Pharmacotherapy in Chronic Kidney Disease Patients Presenting With Acute Coronary Syndrome: A Scientific Statement From the American Heart Association

Current guidelines recommend aspirin should be initiated as soon as an ACS is suspected and should be continued indefinitely, unless a contraindication develops.^26,27 Given that patients with renal insufficiency have an increased bleeding risk, there is some trepidation regarding the use of antiplatelet therapy in these patients. Although patients with CKD were excluded from most randomized trials of aspirin therapy in ACS, data on observational studies evaluating aspirin therapy in patients with renal impairment are shown in Table 3.

The Antithrombotic Trialists’ Collaboration performed a meta-analysis of 287 randomized trials that included 135 000 patients and compared various antiplatelet therapies versus control.³⁷ Some of those trials included patients undergoing hemodialysis. Among those undergoing hemodialysis, antiplatelet therapy reduced the risk of serious vascular events (nonfatal MI, nonfatal stroke, or vascular death) by 41% (standard error, 16%). There was no significant increase in extracranial bleeds, although the absolute number was small (2% in antiplatelet-treated patients versus 2.3% in control subjects).³⁷

Most of the published observational data show similar benefits of aspirin therapy in ACS patients across the spectrum of renal function (Table 3). However, one study did find a significant interaction between discharge aspirin therapy and renal function, with an attenuated benefit with increasing degree of renal dysfunction.³² Although not conducted in ACS patients per se, the United Kingdom Heart and Renal Protection Study and the Dialysis Outcomes and Practice Patterns Study both showed no increased bleeding risk with aspirin therapy among patients receiving hemodialysis, which provides further support for the safety of aspirin in patients with CKD.^40,41 Collectively, the available data suggest that aspirin therapy is safe and effective in ACS patients with CKD and should be used in these patients to reduce the risk of death and vascular events.

Current guidelines recommend the use of a P2Y₁₂ receptor inhibitor across the spectrum of ACS presentations.^26,42 Data evaluating P2Y₁₂ receptor inhibitors in patients with ESRD are limited, and such information is available predominantly for individuals with moderate or no CKD. Data on the use of P2Y₁₂ receptor inhibitors in ACS patients with CKD are summarized in Table 4. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial randomized patients with an ACS without ST-segment elevation to either a 300-mg loading dose of clopidogrel followed by 75 mg per day or placebo. Based on tertiles of renal function, the relative risks (RR) and 95% CIs for the primary composite outcome associated with clopidogrel versus placebo were 0.74 (0.60–0.93) in the upper third, 0.68 (0.56–0.84) in the middle third, and 0.89 (0.76–1.05) in the lower third, with a P_interaction of 0.11.^43,44 In the Clopidogrel for the Reduction of Events During Observation (CREDO, a trial of patients undergoing planned PCI or coronary angiogram)^45,46 and the Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial (a trial of patients with STEMI),^47,48 there was a qualitative decline in the efficacy of clopidogrel versus placebo as renal function worsened; the HRs (95% CIs) across renal function were 0.42 (0.26–0.69), 0.80 (0.51–1.25), and 1.42 (0.81–2.45) in CREDO and 0.6 (0.40–0.90), 0.6 (0.40–0.70), and 1.0 (0.70–1.6) in CLARITY-TIMI 28. In a substudy of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, among patients with and without diabetic nephropathy, the HRs (95% CIs) for clopidogrel versus placebo were 0.9 (0.80–1.0) for those without diabetic nephropathy and 1.1 (0.80–1.6) for those with diabetic nephropathy.^52,53

In terms of safety, more bleeding occurred with clopidogrel than placebo overall; however, there was no significant interaction based on renal function in CURE, CREDO, or CLARITY-TIMI 28. Within the CHARISMA analysis, the frequency of severe bleeding according to the Global Utilization of Streptokinase and tPA for Occluded Arteries (GUSTO) definition among patients with diabetic nephropathy was nonsignificantly higher with clopidogrel than with placebo (2.6% versus 1.5%, P=0.075). In patients without diabetic nephropathy, there was no difference in GUSTO severe bleeding between patients randomized to clopidogrel versus placebo (1.5% versus 1.3%, P=0.28).⁵³

Prasugrel and ticagrelor are P2Y₁₂ inhibitors that exhibit a more rapid onset, higher degrees of platelet inhibition, and less interpatient variability than clopidogrel. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI 38) randomized subjects who presented with moderate- to high-risk ACS with scheduled PCI to either prasugrel or clopidogrel. Within this study, the risk reduction associated with prasugrel versus clopidogrel was 20% among those with CrCl ≥60 mL/min and 14% among those with CrCl <60 mL/min.⁴⁹ The Study of Platelet Inhibition and Patient Outcomes (PLATO) randomized patients admitted to the hospital with an ACS to treatment with ticagrelor or clopidogrel. The HRs (95% CIs) for ticagrelor versus clopidogrel for the primary composite outcome were 0.90 (0.79–1.02) among subjects with CrCl ≥60 mL/min and 0.77 (0.65–0.90) among those with CrCl <60 mL/min.^50,51 The HRs (95% CIs) for ticagrelor versus clopidogrel for major bleeding events were 1.08 (0.96–1.22) among patients with CrCl >60 mL/min and 1.07 (0.88–1.30) among those with CrCl <60 mL/min. Thus, the efficacy associated with prasugrel and ticagrelor compared with clopidogrel was apparent among subjects with reduced and normal renal function.

In summary, randomized placebo-controlled trial data on the use of clopidogrel in ACS patients with CKD have been derived primarily from patients not undergoing an early invasive strategy or primary PCI.^43,47 The lack of a treatment- by–renal function interaction suggests clopidogrel should be considered as a treatment option in this population. In addition, although the observed rates of bleeding have been higher with clopidogrel than with placebo in CKD patients, the lack of a treatment interaction suggests no significant increase in risk with the use of clopidogrel in ACS patients with CKD. The efficacy associated with prasugrel compared with clopidogrel and the efficacy and safety associated with ticagrelor compared with clopidogrel were evident in patients with and without CKD, and the data suggest these agents should be considered in CKD patients who are not considered to be at high risk of bleeding. However, patients with ESRD have been excluded from the landmark trials of these newer agents.^49,50

The glycoprotein (GP) IIb/IIIa receptor antagonists have been studied extensively in patients undergoing PCI and in patients presenting with ACS. In the setting of STEMI, recent guidelines give a Class IIa recommendation for the use of the GP IIb/IIIa receptor antagonists at the time of primary PCI in patients receiving unfractionated heparin (UFH).²⁶ Among patients presenting with unstable angina (UA)/NSTEMI with medium- or high-risk features in whom an initial invasive strategy is selected, current recommendations for the use of GP IIb/IIIa receptor antagonists include the option for upstream initiation or initiation at the time of PCI.⁴² Additionally, the guidelines favor a selective strategy of upstream use of GP IIb/IIIa receptor antagonists, and the use of these agents as part of an upstream triple-antiplatelet therapy regimen may not be supported when there is a concern for increased bleeding risk.⁴² Of the 3 agents currently available in the United States, eptifibatide and tirofiban are dependent on renal clearance for elimination, and dose adjustment is required for the 2 agents in patients with CrCl <50 mL/min and CrCl ≤60 mL/min (Table 1), respectively.^54,55 In addition, eptifibatide is contraindicated in patients requiring dialysis.⁵⁴

Abciximab is cleared via the reticuloendothelial system, and no current recommendations exist for dose adjustment for patients with CKD. Data from randomized trials and observational studies on the clinical outcomes of ACS patients with CKD receiving a GP IIb/IIIa receptor antagonist are summarized in Table 5.

When used at the time of PCI in ACS patients with CKD, outcomes with the use of GP IIb/IIIa receptor antagonists have been variable. A subgroup analysis of the Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy (ESPRIT) trial showed the treatment effect of eptifibatide was maintained among those with CrCl <60 mL/min, and the presence of CKD was not associated with an increased risk of bleeding with eptifibatide therapy.⁵⁸ Observational cohorts of ACS patients receiving GP IIb/IIIa receptor antagonists at the time of PCI have provided additional insight into use in patients with CKD. Best et al⁵⁷ assessed patients undergoing PCI in a large registry that divided patients into 3 categories according to creatinine clearance: >70, 50–69, or <50 mL/min. Among patients receiving abciximab, the interaction between CrCl and major bleeding was not statistically significant. Additionally, no interaction was seen between CrCl and abciximab for the frequency of death or MI (HR, 1.03; 95% CI, 0.97–1.08). A second observational study categorized patients undergoing PCI into 5 strata by CrCl (≥90 mL/min, 60–89 mL/min, 30–59 mL/min, <30 mL/min, and requiring dialysis).⁵⁹ After controlling for CrCl stratum, GP IIb/IIIa receptor antagonist use was associated with a lower risk of in-hospital mortality (OR, 0.34; 95% CI, 0.12–0.98) and an increased risk of a major bleeding event (OR, 2.13; 95% CI, 1.39–3.27). A final observational study reported the clinical outcomes of patients undergoing PCI who received abciximab.⁶⁰ Of the 1040 patients included, 44 were classified as having renal insufficiency. The authors reported no significant differences in the rates of in-hospital mortality or nonfatal major adverse cardiac events among patients with renal insufficiency compared with those without, although major bleeding occurred more frequently among patients with renal insufficiency (4.5% versus 0.6%; P=0.003). Although limited data are available on the comparative safety and effectiveness of different GP IIb/IIIa receptor antagonists among patients with CKD, a subgroup analysis of the Do Tirofiban and ReoPro Give Similar Efficacy Outcome (TARGET) trial compared the outcomes of patients with renal insufficiency undergoing PCI who received either abciximab or tirofiban.⁶¹ The 4623 patients with a baseline SCr level available were divided into CrCl quartiles (<70, 70–90, 90–114, and >114 mL/min). Although the rates of both ischemic and bleeding events were higher among patients with lower creatinine clearances, there was no interaction between the assigned GP IIb/IIIa receptor antagonist, CrCl, and clinical outcome.

An analysis of the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial provided outcome data on the upstream use of GP IIb/IIIa receptor antagonists among patients presenting with ACS.⁵⁶ This analysis showed tirofiban therapy to be effective in reducing ischemic events, with no evidence of treatment-by-CrCl interaction. Additionally, although decreasing renal function (P<0.001) and tirofiban (P<0.001) were each associated with an increased risk for bleeding events, tirofiban therapy was not associated with an incremental increase in the risk for hemorrhage among those with CKD. A subgroup analysis of the Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial provided a comparative assessment of the early versus delayed provisional use of eptifibatide among patients with CKD presenting with non–ST-segment elevation ACS in whom coronary angiography was planned.⁶² This was the first large-scale randomized trial of eptifibatide that used the currently recommended dosing regimen of 2 μg·kg⁻¹·min⁻¹ for patients with CrCl ≥50 mL/min and 1 μg·kg⁻¹·min⁻¹ for patients with CrCl <50 mL/min, with patients requiring dialysis excluded from the trial. Among patients with CrCl <50 mL/min, early eptifibatide compared with a delayed provisional eptifibatide strategy was not associated with a reduction in the composite ischemic end point(s) at 96 hours or at 30 days. Among patients with CrCl <50 mL/min, rates of non–coronary artery bypass graft–related TIMI major bleeding and GUSTO severe/moderate bleeding were significantly higher with the early eptifibatide strategy.

In summary, data on the use of GP IIb/IIIa receptor antagonists in CKD patients with ACS indicate a reduction in ischemic events and a variable but overall increase in the risk of bleeding events. In addition, in a recent trial comparing a strategy of early versus delayed provisional GP IIb/IIIa receptor antagonist therapy in UA/NSTEMI patients, no reduction in ischemic events and an increase in bleeding events were seen with the early strategy in patients with CKD.⁶²

Although the existing data do not support a preferred GP IIb/IIIa receptor antagonist for use in patients with CKD, it is important that clinicians follow dosing recommendations for eptifibatide and tirofiban when either of these agents is used.

UFH has been a mainstay in the treatment of ACS for several decades.⁶³ Current guidelines recommend UFH as an anticoagulant option across the spectrum of ACS presentations.^26,42 Once administered, the primary route of UFH elimination is via the reticuloendothelial system, with renal clearance being a minor route for elimination.⁶⁴ Few data are available from early placebo-controlled trials on the treatment effect of UFH therapy in CKD patients presenting with ACS. In addition, given that UFH has often been the standard anticoagulant with which newer agents have been compared, the outcome data for UFH use in CKD patients will be discussed in the sections below.

Fondaparinux is an indirect factor Xa inhibitor that has recently been evaluated in the management of patients presenting with ACS. Current guidelines for fondaparinux in ACS patients include a Class I recommendation for fondaparinux use as an adjunctive anticoagulant for STEMI patients receiving fibrinolytic therapy and a Class I recommendation for UA/NSTEMI patients being managed with either an invasive or conservative strategy.^26,73 In addition, the guidelines recommend fondaparinux as the preferred anticoagulant in UA/NSTEMI patients being managed with a conservative strategy who have an increased risk of bleeding.⁷³ Fondaparinux is primarily excreted unchanged through renal elimination, and is contraindicated in the United States for patients with severe CKD (CrCl <30 mL/min).⁷⁴

The Organization for the Assessment of Strategies for Ischemic Syndromes (OASIS) 5 trial compared fondaparinux to enoxaparin in 20 078 patients with non–ST-segment– elevation ACS randomized to fondaparinux 2.5 mg subcutaneously once daily or enoxaparin 1 mg/kg subcutaneously twice daily (dose adjusted to 1 mg/kg once daily in patients with CrCl <30 mL/min).⁷⁵ Although patients with SCr >3 mg/dL were excluded, a specific analysis was designed to examine efficacy and safety outcomes by quartiles of GFR (as estimated by the MDRD formula).⁶⁹ This study showed a direct relationship between degree of renal impairment and the risk of death, MI, refractory ischemia, and bleeding. Among patients with a GFR ≥58 mL·min⁻¹·1.73 m⁻², no significant difference was seen between treatment groups in the primary composite outcome of death, MI, or refractory ischemia at 9 days. However, at 30 days, the rate of the primary composite outcome was significantly lower among patients with a GFR <58 mL·min⁻¹·1.73 m⁻² with fondaparinux (HR, 0.81; 95% CI, 0.69–0.96). Fondaparinux treatment was associated with lower rates of major bleeding events at 9 days among patients with a GFR <58 mL·min⁻¹·1.73 m⁻² (HR, 0.42; 95% CI, 0.32–0.56). In addition, in the subgroup of patients with CrCl <30 mL/min, the rates of major bleeding at 9 days were significantly lower in the group receiving fondaparinux (2.4% versus 9.9%, P=0.001).⁷⁵ Although the rates of major bleeding were lower with fondaparinux across all quartiles of estimated GFR, the difference was most marked among patients with a GFR <58 mL·min⁻¹·1.73 m⁻².⁶⁹

Bivalirudin, a bivalent direct thrombin inhibitor, has been well studied in patients undergoing PCI, including patients presenting with ACS. Current guidelines recommend bivalirudin as an anticoagulant option in STEMI patients undergoing primary PCI (Class I) and in UA/NSTEMI patients in whom an invasive strategy is selected (Class I).^26,42 Elimination of bivalirudin occurs through both proteolysis and renal clearance. In patients with normal renal function (CrCl > 90mL/min) or mildly impaired renal function (CrCl >60 mL/min), the pharmacokinetics of bivalirudin are linear, with an elimination half-life of 25 minutes. The elimination half-life is increased to 34 to 57 minutes in patients with moderate to severe renal impairment (CrCl between 10 and 59 mL/min) and ≈3.5 hours in patients with renal failure necessitating hemodialysis.^76–78 For patients with renal insufficiency, the product labeling recommends no reduction in the bolus dose for any degree of renal impairment, although the infusion dose of bivalirudin may need to be reduced and anticoagulant status monitored in patients with renal impairment (Table 1).²⁸ Data from randomized trials and observational studies on the use of bivalirudin in ACS patients with CKD are shown in Table 7.

A meta-analysis⁷⁹ of 3 randomized trials comparing bivalirudin with UFH at the time of PCI (majority ACS) stratified by CrCl >90 mL/min (n=1578), CrCl 90 to 60 mL/min (n=2163), CrCl 59 to 30 mL/min (n=1255), and CrCl <30 mL/min (n=39) showed an increasing risk of ischemic and bleeding events with increasing degrees of renal impairment. The absolute benefit of bivalirudin on the ischemic and bleeding composite end point increased with decreasing CrCl strata (2.2%, 5.8%, 7.7%, and 14.4%, respectively; P_interaction=0.044). Similarly, the association of CKD with adverse outcomes for patients undergoing PCI (43% ACS) randomized to bivalirudin and provisional GP IIb/IIIa inhibition or UFH and planned GP IIb/IIIa inhibition was examined in the Second Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events (REPLACE-2) trial.⁸⁰ Patients were grouped according to CrCl ≥60 mL/min (n=4824) and CrCl <60 mL/min (n=886). Among patients with CrCl <60 mL/min, rates of 30-day ischemic events (death, MI, or urgent revascularization) were 9.7% and 9.4% (P=0.870) in the bivalirudin and UFH and GP IIb/IIIa receptor antagonist groups, respectively, but there were significantly lower rates of TIMI major or minor hemorrhage (3.2% versus 7.1%; P=0.009) with bivalirudin. There was no observed interaction between treatment, bleeding or ischemic events, and renal function. Although these bivalirudin studies excluded dialysis-dependent patients, a retrospective analysis comparing bivalirudin with UFH (GP IIb/IIIa receptor antagonists were excluded) in dialysis-dependent patients undergoing PCI showed no significant difference in the rates of in-hospital major bleeding (3.4% versus 3.1%, respectively; P=0.9)⁸¹ or in the rates of the primary composite ischemic end point of in-hospital death, Q-wave MI, and urgent target-vessel revascularization (1.8% versus 0.8%, respectively; P=0.7).

Analyses from 2 randomized trials provide data on the association of CKD with outcomes among patients with ACS receiving bivalirudin. In a substudy of the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, Mehran and colleagues⁸² showed that patients with CKD (defined as CrCl <60 mL/min) had worse 30-day and 1-year clinical outcomes than those with normal renal function. Patients with CrCl <30 mL/min were excluded from this trial. There were no significant differences between bivalirudin monotherapy and heparin plus a GP IIb/IIIa receptor antagonist in rates of 30-day composite ischemia (11.1% versus 9.4%; P=0.27) and net clinical adverse outcomes (16.1% versus 16.9%; P=0.65). There was significantly less major bleeding (6.2% versus 9.8%; P=0.008) at 30 days but no significant difference in 1-year composite ischemia (22.0% versus 18.9%; P=0.10) or mortality (7.1% versus 7.3%; P=0.96). A substudy of the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial provided an assessment of the association of CKD with outcomes with bivalirudin use among patients undergoing primary PCI. Approximately 15% of patients enrolled had CrCl of 30 to 60 mL/min, whereas 1.4% had CrCl of ≤30 mL/min. This analysis showed patients with CKD had higher rates of clinical events at 30 days, including death and major bleeding.⁸³ Multivariable analysis identified baseline creatinine as an independent predictor of death at 3 years (HR, 1.51; 95% CI, 1.21–1.87; P<0.001). Patients with CKD (defined as CrCl <60 mL/min) randomized to bivalirudin monotherapy versus heparin plus GP IIb/IIIa receptor antagonist had no significant difference in major bleeding (12.3% versus 15.3%; HR, 0.79; 95% CI, 0.50–1.25) or death (8.4% versus 7.9%; HR, 1.09; 95% CI, 0.61–1.95) at 30 days.

Taken collectively, the randomized controlled trial data on anticoagulation therapy in CKD patients presenting with ACS are limited by the underrepresentation of patients with stage 4 and 5 CKD, which makes definitive conclusions about the treatment effect of anticoagulant agents challenging. Although a number of trials excluded patients with CrCl <30 mL/min, the ExTRACT-TIMI-25, OASIS-5, and HORIZONS-AMI trials did not.^75,84,85 The association of treatment with enoxaparin and increased bleeding risk with worsening renal function observed in the ExTRACT-TIMI-25 trial, as well as the increased rates of major bleeding in patients with CrCl <30 mL/min with enoxaparin therapy observed in the OASIS-5 trial, suggests that caution is warranted when enoxaparin is used in this population.^67,75

β-Blockers are recommended for all patients with ACS unless contraindicated.^86,87 Metoprolol, atenolol, and propranolol have been studied in the setting of AMI, and carvedilol has been studied in the setting of AMI with left ventricular dysfunction.^88–92 Atenolol is renally eliminated and requires dose adjustment in those with renal impairment. Dose adjustment is recommended with CrCl <35 mL/min (50 mg once daily for 15–35 mL/min and 25 mg once daily for CrCl <15 mL/min).⁹³ Metoprolol, propranolol, and carvedilol are all extensively hepatically metabolized, with <5% of an oral dose excreted in the urine unchanged, so they do not require dose adjustments in renal impairment. Observational studies assessing CKD patients have analyzed all β-blockers together. Data on the use of β-blockers for ACS patients with CKD are summarized in Table 8.

Limited data are available from randomized trials on the use of β-blockers in ACS in patients with CKD. A post hoc analysis of pooled data from patients enrolled in the Carvedilol Postinfarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) and Carvedilol Prospective Randomized, Cumulative Survival (COPERNICUS) trials assessed carvedilol therapy in MI patients with left ventricular dysfunction (CAPRICORN) and in chronic systolic heart failure patients with CKD (COPERNICUS).⁹⁴ In the group of patients with CKD (defined as eGFR ≤60 mL·min⁻¹·1.73 m⁻²), treatment with carvedilol was associated with a reduction in all-cause mortality (HR, 0.76; 95% CI, 0.63–0.93) and cardiovascular mortality (HR, 0.77; 95% CI, 0.62–0.94). However, a sensitivity analysis among the subgroup of patients with an eGFR <45 mL·min⁻¹·1.73 m⁻² (n=1116) failed to show a significant benefit for carvedilol therapy with regard to the primary or secondary outcomes. Several observational cohort studies have evaluated whether β-blockers were beneficial among patients with various degrees of renal impairment. These observational studies have found that the benefit of discharge β-blocker use was preserved across all degrees of renal dysfunction.^2,32,38,95 One of the largest observational studies evaluated Medicare beneficiaries with AMI included in the ESRD program as part of the Cooperative Cardiovascular Project (CCP).¹⁹ This study identified a cohort of 145 765 patients with AMI, among whom 1025 had stage 5D CKD. They found that although β-blocker use did not reduce mortality to as great an extent among those receiving dialysis as among those without ESRD, the benefit was still significant. β-Blocker use was associated with a 40% relative reduction in mortality among those undergoing dialysis and a 56% relative reduction among those without ESRD (P<0.001 for both groups).¹⁹

Collectively, the data from randomized and observational studies support the routine use of β-blocker therapy in CKD patients presenting with ACS when no contraindications are present.

For patients with ACS, angiotensin-converting enzyme (ACE) inhibitors are recommended by current guidelines to be initiated and continued indefinitely in all patients with a left ventricular ejection fraction <40% and for those with hypertension, diabetes mellitus, and CKD unless contraindicated.^73,87 For patients who are considered intolerant to ACE inhibitors, angiotensin receptor blockers (ARBs) can be considered as an alternative.^73,87 These Class I recommendations are based on data from several large randomized trials and meta-analyses documenting significant reductions in mortality among patients with ACS, in which the greatest benefit was demonstrated when angiotensin blockade was administered within the first 24 hours after an MI.^96–100 Additionally, receipt of an ACE inhibitor or ARB after ACS for patients with left ventricular systolic dysfunction at the time of hospital discharge has become an important reportable quality performance measure via which many hospitals are compared.¹⁰¹ Unfortunately, among patients with renal dysfunction, these evidenced-based pharmacotherapies in the hospital and at discharge are often significantly underused, particularly for those with ESRD.^{3,19,21,102–107}

The most common concerns with ACE inhibitors or ARBs include perceived worsening renal function and hyperkalemia.¹⁰⁸ There is no absolute level of SCr that precludes the use of these agents; however, if the SCr exceeds 2.5 mg/dL, caution is warranted.^109,110 In a review of 12 randomized controlled trials of ACE inhibitor use in patients with renal dysfunction (SCr >1.4 mg/dL), acute increases in SCr of up to 30% that stabilized within the first 2 months of therapy initiation were associated with a 55% to 75% risk reduction in renal disease progression compared with those with normal renal function.¹¹¹ Practically, the use of ACE inhibitors or ARBs can be considered in patients with CKD as long as the SCr does not increase beyond this point and the serum potassium remains <5.5 mEq/L.¹¹² For patients with ESRD, the administration of these medications can be problematic. The use of ACE inhibitors or ARBs in patients undergoing chronic dialysis has been associated with an increased risk of hyperkalemia, although study results have been variable.^113–115

Most of the large randomized controlled trials evaluating the effectiveness of ACE inhibitors or ARBs in post-MI patients with left ventricular dysfunction have excluded patients with ESRD, with SCr cut offs ranging from 2 to 3.4 mg/dL. Nonetheless, the ability of these agents to prevent ventricular dilation and to significantly improve mortality for patients with compromised cardiac function should not be underestimated. Although randomized trials of ACE inhibitor therapy in ACS have systematically excluded patients with ESRD, the Fosinopril in Dialysis (FOSIDIAL) study was undertaken in chronic ESRD patients to assess the impact of fosinopril therapy on cardiovascular events.¹¹⁶ No significant benefit was seen with fosinopril in the intention-to-treat analysis for the composite of cardiovascular events (RR, 0.93; 95% CI, 0.68–1.26), although a per protocol analysis suggested a trend toward benefit for fosinopril (RR, 0.79; 95% CI, 0.59–1.1). Subgroup analyses from randomized trials and observational studies have suggested that among patients with ACS with reduced left ventricular ejection fraction, the use of ACE inhibitors or ARBs may be more beneficial when renal insufficiency coexists.^{103,117–122} Data on the use of ACE inhibitors or ARBs in ACS patients with CKD are summarized in Table 9.

In summary, the data on the use of ACE inhibitors in patients with post-MI left ventricular dysfunction and CKD consistently show improved outcomes with ACE inhibitor therapy. Caution is warranted at the time of initiation, and monitoring of serum creatinine and potassium is required.

According to the American College of Cardiology/American Heart Association guidelines, the use of aldosterone antagonists such as spironolactone and eplerenone have a Class IA recommendation for post-MI patients who are receiving therapeutic doses of an ACE inhibitor and a β-blocker, have a left ventricular ejection fraction <40%, and have either diabetes mellitus or heart failure.⁸⁷ These recommendations are primarily derived from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) trial, which demonstrated a 15% all-cause mortality risk reduction (P=0.008) and a 13% reduction in cardiovascular-related mortality or cardiovascular hospitalizations (P=0.002) among post-MI patients with a left ventricular ejection fraction ≤40% who received eplerenone 25 to 50 mg/d in addition to background heart failure therapy with an ACE inhibitor or ARB and β-blocker.¹²³ However, important exclusion criteria for the EPHESUS trial were SCr >2.5 mg/dL or a serum potassium >5.0 mEq/L. Serious hyperkalemia (≥6.0 mEq/L) occurred in 5.5% of patients receiving eplerenone compared with 3.9% in the placebo group (P=0.002). For patients with CrCl <50 mL/min, the incidence of serious hyperkalemia increased to 10.1% among those receiving eplerenone compared with 5.9% in the placebo group (P=0.006). Since the publication of the Randomized Aldactone Evaluation Study (RALES), concerns have been raised regarding the increased risk of life-threatening hyperkalemia attributable to aldosterone antagonists, particularly when combined with angiotensin blockade.¹²⁴ Therefore, the American College of Cardiology/American Heart Association guidelines recommend against using aldosterone blockade if significant renal dysfunction (SCr >2.5 mg/dL in men and >2.0 mg/dL in women) or hyperkalemia (serum potassium >5.0 mEq/L) coexists.⁸⁷

A post hoc analysis of the EPHESUS trial evaluated serial changes in eGFR related to eplerenone use in patients after ACS. In this analysis, Rossignol et al¹²⁵ found that 5792 patients assigned to eplerenone 25 to 50 mg/d had a significant decline in their eGFR, with a mean adjusted difference of −1.4±0.3 mL·min⁻¹·1.73 m⁻² compared with placebo (P<0.0001). This effect occurred within the first month and persisted throughout the 24-month follow-up. Patients receiving eplerenone had a 1.15-fold increased odds of experiencing a >20% decline in eGFR within the first month compared with placebo (P=0.017).¹²⁵ However, an eGFR ≤60 mL·min⁻¹·1.73 m⁻² was not associated with early worsening renal function, and there was no interaction between worsening renal function and the favorable effects of eplerenone on cardiovascular death or hospitalization (P=0.77 for interaction) and hospitalization for heart failure (P=0.82 for interaction).¹²⁵

A large body of literature supports of the use of statins after an ACS to reduce the risk of death or vascular events. Current guidelines recommend statins regardless of baseline low-density lipoprotein level in all ACS patients in the absence of contraindications.^26,27 With regard to CKD patients, those receiving chronic dialysis in particular, the use of statins has been more controversial. No randomized controlled trials have assessed the safety and efficacy of statins in patients with ACS and CKD. Furthermore, patients with SCr >2 mg/dL were excluded from the original ACS randomized trials of early initiation of statins.^126,127 However, in primary prevention, randomized trials of statin therapy in patients with CKD have yielded mixed results.^128–131 Early studies found no benefit of statin therapy among patients with CKD (mostly dialysis dependent),^129–131 which led to speculation that in ESRD, there may be a more advanced atherosclerotic state that leads to more sudden deaths caused by arrhythmias than among patients without ESRD. However, more recently, the largest of these studies, the Study of Heart and Renal Protection (SHARP), included patients with CKD both on dialysis and not on dialysis and showed a benefit of simvastatin plus ezetimibe therapy on the risk of the primary composite end point of first major atherosclerotic event (RR, 0.83; 95% CI, 0.74–0.94; P=0.0021), although no statistically significant difference was observed for the risk of vascular death (RR, 0.93; 95% CI, 0.80–1.07).¹²⁸ Although statin trials in ACS have largely excluded patients with CKD, observational studies have evaluated the safety and efficacy of statins in these patients.^32,132–134 The data on the use of statins in ACS patients with CKD are summarized in Table 10. The Korea Acute Myocardial Infarction Registry (KAMIR) study was observational and evaluated 12 865 patients with MI, 3256 of whom had renal dysfunction (defined as eGFR <60 mL·min⁻¹·1.73 m⁻²).¹³² The study found that patients with renal dysfunction not taking statins were at significantly increased risk of in-hospital and 1-month major adverse cardiovascular events and cardiac death at 1 year. These results were also consistent among those with severe renal insufficiency (eGFR <30 but ≥15 mL·min⁻¹·1.73 m⁻² and eGFR <15 mL·min⁻¹·1.73 m⁻²).¹³² Although the Cholesterol and Recurrent Events (CARE) study excluded participants with >2+ proteinuria or SCr >1.5 times the upper limit of normal, subgroup analysis of those with mild renal insufficiency (CrCl ≤75 mL/min) found that pravastatin reduced the risk of death of coronary disease or symptomatic nonfatal MI by 28% (adjusted HR, 0.72; 95% CI, 0.55–0.95; P=0.02) among patients with AMI between 3 and 20 months before randomization (Table 10).¹³⁵ The analysis also found that adverse events were infrequent among those with chronic renal insufficiency, with no significant differences in frequency compared with placebo.¹³⁵

Taken together, these data show a consistent benefit with regard to a reduction in cardiovascular events with statin therapy in CKD patients who present with ACS and support the routine use of statins in this population. However, the data are somewhat limited by the lack of information on statin dose, as well as medication side effects. These are important considerations, because patients with CKD may be at higher risk for muscle-related side effects associated with statin therapy,¹³⁶ although randomized trials evaluating moderate-intensity statin therapy in patients with advanced CKD (including ESRD) without ACS have not supported this observation.^128,129,131