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© JAPI • november 2012 • VOL. 60
Review Article
Management of Acute Coronary Syndrome in Chronic
Kidney Disease
Suman Bhandari*, Peeyush Jain**
Abstract
Few trials have addressed the management of acute coronary syndromes (ACS) in chronic kidney disease (CKD).
Hence guidelines for the management of coronary heart disease (CHD) in CKD are based on meta-analysis,
subgroup analyses, small prospective studies or retrospective analyses of controlled trials and registry data. The
short-term as well as long-term prognosis of ACS patients with poor renal function is worse than those with normal
renal function. The risk of cardiovascular (CV) events and mortality is inversely proportional to the estimated
glomerular filtration rate (eGFR). Nevertheless, CV event rates increase even in early CKD. Contrast induced
nephropathy (CIN) occurs in 15% of patients following diagnostic or therapeutic invasive procedures; less than 1%
of these require dialysis. While treatment of CIN is not so effective, it is predictable and can be largely prevented.
Despite a higher risk of adverse outcomes, patients with moderate-severe CKD are often treated less aggressively
than patients with normal renal function due to safety concerns. Patients with CKD are less likely to receive
aspirin, clopidogrel, or beta blockers and are less likely to undergo reperfusion or revascularization. Conservative
treatment of ACS may partially account for worse outcome in CKD. Large registry data suggests that in-hospital
revascularization is associated with improved survival, irrespective of eGFR. It is not clear whether coronary
artery bypass grafting (CABG) surgery or percutaneous coronary intervention (PCI) leads to better outcomes in
patients suitable for either procedure. While short-term risk of CABG in CKD is high, its long-term results have
been better than medical treatment or PCI in registry data. Recent data suggest no differentials in outcomes with
CABG or PCI. Randomized controlled trials involving patients with renal dysfunction are needed to confirm
whether aggressive treatment of ACS will improve clinical outcomes.
Background
D
eath from cardiac causes is 10-20 times more common in
chronic kidney disease (CKD) patients than in age- and
gender- matched population.1 In end-stage renal disease (ESRD),
cardiovascular (CV) mortality accounts for 45% of all-cause
mortality.2 Sudden cardiac death (SCD) constitutes 62% of the CV
mortality in ESRD and 25% of all-cause mortality.3,4 The annual
rate of SCD in ESRD patients on dialysis is 7%.4
100
2-year mortality (%)
80
40
Patients with poor renal function carry worse prognosis than
those with normal renal function after acute coronary syndromes
(ACS), including myocardial infarction (MI), percutaneous
coronary intervention (PCI), and coronary artery bypass grafting
(CABG) surgery6 (Figure 1).
20
PCI
No CKD
CABG
CKD
MI
ESRD
Fig. 1 : Mortality in CKD vs. non- Patients after MI, PCI, and CABG
Surgery11
Director, Cath Lab, Fortis-Escorts Heart Institute, Okhla Road, New
Delhi 110 025; **Principal Consultant Cardiologist, Fortis-Escorts Heart
Institute, Okhla Road, New Delhi 110 025, India.
Received: 24.03.2011; Revised: 09.06.2011; Accepted: 20.06.2011
*
Few trials have addressed the management of coronary heart
disease (CHD) and acute coronary syndrome (ACS) in CKD. A
meta-analysis of 153 randomized controlled trials (RCTs) of CV
interventions proven efficacious for CV disease (CVD) revealed
that patients with renal disease were excluded in 86 (56%) trials.
Only 5% of original articles reported the proportion of enrolled
patients with renal disease, and only 10% reported baseline renal
function. Only in 3% of the original articles, subgroup analyses
of treatments stratified by renal function were performed. Hence
guidelines for the management of CHD in CKD are mostly
opinion based.5
Mortality in CKD Patients after MI,
PCI, and CABG
60
0
Cardiovascular Outcomes Trials and
CKD
Estimated Glomerular Filtration Rate
(eGFR) and CV Outcomes
Most studies have found that a threshold for development of
accelerated atherosclerosis, plaque rupture and ACS, CHF, and
CV death is eGFR below 60 ml/min/1.73 m2 that corresponds
roughly to a serum creatinine of 1.5 mg/dl.7 The risk of CV
events and mortality increases as eGFR falls progressively
© JAPI • november 2012 • VOL. 60 Table 1 : CV Events and Death Risk as a Function of eGFR12
Estimated GFR
(eGFR)
45-59
30-44
15-29
<15
Hazard Ratio for
Cardiovascular Events
1.4
2.0
2.8
3.4
49
Hazard Ratio for
Death
1.2
1.8
3.2
5.9
(Table 1).7 While patients with end-stage renal disease (ESRD)
are at extreme risk, CV event rates increase even in early CKD.
Therefore, CKD is considered to be CHD risk equivalent for risk
factor management.
CVD Treatment Outcomes in CKD
Patients
As there is little evidence on which to base CVD treatment
in CKD, current treatment strategies are based upon small
prospective studies or retrospective analyses of controlled
trials and registry data. It is thus uncertain whether CKD
patients benefit similar to patients with normal renal function.
Revascularization by CABG in CKD has been reported in registry
data to provide better long-term results than medical treatment
or PCI. Recent data however shows improvement in outcomes
with PCI. Short-term risk of CABG in CKD remains high. It is
not clear which revascularization technique has a better outcome
in patients suitable for either procedure.
Contrast-Induced Nephropathy
Wide use of diagnostic and therapeutic procedures utilizing
iodinated contrast media in CV practice has led to an increase
in the incidence of contrast-induced nephropathy (CIN) (overall
incidence 15%, < 1% require dialysis).8 The most important risk
factor for the development of CIN is baseline eGFR < 60. Other
risk factors include diabetes, proteinuria, volume depletion,
CHF, and intraprocedural adverse events. For those who require
dialysis for CIN, in-hospital mortality rate is 30% and with 80%
2-year mortality. Nevertheless, CIN is predictable and may be
largely prevented. Since treatment of CIN is not so effective,
prevention of renal injury is important.
A simple ‘Risk Score’ based on 8 independent predictors has
been suggested to predict the risk of CIN (Figure 2).9 Rate of CIN
increased exponentially with increasing risk score. The ability to
diagnose CIN is limited by the lack of a sufficiently sensitive and
specific marker of renal injury. Neutrophil gelatinase associated
lipocalin, kidney injury molecule-1, interleukin-18 and others
are under evaluation. Till such validation occurs, eGFR remains
the most reliable single marker of CIN. In clinical practice, an
increase in serum creatinine of ≥0.5 mg/dl or ≥25% occurring 48
to 72 hours after contrast exposure is often taken as an indication
of CIN but changes in serum creatinine are not specific for a
decrease in GFR. Furthermore, the time lag between a fall in GFR
and a rise in creatinine may affect the sensitivity of the test.10
Cystatin C may be a more sensitive marker of a fall in GFR.11
Pharmaco-Prevention of CIN
Several approaches for preventing CIN e.g. systemically
administered vasodilators (dopamine agonists, adenosine
antagonists, prostaglandins, endothelin antagonists) and
antioxidants (N-acetylcysteine, ascorbic acid), and bicarbonate
have been tried and failed. A recent meta-analysis found that
bicarbonate therapy did not reduce the need for dialysis or
Risk Factors
Integer Score
Hypotension
5
IABP
5
CHF
5
Age >75 years
4
Anemia
3
Diabetes
3
Contrast media volume
Serum creatinine>1.5mg/dl
OR
eGFR <60 ml/min/1.73 m2
eGFR (ml/min/1.73 m2)=
186 x (SCr)-1.154 x (Age)-0.203
x (0.742 if female) x (1.210
if African American)
Risk
Score
Risk of Risk of
CIN Dialysis
≤5
7.5%
0.04%
6 to 10
14.0%
0.12%
1 for each 100 cc
11 to 16
26.1%
1.09%
4
≥ 16
57.3%
12.6%
Calculate
3
2 for 40 - 60
4 for 20 - 40
6 for < 20
Fig. 2 : Risk Score to Predict Contrast-induced Nephropathy (CIN)
after PCI16
mortality when compared to normal saline.12 Bicarbonate was
most effective in patients who had urgent or emergency contrast
administration or in those receiving low osmolality contrast
media.
Under-treatment of ACS in CKD
Despite a higher risk of adverse outcomes, patients with
moderate-severe CKD are treated less aggressively. In a study
of 45,343 patients with non–ST-segment elevation (NSTE) ACS
enrolled in the CRUSADE Quality Improvement Initiative,
adherence to Class IA/IB recommendations was lower in patients
with moderate-severe CKD, who were significantly less likely
to be treated with medications or undergo invasive cardiac
procedures possibly because of safety concerns about adverse
outcomes and absence of trial data.13
Conservative treatment of ACS may partially account for
worse outcome in CKD. Registry data suggests that in-hospital
revascularization is associated with improved survival,
irrespective of eGFR. In the prospective, multicentre, Canadian
ACS I (n=3295; 1999-2001), ACS II (n=1956; 2002-03) registries
and Global Registry of Acute Coronary Events (GRACE) (n=6491;
2004-07), patients with renal dysfunction were less likely to
undergo invasive management. Unadjusted 1- year mortality
was lower among patients receiving in-hospital coronary
angiography within all eGFR categories Revascularization was
independently associated with lower 1-year mortality (adjusted
OR=0.52, 95% CI 0.36–0.77, P=0.001) irrespective of eGFR.14
The Acute Coronary Treatment and Intervention Outcomes
Network Registry suggests that patients admitted with acute
MI and CKD also receive fewer evidence-based therapies and
have substantially higher mortality rates.15 CKD was present
in 30.5% of STEMI (n=19,029) and 42.9% of NSTEMI (n=30,462)
patients respectively. Regardless of MI type, patients with
progressively more severe CKD had higher rates of death. In
addition, patients with progressively more severe CKD were
less likely to receive aspirin, beta blockers, or clopidogrel,
and were less likely to undergo any reperfusion (STEMI) or
revascularization (NSTEMI). Recent increase in awareness about
possible improvement in prognosis with standard management
may be reducing under-treatment of ACS in CKD.16
50
© JAPI • november 2012 • VOL. 60
Conservative vs. Early Invasive
Strategy in CKD
An early invasive strategy is superior to conservative strategy
in ACS but underutilized in patients with CKD partly due to
concern about nephrotoxicity of radiocontrast agents. However, a
recent meta-analysis of 5 randomized trials (n=1453 patients with
CKD) concluded that an early invasive strategy was associated
with a trend toward reductions in all-cause mortality, nonfatal
MI, and a composite of death or nonfatal MI and a significant
reduction in re-hospitalization.17 This is further reiterated by
another recent meta-analysis of patients with unstable angina/
NSTEMI (n=5467) that found that 5- year incidence of CV death
or nonfatal MI in CKD patients was lower in routine invasive
vs. selective invasive strategy (14.7% vs. 17.9%, hazard ratio-HR:
0.81, 95% confidence interval-CI: 0.71-0.93; p=0.002).18
PCI in ACS with CKD
CKD is the most important factor in predicting adverse shortand long-term outcomes after PCI. The risks involved seem to
be warranted, given comparative outcomes in conservatively
treated patients.19 The presence of CKD should not preclude
a potentially beneficial CV intervention like PCI. This is
corroborated by the findings in a cohort of 4631 subjects with
ACS, where cardiac catheterization with or without PCI was
not associated with significant differences in long-term renal
function when compared to medical therapy. Among CKD
subjects, the risk of death greatly outweighed the risk of reduced
eGFR or development of ESRD following ACS.20
Management of Acute MI in CKD and
Dialysis Patients
CKD patients presenting with acute MI are also less likely
to receive aggressive therapy and twice as likely to die in the
hospital. The overall 1-year mortality rate of dialysis patients
after MI is greater than 50%.21
To assess the impact of advanced CKD (stages 3-5) on the inhospital mortality of PCI in acute MI, all patients who underwent
PCI in New York State between 1997 and 1999 were evaluated
(n=9,015). After adjusting for co-morbidity, cardiogenic shock or
heart failure, advanced CKD remained an independent predictor
of in-hospital mortality (odds ratio 2.4, 95% CI 1.002-5.804, p =
0.049).22 Notwithstanding higher mortality, primary PCI remains
the preferred approach in ESRD due to unacceptably high
complication and mortality rates with thrombolysis in ESRD.22
The long-term prognostic importance of CKD in patients
undergoing primary PCI for STEMI was assessed from data
from 1933 patients in the Controlled Abciximab and Device
Investigation to Lower Late Angioplasty Complications trial
(CADILLAC) in whom baseline serum creatinine values were
available.23 Of these, 350 had an eGFR <60 in whom, procedural
success rates were lower (87.2% vs. 92%, p=0.01), and 9- fold
greater mortality at 1 month and a 5- fold increase in mortality
at 1 year. CKD was independently related to severe (>70%)
restenosis and late occlusion of coronary vessels and there was
an inverse relationship between eGFR and mortality throughout
the follow-up.
Drug-Eluting Stents in CKD
A recent analysis of observational studies published till
January 2009 concluded that DES implantation in patients with
various degrees of renal insufficiency was associated with less
favourable outcomes than in those with normal renal function
though DES implantation yielded better outcomes than did use
of bare-metal stents.24
CABG Surgery vs. PCI in CKD
To compare long-term clinical outcomes after CABG or PCI
with multivessel stenting in patients with CKD, the Arterial
Revascularization Therapies Study (ARTS) randomly assigned
participants with CKD to CABG (n=139) or multi-vessel PCI
(n=151) and followed up for a mean of 3 years. No difference was
observed in the primary endpoint of a composite of death, MI, or
stroke with CABG or PCI among CKD participants (adjusted HR
CABG vs PCI: 0.93; 95% CI: 0.54-1.60; p=0.97). However, CABG
was associated with a reduced risk for repeat revascularization
(HR=0.28; 95% CI 0.14-0.54; P <0.01).25
Coronary Revascularization in Patients
on Maintenance Dialysis
Underutilization of medical and interventional therapies
may be partially responsible for high risk of CV death with MI
in patients on dialysis.26 Optimal method of coronary artery
revascularization in patients on dialysis is controversial. In an
exploratory meta-analysis, 30- days or in-hospital mortality was
higher with CABG compared to PCI but there was no difference
in mortality over subsequent 1-5 years.27
ACS and Anti-thrombotic Agents in
CKD
Due to excessive risk of bleeding, anti-thrombotic agents
should be used with caution in CKD. The dose of low molecular
weight heparin should be reduced when eGFR is <30. Amongst
GpIIb/IIIa inhibitors, the infusion rate of tirofiban should be
reduced to half when eGFR is <30. Both bolus dose and infusion
rate of eptafibatide should be modified when serum creatinine
is between 2 and 4 mg/dl.28
The direct thrombin inhibitor bivalirudin reduces ischemic
and bleeding events after PCI. To assess whether this benefit is
influenced by renal function, a meta-analysis of 3 randomized
trials (n = 5,035) in different strata of eGFR concluded that the
relative benefit of bivalirudin with respect to ischemic and
bleeding events was maintained.29
In Acute Catheterization and Urgent Intervention Triage
strategy (ACUITY) substudy (n=13,819 moderate and high
risk ACS, early invasive strategy), the safety and efficacy of
bivalirudin monotherapy vs. bivalirudin plus a glycoprotein IIb/
IIIa inhibitor (GPI) vs. heparin plus a GPI were compared.30 There
were no significant differences between bivalirudin monotherapy
and heparin plus a GPI in rates of 30-days composite ischemia
or net clinical adverse outcomes as well as 1-year composite
ischemia or mortality, the incidence of major bleeding at 30
days was remarkably less with bivalirudin alone (6.2% vs. 9.8%,
p=0.008).
Conclusions
Though routine invasive approach for ACS in renal
dysfunction may increase the risk of short-term adverse
outcomes, there is likely to be an improvement in long-term
outlook. The fear of CIN continues to cause underutilization of
routine invasive approach in this setting. Lack of randomized
© JAPI • november 2012 • VOL. 60 controlled trial data is another major barrier to implementation
of standard therapies for ACS in renal dysfunction.
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