The Management of Acute Coronary Syndromes in Patients With Chronic Kidney Disease John K. Roberts and Peter A. McCullough Coronary heart disease is highly prevalent in patients with CKD, and survival after acute coronary syndrome (ACS) is worse compared with the general population. Many trials that define guidelines for cardiovascular disease excluded patients with kidney disease, leaving a gap between the evidence base and clinical reality. The underlying pathophysiology of vascular disease appears to be different in the setting of CKD. Patients with CKD are more likely to present with myocardial infarction and less likely to be diagnosed with ACS on admission compared with the general population. Patients with CKD appear to benefit with angiography and revascularization compared with medical management alone. However, the increased risk of in-hospital bleeding and risk of contrast-induced acute kidney injury are 2 factors that can limit overall benefit for some. Thus, judicious application of available therapies for the management of ACS is warranted to extend survival and reduce hospitalizations in this high-risk population. In this review, we highlight the clinical challenges and potential solutions for managing ACS in patients with CKD. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Chronic kidney disease, Acute coronary syndrome, Mortality, Bleeding

Introduction An estimated 26 million Americans have CKD and are at increased risk for cardiovascular disease-related mortality.1 A population cohort study in Alberta, Canada, found a significantly higher rate of incident acute myocardial infarction (AMI) among patients with CKD and proteinuria.2 This association was stronger in patients with CKD than in those with diabetes mellitus but without CKD (12.4 vs 6.6 per 1000 person years), supporting the argument that CKD be considered a coronary heart disease risk equivalent. An analysis of 14,527 patients with AMI in the Valsartan in Acute Myocardial Infarction Trial found that patients with estimated glomerular filtration rate (eGFR) less than 81 mL/min/1.73 m2 had an increased hazard ratio for death and nonfatal cardiovascular outcomes (1.10, 95% confidence interval [CI] 1.08-1.12) for every 10 mL/min decline in eGFR.3 The USRDS databank supports this: the 2-year survival of Medicare enrollees after AMI drops from 57% in those without CKD to 38% in patients with CKD with an overall trend favoring worse outcomes with worse kidney disease: 47% survival for stages 1 to 2 CKD vs 30% survival for stages 4 to 5 CKD.4 Mortality after AMI for patients with the poorest renal function, those on dialysis, is worst with a reported 1-year mortality of 59% after the event.5 Americans with CKD, thus, represent a high-risk subpopulation for coronary heart disease and subsequent From Division of Nephrology, Duke University Medical Center, Durham, NC; Baylor University Medical Center, Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX; and The Heart Hospital, Plano, TX. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to John K. Roberts, MD, MS, Division of Nephrology, Duke University Medical Center, 2424 Erwin Road, Suite 605, Durham, NC 27710. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.08.005

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acute coronary syndromes (ACS). New therapies in the management of ACS have been developed over the last few decades, thanks to large-scale trials. Unfortunately, many of these studies excluded patients with kidney disease.6 Thus, the management of ACS in the patient with CKD is not strictly evidence based but relies on carefully interpreting the available data and guidelines to maximize the benefits of treatment while minimizing harms. In this review, we hope to highlight unique features and quandaries associated with managing ACS in the CKD population while briefly reviewing the available evidence for the management of this common clinical problem.

Pathophysiology of Coronary Disease in the Setting of CKD The phenotype of cardiovascular disease in CKD (accelerated incidence, diffuse burden of disease, and higher mortality) suggests a slightly different pathophysiology of disease compared with the non-CKD population, and several studies support this hypothesis. Typical CAD is characterized by the classic fibroatheromatous plaque, when ruptured, classically leads to ACS. Atherosclerotic disease is highly prevalent in patients with CKD, but they had a more severe clinical and pathological phenotype. Autopsy studies and angiographic studies in patients with CKD have shown a higher burden of multivessel disease, more long and tapered stenoses, the presence of profound medial calcification, and more chronically occluded lesions compared with the Intravascular ultrasound general population.7-11 studies during ACS have showed that patients with CKD had significantly higher plaque burden with plaques more likely to contain a necrotic core and dense calcium compared with patients with ACS without CKD.12 Despite having a greater burden of CAD, patients with CKD have a weaker association with the “traditional” atherosclerotic risk factors, such as low-density lipoprotein cholesterol, tobacco use, and family history of

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CAD.13,14 This accelerated disease might be under the influence of unique CKD risk factors such as chronic inflammation, changes in nitric oxide availability, and chronic oxidative stress.14-16 Chronic phosphate retention, secondary hyperparathyroidism, and elevated levels of fibroblast growth factor 23 have been implicated in driving both left ventricular hypertrophy17,18 and intravascular calcium-phosphate crystallization.19-21

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with the general population. One study combining 3 large registries showed that patients with ACS and both eGFR 30 to 59 mL/min/1.73 m2 and less than 30 mL/ min/1.73 m2 were significantly less likely to receive inhospital coronary angiography compared with patients with normal kidney function.28 Even if patients with CKD receive angiography, they may not undergo revascularization. One series showed that patients with CKD who do not undergo revascularization have high inhospital mortality and were also less likely to receive Diagnosis of Acute Coronary Syndromes in guideline-recommended therapies.29 The Swedish WebSystem for Enhancement and Development of Patients With CKD Acute coronary syndrome is a term that encompasses the Evidence-Based Care in Heart Disease Evaluated Accordspectrum of symptomatic ischemic heart disease from uning to Recommended Therapies study also found a lower rate of invasive management for STEMI on as a function stable angina (UA) to non-ST-elevation myocardial infarction (NSTEMI) and to ST-elevation myocardial of declining baseline eGFR.30 The Analysis of the Acute Coronary Treatment and Intervention Outcomes infarction (STEMI). The diagnosis of ACS is still depenNetwork registry also found that patients with progresdent on a constellation of ischemic symptoms, cardiac sively more severe CKD were less likely to receive biomarkers, and characteristic electrocardiographic findevidence-based AMI therapy such as aspirin, clopidoings.22 Compared with the general population, patients grel, beta-blockers, urgent with CKD having AMI are less likely to present with reperfusion for STEMI, typical angina symptoms and revascularization for CLINICAL SUMMARY and are also less likely to NSTEMI.31 This is consistent with prior studies showing have ST elevations, patho
The pathophysiology of coronary heart disease in patients a trend away from using logic Q waves, ST depreswith CKD is driven by atherosclerosis and accelerated by evidenced-based therapies sions, or a new left bundle vascular calcification. like beta-blockers, angiobranch block on the electro
Patients with CKD have more severe coronary artery tensin-converting enzyme cardiogram. Rather, patients disease (CAD), and when acute coronary syndromes inhibitors, and statins in with CKD and ACS are (ACS) events occur, there are greater rates of treatment patients with CKD after more likely to present with complications, morbidity, and mortality. AMI.32,33 However, a study heart failure symptoms and
Patients with mild and moderate CKD appear to benefit by Nauta and colleagues more likely to get admitted from invasive therapy for ACS, while selected patients found that adjusted 30-day with a diagnosis other than 23,24 with advanced CKD likely benefit from invasive therapy To add to the and 12-month mortality ACS. when the risk/benefit ratio is favorable. conundrum, many patients after AMI improved over
Patients with CKD benefit from standard antithrombotic with CKD have elevated time (from 1985-1990 to and antiplatelet therapy, but the risk of major bleeding is 2000-2008) in all CKD cardiac troponins (both greater than the general population. cTnT and cTnI) even in the subgroups as the use of absence of ACS.25 One study reperfusion therapies and evidence-based medications of patients with both CKD and AMI found that serum high-sensitivity cardiac increased.34 This suggests that patients with CKD significantly benefit when they receive the standard of troponin T levels required a significantly higher diagACS care. nostic threshold to preserve the specificity of the test compared with patients without CKD.26 Chronically Reperfusion Strategies in Patients With CKD elevated serum troponin levels associate with structural heart disease, especially left ventricular hypertrophy, in In the general population, STEMI is treated with urgent revascularization and UA/NSTEMI is usually treated patients with advanced CKD.27 Thus, as CKD progresses and patients are more at risk for left ventricular hypertrowith an early invasive strategy in patients with little cophy, heart failure, and arrhythmias, ischemic imbalance is morbidities and high risk for future clinical events. Pamore apt to precipitate ACS by a nonatherosclerotic tients with CKD usually have more comorbid conditions, mechanism. Thus, diagnosing ACS in the CKD populabut they are also at high risk for future cardiovascular tion remains challenging, and these unique features events. Thus, the optimal management strategy for ACS possibly lead to differential care in this high-risk group. in patients with CKD is unclear, and many investigators have compared outcomes after various management straDifferential Treatment in Acute Coronary tegies. For example, a collaborative systematic review Syndromes from 2009 evaluated the effectiveness of early invasive In addition to being excluded from major trials evalustrategy vs conservative strategy across all CKD subating therapies and interventions for ACS, patients with groups.35 The meta-analysis found that the invasive strategy was associated with a significant reduction in 1-year CKD and ACS are less likely to receive reperfusion therhospitalization rates and a nonsignificant trend toward apy and standard of care medical therapy compared

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lower all-cause mortality and incidence of myocardial infarction (MI) compared with a conservative strategy. The Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies trial was a large registry analysis that measured outcomes after invasive management or medical management in patients with NSTEMI and varying degrees of renal dysfunction.30 Propensity-adjusted hazard ratios for mortality at 1 year were significantly lower with invasive therapy in both the mild CKD (hazard ratio 0.64, 95% CI 0.52-0.80) and moderate CKD (hazard ratio 0.68, 95% CI 0.54-0.86) subgroups. There was no significant change in mortality at 1 year among those with severe CKD (hazard ratio 0.91, 95% CI 0.51-1.61) or on dialysis (hazard ratio 1.61, 95% CI 0.84-3.09). Thus, the 2012 American College of Cardiology Foundation/American Heart Association (ACCF/ AHA) guidelines on management of UA/NSTEMI gave a class IIA recommendation that an invasive strategy is reasonable for patients with mild and moderate CKD, whereas data are insufficient for those with severe CKD and on dialysis.36 Of note, a recent meta-analysis including data from 3 major trials30,37,38 found a 1-year mortality benefit across all GFR subgroups (including dialysis patients) with revascularization compared with medical management after NSTEMI.39 Randomized, controlled trials comparing the efficacy of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) for multivessel CAD do exist, and both are reasonable revascularization options, but CABG is preferred for diabetics and those with complex anatomy. However, most of these trials excluded patients with kidney disease, and none of these trials have included patients on hemodialysis.40-43 Only observational studies have been performed comparing the efficacy of CABG and PCI among patients with CKD and ESRD. Some of these representative studies found lower all-cause mortality, lower rates of ACS, and reduced need for revascularization after CABG compared with PCI or medical management alone in patients with CKD across all eGFR strata.44,45 A meta-analysis of 28 retrospective studies from 1977 to 2012 found that CABG was associated with reduced rates of MI, repeat revascularization, and reduced long-term mortality compared with PCI among nondialysis patients with CKD.46 One would hypothesize that the effects of revascularization would diminish for dialysis patients, but retrospective analyses of USRDS data have shown improved 2-year survival with CABG (especially using an internal mammary graft) compared with PCI alone.47,48 In-hospital mortality was significantly higher for the CABG group compared with the PCI group (8.2% vs 3.2%), but the probability of repeat revascularization at 1 year was significantly lower in the CABG group compared with the drug-eluting stent (DES) and bare-metal stent (BMS) groups (6%, 19%, and 18%, respectively).48 Another recent large study using data from a single, integrated health care system also found a long-term mortality benefit with CABG over PCI in dialysis patients.49 A recent meta-analysis and slightly older exploratory meta-analysis of retrospective cohort studies both noted significant heterogeneity of all the avail-

able studies to date, but they found lower rates of cardiac events and reduced long-term mortality with CABG.50,51 For patients with CKD who undergo PCI, it is unclear how the choice of stent matters. It is possible that the deranged pathophysiology of advancing CKD attenuates the benefits of DES over BMS, but this is not clear. Baseline renal function remains the strongest predictor of survival after PCI regardless of stent,52 and some studies have found no difference in outcomes with DES compared with BMS,53,54 whereas others found that DES was associated with reduced rates of MI and death but no difference in the need for repeat revascularization in patients with nondialysis CKD.55 The available retrospective analyses in patients with CKD are heterogeneous and despite adjustment, subject to significant confounding. These database analyses suggest that CABG may have survival benefits in patients with CKD, including those on dialysis. Prospective, randomized trials are necessary to make any firm conclusions.

Complications in Patients With CKD: Bleeding and Acute Kidney Injury Patients with CKD have a higher baseline risk of bleeding that can complicate the management of ACS. Patients with CKD are known to have prolonged bleeding times because of functional platelet disorders, despite having high levels of thrombin-antithrombin complexes and fibrinogen that are typically associated with prothrombotic states.56 In fact, higher baseline levels of circulating thrombinantithrombin complexes mean that patients with CKD experience a more profound anticoagulant effect from indirect thrombin or factor Xa inhibition.57 This association between CKD and major in-hospital bleeding events after ACS has been well described.29,58 Antithrombotic therapy, the cornerstone of ACS management and secondary prevention, modifies the bleeding risk in patients with and without CKD. Primary prevention studies in the general population found a higher absolute rate of major extracranial bleeding with aspirin compared with controls (0.10% vs 0.07%).59 However, in a meta-analysis of 26 trials involving patients with CKD, the absolute rate of major bleeding events with antiplatelet therapy was 4.4% compared with 2.9% in CKD controls.60 The benefits of antiplatelet therapy are retained in patients with CKD, but the baseline risk of bleeding is increased and physicians will need to be aware of this when prescribing antithrombotic therapy. Contrast-induced nephropathy, now termed contrastinduced acute kidney injury (CI-AKI), is a well-defined complication after angiography. Patients with CKD are at higher risk for CI-AKI, and when this occurs, they suffer a longer hospital stay and higher in-hospital mortality.61 This higher risk of CI-AKI can be 1 factor that leads to a bias against pursuing an invasive strategy in patients with CKD.62 The ACCF/AHA guidelines on the management of ACS addressed the risk of CI-AKI in patients with CKD undergoing angiography. The committee did not make a distinction between the types of contrast media used (low osmolar vs iso-osmolar media) because of lack of consistent evidence, but they did make a class I recommendation for preprocedure volume expansion and

Management of ACS in Patients With CKD

adjustment of the total contrast dose.36 The volume-tocreatinine clearance ratio (total volume of contrast media in milliliter divided by the calculated creatinine clearance using the Cockroft-Gault formula) can be used to predict the maximum allowed contrast media volume. Risk for CI-AKI begins when this ratio exceeds 2.0, and a volume-to-creatinine clearance ratio more than 3.7 was an independent predictor for rising serum creatinine after PCI.63 Strategies to prevent CI-AKI remain an area of active investigation. We have found that N-acetylcysteine is ineffective,64 sodium bicarbonate is likely no better than sodium chloride expansion,65-67 and a sliding scale volume expansion strategy guided by left ventricular end-diastolic pressure is effective at reducing CI-AKI.68 In addition to volume expansion, other prophylactic strategies have recently emerged. For example, both ascorbic acid and rosuvastatin have been associated with a reduction in the incidence of CI-AKI in patients undergoing diagnostic angiography.69,70 In a randomized trial of patients with type 2 diabetes and CKD, rosuvastatin (10 mg) for 5 days was associated with a small but significantly lower incidence of CIAKI compared with the standard of care (2.3% vs 3.9%; P ¼ .01).71

Medical Management: Implications on Antiplatelet, Antithrombotic, and Other Medical Therapies Although there is a lack of prospective therapy trials for ACS in the CKD population, the medical management of ACS can be safe and effective by eGFR-guided dose adjustment and bleeding risk stratification. For all patients with STEMI, including those with CKD, early PCI with stenting within 90 minutes of presentation is considered first-line therapy.72 For those outside this window or with an anticipated delay in PCI, reperfusion with thrombolysis is indicated as an alternate strategy. The commercially available thrombolytics (alteplase, reteplase, tenecteplase, and streptokinase) do not require dose adjustment for CKD. After reperfusion, medical therapy for STEMI is similar to that for UA/NSTEMI.36,72 Aspirin, if tolerated, is still recommended at presentation and indefinitely for all patients with ACS. Patients with UA/NSTEMI undergoing an early invasive strategy should receive dual antiplatelet therapy: aspirin plus either a P2Y12 receptor inhibitor (clopidogrel, ticagrelor, or prasugrel) or an intravenous glycoprotein (GP) IIb/IIIa inhibitor.36 UA/NSTEMI patients undergoing a conservative strategy should have clopidogrel or ticragrelor added to aspirin and anticoagulant therapy. The 2012 ACCF/AHA guidelines on the management of UA/NSTEMI made a class I recommendation to estimate creatinine clearance in patients with UA/NSTEMI and adjust all renally cleared medications according to known pharmacokinetic data. For aspirin and P2Y12 receptor inhibitors, there are no specific dose adjustments necessary for patients with CKD.57 The guidelines also make a class IIB recommendation for the use of a GP IIb/IIIa inhibitor in addition to aspirin and a P2Y12 receptor inhibitor only for selected high-risk patients with UA/NSTEMI selected for an invasive strat-

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egy.36 Among these agents, eptifibatide is excreted renally and a 50% dose reduction is required for a creatinine clearance less than 50 mL/min. It is contraindicated in patients on dialysis because of an increased risk of bleeding.73 Tirofiban is renally excreted and requires a 50% dose reduction for a creatinine clearance less than 30 mL/min, whereas abciximab does not require dose adjustment for renal failure and is the preferred agent for patients on dialysis.57 Although associated with increased bleeding events, the GP IIb/IIIa inhibitors have been associated with reduced in-hospital mortality among patients with CKD and ACS, but these findings need to be confirmed.74 Initial anticoagulant therapy with unfractionated heparin (UFH), enoxaparin, or fondaparinux is recommended for patients with UA/NSTEMI who are undergoing either an invasive or conservative strategy.36 UFH is partially affected by renal function, and as long as doses are appropriately reduced (60 IU/kg bolus up to a max of 4000 units, followed by 12 units/kg/h with initial rate not to exceed 1000 units/h), it can safely be used in patients with CKD. Enoxaparin has been shown to be superior to UFH in patients with UA/NSTEMI,75,76 but it is renally excreted and requires dose adjustment for creatinine clearance less than 30 mL/min (recommended dose: 1 mg/kg subcutaneously once daily). For patients on dialysis, enoxaparin is associated with increased bleeding events and its use is contraindicated.73 Fondaparinux is an indirect Xa inhibitor that is nearly completely dependent on renal excretion. It is contraindicated for use in patients with a creatinine clearance less than 30 mL/min and should be used with caution in patients with a creatinine clearance of 30 to 50 mL/min.57 The 2012 ACCF/AHA guidelines on the management of UA/NSTEMI made a class IIB recommendation that bivalirudin may be used as the anticoagulant of choice in conjunction with clopidogrel for patients receiving an early invasive strategy.36 Bivalirudin is a direct thrombin inhibitor that is renally excreted and requires dose adjustment for patients with reduced eGFR (with PCI: 0.75 mg/ kg intravenous bolus, followed by infusion of 1 mg/kg/h if CrCl 10-29 mL/min and 0.25 mg/kg/h for dialysis patients).57 When dosed appropriately, bivalirudin is associated with fewer ischemic events and fewer bleeding events compared with UFH.77 It can be safely used in dialysis patients with ACS, but it should be known that hemodialysis treatments clear about 25% of the active drug.57 The general medical therapy after ACS for patients with CKD is less complex. b-receptor blockers are indicated in the initial management of ACS, and the most commonly used in this class (metoprolol, carvedilol, and esmolol) do not require dose adjustment for renal dysfunction. Likewise for renin-angiotensin-aldosterone system inhibitors, which are usually well tolerated in patients with CKD, they have been shown to reverse left ventricular hypertrophy among patients on dialysis.78,79 HMG Co-A reductase inhibitors (statins) have proved effective in preventing cardiovascular events in the general population, and these benefits appear to extend to patients with CKD. For example, the Study of Heart and Renal Protection trial randomized patients with CKD (both on dialysis

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Figure 1. The relationship between CKD, acute coronary syndrome, and the complex effect on important outcomes.

and not on dialysis) to 20 mg simvastatin plus 10 mg ezetimibe or placebo. The statin group had significantly fewer atherosclerotic events (11.3% vs 13.4%) compared with placebo, corresponding to a 17% relative risk reduction.80 A meta-analysis of randomized trials came to a similar conclusion: statin use for primary prevention consistently lowers the risk of death and major cardiovascular events by 20% in patients with CKD and not on dialysis.81 Thus, using statins in patients with CKD is supported by randomized trials, and it should be used in the medical management of ACS or CAD in patients with CKD.

Individualized Care and Need for Collaboration The management of ACS among patients with CKD is complicated and fraught with uncertainty and lack of a rigorous evidence base (Fig 1). The standard of ACS care in the general population likely has benefit for patients with mild and moderate CKD. For patients with severe CKD or on dialysis, comorbid conditions and competing

risks of all-cause mortality may limit the benefits of aggressive management. For these groups, clinicians will need to make an individualized estimate on the risks and benefits of invasive management and revascularization. Making this discrimination is difficult and prone to physician bias. One solution could increase collaborative care between cardiology and nephrology as early consultation with nephrology could possibly help identify which patients would benefit from angiography and revascularization. For instance, a dialysis patient with progressive functional decline and mild dementia may be best managed conservatively, whereas a dialysis patient with few comorbidities and 4 years accrued on the kidney transplant waiting list would benefit from invasive management and surgical revascularization. Because outcomes in retrospective trials tend to favor more invasive or surgical treatments, this may actually reflect appropriate allocation of patients with CKD to the appropriate strategy based on comorbidity burden, estimated life expectancy, or surgical candidacy.

Management of ACS in Patients With CKD

Thus, improved dialogue and collaborative decision making between nephrology, cardiology, and cardiac surgery services may lead to optimal decisions in these areas of uncertainty.

Conclusions The presence of CKD alone does not preclude receiving the standard of ACS care. Improved adherence to guideline-based therapy in the CKD population appears to be associated with improved short- and long-term mortality.34 Patients with CKD can receive doseadjusted antithrombotic therapy, dual antiplatelet therapy, and standard medical therapy, however, with the accepted higher risk of bleeding. Individualized decisions supported by collaborative care will likely improve the selection of patients who will benefit from invasive management. Until rigorous prospective trials are performed, these critical decisions will need to be guided by a combination of the evidence at hand and clinical acumen.

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