Current Cardiology Reports

, 15:386

Patients with Chronic Kidney Disease/Diabetes Mellitus: The High-Risk Profile in Acute Coronary Syndrome

Authors

    • The Zena and Michael A. Wiener Cardiovascular InstituteThe Icahn School of Medicine at Mount Sinai
  • Uschi Auguste
    • The Zena and Michael A. Wiener Cardiovascular InstituteThe Icahn School of Medicine at Mount Sinai
Management of Acute Coronary Syndromes (R Mehran, Section Editor)

DOI: 10.1007/s11886-013-0386-y

Cite this article as:
Baber, U. & Auguste, U. Curr Cardiol Rep (2013) 15: 386. doi:10.1007/s11886-013-0386-y
Part of the following topical collections:
  1. Topical Collection on Management of Acute Coronary Syndromes

Abstract

Chronic kidney disease (CKD) and diabetes mellitus (DM) are highly prevalent, morbid diseases that are very common among patients presenting with acute coronary syndromes (ACS). Despite significant reductions in cardiovascular morbidity and mortality over the last half century, residual vascular risk remains disproportionately high in these populations. In large part, this is attributable to pre-existing vascular morbidity and substantial enrichment of traditional risk factors among those with either CKD or DM. Other factors, such as less aggressive therapeutic intervention and a unique atherothrombotic phenotype, are also contributory. The introduction of novel antiplatelet and antithrombotic agents over the last several years provides fresh opportunities to improve the adverse prognosis among patients with CKD or DM and concomitant ACS.

Keywords

Diabetes mellitusChronic kidney diseaseAcute coronary syndrome

Introduction and Epidemiology

In the early 1900s, management of acute myocardial infarction primarily involved prolonged bed rest and use of digitalis [1]. Post-MI prognosis was largely unchanged by mid-century with an in-hospital mortality rate approaching 30 % [2]. Over the last 60 years, however, substantial strides in the prevention, diagnosis and management of cardiovascular disease (CVD) have led to marked reductions in CVD-related morbidity and mortality [3••]. In large part, this revolution in cardiovascular medicine can be traced to landmark epidemiologic studies elucidating underlying risk factors for heart disease [4], improvements in post-MI care through continuous telemetry monitoring [5], large scale public health awareness programs and the development of novel medical and device-based interventions. Although impressive, these advances must be tempered with the sobering reality that CVD remains the leading cause of death in industrialized nations and is an ever growing concern for middle and low income countries. In addition, CVD risk remains disproportionately high in certain populations, including those with underlying chronic kidney disease (CKD) and diabetes mellitus (DM) [3••, 6].

CKD and DM are highly morbid disease states affecting approximately 13.1 % and 8.3 % of the stable US adult population, respectively [7, 8]. In the acute coronary syndrome (ACS) setting prevalence is even higher, as CKD and DM are present in up to 43 % and 27 % of patients presenting with non-ST segment elevation MI (NSTEMI) [9••, 10]. Both conditions are enriched with traditional risk factors and CVD remains the leading cause of morbidity and mortality for both populations. The public health and fiscal implications of CKD and DM are highlighted by their rising incidence and substantial health care expenditures resulting from disease-related complications. For example, direct costs attributable to dialysis-dependent renal failure and DM were $26.8 billion and $116 billion in 2008 and 2007, respectively [11, 12]. These figures are expected to grow substantially as the population ages and contributing risk factors such as obesity and hypertension continue to increase.

Epidemiologic observations linking CKD and DM to increased cardiac risk were initially made 15 and 40 years ago, respectively [13, 14]. These associations have remained remarkably consistent over time as multiple studies involving various patient populations and different clinical settings have shown higher relative and absolute risk for adverse events due to either condition [14]. Findings are unchanged even in contemporary randomized ACS trials using state of the art pharmacotherapy and device-based therapeutics. In the PLATO (Platelet inhibition and patient Outcomes) trial, for example, patients with DM (n = 4662, 25 %) were at significantly increased risk for all-cause death (HR (95 % CI): 1.84, 1.61-2.10) and MI (1.53 (1.35-1.73) compared to those without DM [15]. In a separate report, Mehran et al. found that patients with CKD enrolled in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategy) trial were at significantly increased risk for composite ischemia (21.6 % vs. 14.4 %, p < 0.001) and mortality (7.9 % vs. 2.8 %, p < 0.001) at 1 year [16].

In this report we will explore the unique clinical and pathophysiologic aspects of these patient populations that might contribute to increased cardiac risk and the potential role of novel therapeutic agents in the context of ACS.

ACS Presentation in CKD or DM

The clinical spectrum of ACS ranges from unstable angina to ST-segment elevation MI, which corresponds to a pathophysiological substrate of partially to completely occlusive thrombus superimposed on a ruptured or eroded atherosclerotic plaque [17]. Identification of patients with any type of ACS is based on clinical symptoms combined with corroborating biochemical or electrocardiographic data. Rapid identification, risk stratification and treatment initiation is necessary to optimize outcomes in high-risk ACS patients. Important differences in the timing and pattern of ACS presentation among patients with either CKD or DM compared to those with neither condition offers valuable insight on the adverse prognosis of these high-risk populations.

Rapid recognition of ACS among patients with CKD or DM is challenging as both conditions influence the clinical symptoms, electrical findings and biomarker data required for accurate diagnosis. The classical syndrome of substernal chest pain with or without left arm radiation (i.e., ‘typical’ chest pain) is significantly less common among such patients. In a study involving approximately 4000 patients with acute MI and using factor analysis, for example, Sosnov et al. demonstrated that symptoms of dyspnea were strongly correlated with CKD (odds ratio (95 % CI): 1.73, 1.40 – 2.15), while chest pain was much less common (0.48, 0.41-0.57) [18]. Similar findings have been reported by others in the setting of DM [19, 20]. In addition, electrical disturbances comprising arrhythmias, conduction defects and overt bundle branch block are common among those with CKD or DM thereby complicating the accurate interpretation of electrocardiographic findings at the time of ACS presentation [21]. Moreover, serum biomarkers of myocardial necrosis, required to diagnose infarction, may be elevated in the setting of CKD or DM even in the absence of any underlying clinical symptoms. Studying healthy community-dwelling adults residing in Dallas County, for example, Wallace et al. found that CKD and DM were independently associated with a 5 and 20 fold increased odds for elevated Troponin T, respectively [22]. These intriguing findings highlight the potential complexities in using serum biomarkers to diagnose ACS among those with CKD or DM and suggest that different diagnostic thresholds may be warranted in these populations.

Diagnostic challenges notwithstanding, optimal management of high-risk ACS patients with CKD or DM is further complicated by more advanced presentation, greater extent and complexity of angiographic coronary artery disease and treatment delays. Perhaps most relevant are signs and symptoms of hemodynamic instability complicating ACS among these patients. In the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress adverse outcomes with Early Implementation of the American College of Cardiology/American Heart Association guideline) registry, for example, signs of congestive heart failure (CHF) were significantly more common among those with vs. without CKD (43.7 % vs. 19.8 %, p < 0.001) [23]. Not surprisingly, CKD was also significantly associated with developing in-hospital cardiogenic shock (OR 1.37, 95 % CI: 1.16-1.61). Analogously, data from the (GRACE (Global Registry of Acute Cardiac Events) registry demonstrated that presentation with and development of heart failure was significantly higher among those with vs. without DM across the entire spectrum of ACS [10]. The clinical relevance of these findings is highlighted by the fact that ACS complicated by heart failure or shock is a strong and independent correlate of both short and long-term mortality following MI [24, 25].

Pathways for Increased Risk in CKD or DM Following ACS

Traditional Risk Factors

CKD and DM share common risk factors, suggesting similarities in the underlying pathophysiologic substrate for both conditions. More specifically, patients with either abnormality tend to be older, more often female and hypertensive compared to their non-CKD or non-DM counterparts [9••, 10]. Overlap is also substantial as many patients with CKD are also diabetic and vice versa. Prior manifestations of vascular disease including stroke or lower extremity peripheral arterial disease are also highly prevalent in the renal and diabetic populations [26]. Such pre-existing vascular morbidity and traditional risk factor enrichment account for a large proportion of the attributable risk due to CKD or DM following ACS. In a recent multicenter study involving over 4000 patients with MI, for example, Nagashima et al. found that traditional morbidities including older age, hypertension and prior coronary revascularization increased in a dose-dependent fashion with worsening renal function [27]. Compared to those with an estimated glomerular filtration rate (eGFR) > 75 ml/min/1.73 m2, the crude hazard ratios (HR, 95 % CI) for long-term death were 3.95 (3.12-5.00), 1.63 (1.28-2.07) and 1.01 (0.78-1.30) among those with an eGFR < 45, 45-59.9 and 60-74.9 ml/min/1.73 m2, respectively. The analogous values after adjustment, however, were 1.92 (1.50-2.45), 1.10 (0.87-1.41) and 0.88 (0.68-1.14), with a significant association only among those with eGFR < 45 ml/min/1.73 m2. These findings demonstrate that despite their importance, traditional risk factors are unable to fully account for the markedly excess risk among those with CKD or DM as adjustment for these parameters only provides partial, rather than complete, attenuation on the observed associations.

Risk Treatment Paradox

Withholding potentially beneficial therapies in high-risk patients (i.e., risk-treatment paradox) has been well documented in multiple clinical settings and patient populations [28, 29]. A recent report by Marso et al., for example, demonstrated that bleeding avoidance strategies at time of percutaneous coronary intervention were used less frequently among those at highest risk for bleeding complications [30]. A similar paradigm is also apparent in the setting of CKD and DM vis a vis ACS treatment. Using data from a contemporary national registry of NSTEMI and STEMI patients, Fox et al. recently evaluated the associations between renal function, ACS treatments and outcomes [9••]. Compared to those without CKD, patients with advanced stage 4 or stage 5 CKD were approximately 50 % less likely to receive any reperfusion or any revascularization following STEMI and NSTEMI, respectively. In addition, prescription of evidence-based discharge medications including aspirin, clopidogrel, beta-blockers and statins decreased with worsening renal function. Even discharge counseling for cardiac rehab or exercise was used much less frequently among those with greater levels of renal impairment. Similar findings have been reported by others in the setting of DM. Using data from a national Swedish registry of STEMI and NSTEMI patients, for example, Norhammar et al. demonstrated that diabetic patients were less likely to receive aspirin, lipid lowering drugs and undergo revascularization within 14 days compared to those without DM [31]. In a separate registry of STEMI patients, Gitt et al. also found that aspirin (89.9 % vs. 91.0 %, p = 0.04), beta-blocker (66.2 % vs. 70.7 %, p < 0.001) and statin (36.6 % vs. 37.0 % p = 0.06) use was less common among those with vs. without DM [32]. Complicating the issue of withholding treatment at the time of ACS is the fact that patients with CKD or DM are also less likely to receive evidence-based therapies in the outpatient stable setting [33, 34]. Even when on therapy, these patients are less likely to reach recommended therapeutic targets compared to those without CKD or DM [33, 34]. In aggregate, these findings not only provide insight on increased cardiac risk among these patients but also provide opportunities to address critical gaps in care that might substantially improve prognosis after ACS.

Unique Pathophysiology

The sine qua non of atherothrombosis is the interaction between elements of circulating blood and the atherosclerotic plaque, culminating in thrombotic events such as myocardial infarction. Both CKD and DM are prothrombotic, inflammatory conditions resulting in high-risk atherothrombotic phenotypes (Fig. 1). Pathologic abnormalities associated with DM such as insulin resistance and hyperglycemia, for example, directly modulate platelet function leading to high levels of platelet reactivity even in the absence of CKD [35]. Similarly, high levels of circulating procoagulant factors and abnormalities of nitric oxide synthesis may account for platelet hyperreactivity among those with renal dysfunction with or without concomitant DM [3638]. In a recent study, we evaluated the combined influence of both conditions on residual platelet reactivity to clopidogrel among patients undergoing PCI [39]. When considered together, we found that CKD and DM exert a synergistic impact on platelet function and may be an important contributor to increased risk among such patients. In addition to augmenting platelet reactivity, however, CKD and DM are also associated with high levels of circulating inflammatory and procoagulant biomarkers, suggesting alternative pathways by which blood thrombogenicity might be enhanced. In a cross-sectional analysis of elderly community dwelling adults, for example, Shlipak et al. found graded and independent associations between renal dysfunction and increasing levels of serum fibrinogen and C-reactive protein [40]. Similar findings have been reported by others in the setting of DM [41, 42]. These physiological differences might translate into larger and more stable thrombus formation at the time of ACS. Using a validated ex-vivo perfusion model to study platelet-dependent thrombus formation, for example, Rauch et al. demonstrated that thrombus size was significantly larger among those with vs. without DM [43]. Moreover, thrombus size was linearly associated with serum glucose levels [44]. In a separate report we also found a graded, linear association between eGFR and time to thrombus formation demonstrating that thrombus formation was most rapid among those with the most severe renal dysfunction [45]. These pathophysiological studies provide insight and a biologic rationale for the varying response to antiplatelet agents and differences in infarct size among those with CKD or DM at time of ACS [46, 47].
https://static-content.springer.com/image/art%3A10.1007%2Fs11886-013-0386-y/MediaObjects/11886_2013_386_Fig1_HTML.gif
Fig. 1

Risk factor relationships contributing to a unique atherothrombotic phenotype in CKD and DM

Management of ACS

Pharmacotherapy for ACS is fundamentally grounded in dual inhibition of the coagulation cascade and platelet aggregation (Table 1). This paradigm emerged from landmark studies in the 1980s demonstrating the profound benefits of thrombolytic therapy, unfractionated heparin and aspirin in acute myocardial infarction patients [4850]. Since then, additional studies have shown the incremental advantages of novel antithrombotic and antiplatelet agents providing the present-day clinician a broad therapeutic armamentarium when managing high-risk ACS populations (Table 2).
Table 1

Antiplatelet and anticoagulation therapies used in management of acute coronary syndromes

Therapy class

Mechanism of action

Drug

Indication

Cyclooxygenase inhibitors

Cyclooxygenase-1 inhibitor which inhibits synthesis of thromboxane A2 causing irreversible inhibition of platelet aggregation

Aspirin

ACS type: NSTEMI; STEMI

Management: invasive/conservative

ADP P2Y12 receptor antagonists

inhibits ADP–dependent activation of the glycoprotein IIb/IIIa complex, and subsequently platelet aggregation

  

Thienopyridine

 

Clopidogrel

ACS type: NSTEMI; STEMI

Management: invasive/conservative

  

Prasugrel

ACS type: NSTEMI; STEMI

Management: invasive

Contraindicated in patient with stroke

Non-thienopyridine

oral reversible direct acting antagonist of the P2Y12 receptor

Ticagrelor

ACS type: NSTEMI; STEMI

Management: invasive/conservative

GP IIb/IIIa inhibitors

inhibit the glycoprotein IIb/IIIa receptor, which is involved in the final common pathway for platelet adhesion and aggregation

Eptifibatide

ACS type: NSTEMI; STEMI

Management: invasive/conservative

  

Tirofiban

ACS type: NSTEMI; STEMI

Management: invasive/conservative

  

Abciximab

ACS type: NSTEMI; STEMI

Management: invasive

Indirect thrombin inhibitors

Binds antithrombin and the resultant complex inhibits thrombin, factor Xa, and factor IXa

Unfractionated heparin

ACS type: NSTEMI; STEMI

Management: invasive/conservative

  

Low molecular weight heparin: Enoxaparin

ACS type: NSTEMI; STEMI

Management: invasive/conservative

Direct thrombin inhibitors

bind to the active site as well as substrate recognition site thrombin and block its fibrin interaction

Bivalirudin

ACS type: High risk ACS

Management: invasive

Factor Xa inhibitors

bind to the active site of Xa, both the free form and within the prothrombinase complex, and block its thrombin interaction

Fondaparinux

ACS type: NSTEMI; STEMI

Management: invasive/conservative

Table 2

Results of sub-group analyses of major trials comparing the efficacy and safety of antiplatelet therapies for acute coronary syndrome management in patients with diabetes or chronic kidney disease

Cardiovascular deaths, non-fatal MI or stroke endpoints in participants with CKD or DM

 

Cardiovascular death, non-fatal MI or stroke HR

  

Study intervention

Primary outcomes

DM

CKD

Antiplatelet therapies Trials

CURE

clopidogrel and aspirin vs aspirin alone

cardiovascular death, non-fatal MI or non-fatal stroke

0.79

0.89 (0.76-1.05)

 

TRITON TIMI 38

Prasugrel vs clopidogrel

cardiovascular death, non-fatal MI or non-fatal stroke

0.7 (0.58-0.85)

0.86 (no CI reported)

 

ACUITY

bivalirudin monotherapy vs heparin plus a glycoprotein IIb/IIIa inhibitor (GPI)

ischemia and major bleeding

0.92 (0.68-1.25)

1.18 (0.88-1.57)

 

PLATO

ticagrelor vs clopidogrel

cardiovascular death, non-fatal MI or non-fatal stroke

0.88 (0.76-1.03)

0.71 (0.59-0.86)

Major bleeding endpoints in participants with CKD or DM

 

Major Bleeding HR

  

Study intervention

Primary outcomes

DM

CKD

Antiplatelet therapies Trials

CURE

clopidogrel and aspirin vs aspirin alone

cardiovascular death, non-fatal MI or non-fatal stroke

n/a

1.37 (0.89-2.12)

 

TRITON TIMI 38

Prasugrel vs clopidogrel

cardiovascular death, non-fatal MI or non-fatal stroke

1.06 (0.66-1.69)

n/a

 

ACUITY

bivalirudin monotherapy vs heparin plus a glycoprotein IIb/IIIa inhibitor (GPI)

ischemia and major bleeding

0.58 (0.36-0.93)

0.64 (0.45-0.89)

 

PLATO

ticagrelor vs clopidogrel

cardiovascular death, non-fatal MI or non-fatal stroke

1.13 (0.86-1.49)

1.07 (0.97-1.19)

ACUITY acute catheterization and urgent intervention triage strategy

CURE clopidogrel in unstable angina to prevent recurrent events trial

PLATO platelet inhibition and patient outcomes

TRITON TIMI 38 trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel–thrombolysis in myocardial infarction 38

Antiplatelets

Aspirin (ASA) reduces platelet aggregation induced by thromboxane A2 synthesis [51] and its administration in all ACS patients is considered a class I, level of evidence A recommendation [52]. Targeting additional pathways of platelet activation, such as the adenosine diphosphate (ADP) P2Y12 and glycoprotein IIb/IIIa receptors, further reduces ischemic events albeit at an increased cost of bleeding. Thienopyridines inhibit platelet aggregation by irreversibly binding to the ADP P2Y12 receptor and are widely used in contemporary ACS pharmacotherapy. The safety and efficacy of the second generation thienopyridine clopidogrel was compared to placebo in non-ST segment elevation ACS patients in the landmark CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial [53]. Clopidogrel was associated with a significant 20 % reduction in composite ischemic events at 1 year (HR 0.80, 95 % CI 0.72-0.90). A concordant reduction of approximately 17 % in ischemic events was also observed CURE trial participants with DM (n = 2840, 22.6 %) [53]. Although still beneficial, results were modestly attenuated among those with eGFR < 64 ml/min (RR 0.89; 95 % CI: 0.76-1.05) [46]. Similar to the findings in the CURE trial, diabetic patients enrolled in the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel - Thrombolysis in Myocardial Infarction 38) trial derived a large and significant benefit in ischemic risk reduction with prasugrel vs. clopidogrel (12.2 % vs. 17.0 %, p < 0.001) [54]. Among those with CKD, however, results were less robust. Whether or not the numerically greater benefit in ischemic risk reduction observed with thienopyridines among those with DM vs. CKD reflects differences in platelet function or drug inhibition between these populations is unknown. In contrast to clopidogrel and prasugrel, ticagrelor is a reversible non-thienopyridine inhibitor of the P2Y12 receptor. Compared to clopidogrel, results of the PLATO trial demonstrated that ticagrelor was associated with a significant reduction in ischemic events without a significant increased risk for major bleeding in a broad population of ACS patients [15]. The overall effect was consistent in a subgroup analysis of diabetic patients (n = 4662) with no evidence of a treatment by diabetes interaction [55]. In contrast, ticagrelor use was associated with substantially greater reductions in the primary endpoint of cardiac death, stroke and MI among those with CKD (HR: 0.77; 95 % CI: 0.65-0.90) compared to those without renal dysfunction (HR: 0.90; 95 % CI: 0.79-1.02) [56]. Although intriguing, these results must be considered hypothesis generating given the lack of a clear biological mechanistic rationale and the post-hoc nature of subgroup analyses [57].

Antithrombotics

Initial studies evaluating alternatives to anticoagulation with intravenous (IV) unfractionated heparin (UFH) primarily involved low molecular weight heparins (LMWH). Advantages of these agents include a more predictable anticoagulant effect and lower risk of heparin induced thrombocytopenia [58, 59]. Compared to unfractionated heparin, the LMWH enoxaparin was associated with superior net clinical outcomes in several trials involving NSTEMI and STEMI patients [60, 61]. In the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial infarction Treatment-Thrombolysis in Myocardial Infarction 25) trial, for example, enoxaparin was compared to IV UFH among STEMI patients (n = 20,479) treated with fibrinolytics and ASA. Among diabetics (n = 3060), enoxaparin was associated with significant reductions in mortality (9.5 % vs. 11.8 %, p = 0.049), death or nonfatal MI (13.6 % vs. 17.1 %, p = 0.007) and death, nonfatal MI or urgent revascularization (16.0 % vs. 19.7 %, p = 0.007) [62]. Despite an increased risk for major bleeding, the net clinical benefit of death, nonfatal MI and nonfatal major bleed favored enoxaparin (14.8 % vs. 18.0 %, p = 0.19). While major bleeding increased with progressive renal dysfunction, the overall net clinical benefit was preserved among those with a creatinine clearance (CrCl) > 60 ml/min. Among patients with more severe levels of renal impairment, however, enoxaparin was associated with a higher numerical bleeding rate without any further ischemic risk reduction yielding no differences in the net clinical outcome [63].

Fondaparinux is a synthetic pentasaccharide that selectively binds antithrombin providing rapid inhibition of factor Xa [64]. In the landmark randomized OASIS-5 (Fifth Organization to Assess Strategies in Acute Ischemic Syndromes) trial, the safety and efficacy of fondaparinux versus enoxaparin was evaluated in a large population of NSTE ACS patients (n = 20,078) [65]. While there were no differences between groups at 9 days in death, MI or refractory ischemia (5.8 % vs. 5.7 %, p = NS), fondaparinux was associated with significant reductions in major bleeding (2.2 % vs. 4.1 %, p < 0.001) and the composite of major bleeding or ischemic events (7.3 % vs. 9.0 %, p < 0.001). These findings were consistent in multiple subgroups, including diabetics. In a separate report evaluating outcomes stratified by quartiles of renal function, however, the benefits of fondaparinux appeared greater in those with more advanced renal impairment [66]. More specifically, large reductions in major bleeding without any differences in ischemic events resulted in a substantial net clinical benefit with fondaparinux use among those with eGFR < 58 ml/min/1.73 m2 (n = 5141, 8.8 % vs. 12.5 % p < 0.001). While these results were durable at both 30 and 180 days, there were no significant differences between groups in the other three quartiles of less severe CKD. Although intriguing, these results must be interpreted with caution given the inherent disadvantages of subgroup analyses.

Bivalirudin is a direct thrombin inhibitor with several advantages over heparin-based anticoagulants including a shorter half-life, inhibition of circulating and clot-bound thrombin and thrombin-mediated platelet activation [67, 68]. Compared to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin monotherapy yielded significant reductions in major bleeding and net adverse event comprising ischemic and bleeding endpoints among NSTE ACS patients enrolled in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial [69]. Subgroup analyses of this study demonstrated that 30-day rates of major bleeding (9.2 % vs. 5.7 %), composite ischemia (10.8 % vs. 8.7 %) and net clinical outcome (17.5 % vs. 12.9 %) were all numerically higher among those with CKD compared to DM [16, 70]. Compared to heparin plus GPI, bivalirudin monotherapy was associated with significant reductions in 30-day major bleeding in both CKD (3.7 % vs. 7.1 %, p < 0.001) and diabetic (6.2 % vs. 9.8 %, p = 0.008) subgroups. Net clinical benefit with bivalirudin use, however, was only apparent among those with DM (10.9 % vs. 13.8 %, p = 0.02) as there were no differences between anticoagulant groups among those with vs. without CKD (16.1 % vs. 16.9 %, p = 0.65).

Invasive vs. Conservative Management

Increasing safety combined with technical advances in the percutaneous management of CAD led to a series of randomized trials in the late 1990s and early 2000s evaluating a strategy of early coronary angiography with prompt revascularization (invasive) versus initial medical therapy alone and delayed angiography for refractory symptoms (conservative) among patients with NSTE ACS. In aggregate, these studies demonstrated that an early invasive versus conservative approach significantly reduced the composite endpoints of death, non-fatal MI and urgent revascularization [71]. Although randomized trials only enrolling patients with CKD or DM and concomitant ACS have not been performed, subgroup analyses and observational data provide compelling insight on the potential role of an early invasive strategy in these patients. In a meta-analysis comprising nine trials (n = 9904), O’Donoghue et al. recently reported that an invasive versus conservative approach yielded a similar benefit in reducing death, nonfatal MI and revascularization due to ACS among patients with or without DM [72•]. Larger reductions in non-fatal MI among those with DM, however, suggest a differential and accentuated benefit with an invasive strategy among these patients (p interaction = 0.02). These findings are reflected in recent guideline recommendations favoring an early invasive approach among diabetic patients presenting with NSTE ACS [52].

In a separate pooled analysis comprising many of the same trials studied in the O’Donoghue et al. report, Charytan et al. evaluated the comparative efficacy of an early invasive vs. conservative management approach according to level of renal dysfunction [73]. Although a consistent numerical benefit with an invasive approach was observed among those with or without mild to moderate CKD, the small number of patients with advanced CKD (eGFR < 30 ml/min/1.73 m2, n = 267) precludes drawing conclusive inferences. Similar findings were reported from a national Swedish registry of over 20,000 consecutive NSTEMI patients [74]. In this report, an invasive approach was associated with a significant reduction in 1-year mortality among those with eGFR > 30 ml/min/1.73 m2 whereas no differences between strategies was apparent among those with eGFR < 30 ml/min/1.73 m2 or on dialysis (n = 850). Uncertainty regarding the risk/benefit ratio of an early invasive approach among CKD patients with ACS is reflected in current guidelines that provide a class IIa, level of evidence B recommendation for such a strategy only in patients with mild to moderate CKD [52].

Conclusions

Patients with CKD or DM are at markedly increased risk for adverse events following ACS, even when managed with contemporary pharmacotherapy and treatment strategies. Improving post-ACS outcomes in these patients represents an important clinical and public health imperative given the high prevalence and substantial health care expenditures attributable to either condition. While post-hoc analyses of major trials and registries have provided critical insight, dedicated studies evaluating ACS treatments and outcomes in these specific patient populations are long overdue and warranted.

Compliance with Ethics Guidelines

Conflict of Interest

Usman Baber and Uschi Auguste declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Copyright information

© Springer Science+Business Media New York 2013