer
Outcomes in dialysis-dependent ESKD following would require a prospective comparison of CABG
CABG are also adverse, although interestingly, the with PCI in patients with CKD, and at present there
risks are approximately the same as for patients is no prospect of such a trial.
with CKD not requiring dialysis. A retrospective The ARTS trial compared CABG with PCI using
analysis of 15 500 patients undergoing first-time bare-metal stenting in 1205 patients with multi-
CABG between 1992–1997 in the USA, identified vessel CAD disease. CABG and non-drug-eluting
279 dialysis patients. After adjustment for age stenting led to equivalent mortality and morbidity
and confounding co-morbidities, their in-hospital at 1 year, although the requirement for repeat
mortality was 9.6%, vs. 3.1% in reference patients. procedures was significantly higher (21% vs. 4%)
Post-operative morbidity was also increased with in the stent group. Patients with serum creatinine
an adjusted stroke rate of 3.7% vs. 1.7% and 69415 mmol/l were excluded from the ARTS study,
mediastinitis rate of 3.1% vs. 1.2% in other but in a retrospective sub-group analysis, 142
patients.125 patients were identified with moderate CKD, as
defined by eGFR <60 ml/min. There was no
significant difference between CABG and PCI in
CABG compared to PCI in CKD
mortality in this group at 5 years (14.5% with PCI vs.
The comparative merits of bypass surgery and PCI in 12.3% with CABG) or in the combination of
CKD are difficult to ascertain, due to the exclusion death, stroke and MI (30.4% with PCI vs. 23.3%
of patients with established CKD from prospective with CABG). The requirement for repeat
CAD in patients with CKD 731

30

25

20

Outcome (%)
15
CABG (n=73)
10 PCI (n=69)

0
Death Stroke MI TRR

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Clinical outcomes

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).

revascularization with CKD was more than three- difficult in symptomatic patients, and becomes
fold greater in the PCI group (29% vs. 9.6%), but this more difficult when asymptomatic cases are identi-
was very similar to the rate in patients with eGFR fied through the now common policy of using
460 ml/min (29.7% with PCI vs. 8% with CABG) screening tests such as perfusion imaging in
(Figure 6). However, this was a post hoc analysis: candidates for renal transplantation.
the patents with CKD in this trial were not a pre- The limited evidence available would suggest
specified sub-group and the trial was not powered to that both medical and interventional strategies are
detect differences within this group. Despite this probably effective in treating coronary artery disease
caveat and small numbers of patients, this informa- in early stage CKD, but for patients with ESKD,
tion is of great value, as it was obtained from a treatments including statins may be ineffective in
randomized trial, thus minimizing the differences reducing mortality. For patients symptomatic despite
between PCI and CABG patients. In addition, all medical therapy, decisions on revascularization
patients were considered to be ‘equally good’ using CABG or PCI should be made using standard
candidates for either therapy, and although drug- criteria, as both techniques are effective. Patients
eluting stents were not used, in other respects it was with multi-vessel disease and impaired left ventri-
a trial of modern cardiological and cardiac surgical cular function will gain symptomatic and probable
practice. prognostic benefit from CABG. For such patients,
Clearly, adverse cardiac events remain depress- the likelihood of repeat revascularization
ingly common after revascularization by either being required is lower for CABG than for PCI,
technique. Rates of MI, stroke and death in the but an operative risk of up to 10% should be
ARTS patients with CKD were almost double those borne in mind. For patients with less extensive
experienced in patients with normal renal function. disease, PCI is an effective treatment for sympto-
In data from Duke University, even after revascular- matic angina, and there is the possibility that results
ization, outcomes worsened as the severity of may improve further with the use of drug-eluting
CKD increased: with each 10 ml/min decline in stents.
GFR below 85 ml/min, there was an increased For asymptomatic patients with severe coronary
mortality risk of 14%.131 Advances in secondary artery disease, the situation is less clear. Results
preventive strategies in patients with CKD and from a study of 26 diabetic CKD patients undergoing
coronary artery disease following revascularization assessment for renal transplantation, with ‘silent’
by either technique are urgently required. 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)
Conclusion than patients receiving medical treatment.134 It is
In contrast to the abundance of information from difficult to relate this data to modern practice, as it
controlled trials on the treatment of coronary artery predates the widespread use of modern secondary
disease in the general population, there are few high- preventative measures; no patients were on
quality trial data on which to base such treatment statins and only two patients were on aspirin. The
in patients with CKD. Thus decision-making is in-hospital mortality and morbidity rates for the
732 N.C. Edwards et al.

revascularization group were remarkably low. from serum creatinine: a new prediction equation.
While there are still no current trial data on Modification of Diet in Renal Disease Study Group. Ann
Intern Med 1999; 130:461–70.
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