Driving Without a Map: The Difficult Road Toward Improved Outcome in ACS Patients with CKD

Chronic kidney disease (CKD) is frequently encountered in modern medical practice, yet the effect of CKD on prognosis and the impact of therapeutic strategies in this population have received only cursory attention. This is particularly notable in the setting of acute coronary syndromes. With a prevalence of over 30% in patients presenting with acute coronary syndromes, CKD is associated with higher rates of complications and poor prognosis,^1,2 and, along with diabetes mellitus, has been firmly established as a coronary artery disease (CAD) equivalent.³ Despite this increased clinical risk, patients with CKD experiencing ACS are significantly less likely to receive the evidence-based therapy shown to be beneficial in the general population of patients with ACS.⁴ Reasons for failure to reliably provide optimal medical care in such a high-risk population are multiple and include frequent delayed presentation or atypical features, making initial recognition of ACS challenging in this population. Challenges in interpretation of biomarkers, which may be chronically elevated and therefore given less attention in these patients, may also delay or otherwise impact delivery of optimal care. Critically important, however, is the lack of available randomized data and clear guidelines to unequivocally support such specific therapies for a direct pathway toward improved outcome.

Washam and colleagues⁵ provide an important and long-overdue reflection on the current state of evidence for appropriate medical therapy in patients with CKD, and highlight the vast unmet need for specific therapeutic outcomes data in this population. In general, the manuscript is nearly complete in its scope, providing guidance to the practicing clinician and future researcher alike. Highlights include a clear description of CKD staging and associated impairment in prognosis. The clear call for use of estimated creatinine clearance (specifically the Cockcroft-Gault equation) for medication dose adjustment in the setting of renal insufficiency is also critical to the appropriate care of these patients, as many of the agents commonly used in ACS are cleared via renal mechanisms and inadequate or excess dosing may negatively affect outcome. Within the statement is an encyclopedic collection of available clinical trial data pertinent to medical therapy for the CKD population with ACS. These sections dealing with specific agents, while extensive and clearly presented, are limited by the same factors that make this guideline necessary; a combination of regulatory, pragmatic, economic, and clinical considerations have limited trial enrollment of patients with CKD and left us with a lack of data specific to this population. Despite this lack of specific trial data, the authors are able to make several helpful recommendations for the medical management of these patients:

1. Adjusting medication dosing according to estimated creatinine clearance is essential.
2. Many medications commonly recommended in the general population of patients with ACS are similarly suitable for use in patients with CKD suffering ACS, including aspirin, the oral P2Y12 receptor antagonist clopidogrel (or prasugrel or ticagrelor in patients not requiring hemodialysis), beta blockade, and statin therapy. Fibrinolytic agents are effective in CKD patients with ST-elevation myocardial infarction (STEMI), although the potentially higher relative risk of intracranial hemorrhage in this population requires consideration.
3. Some medications commonly recommended for use in ACS patients may be considered in ACS patients with CKD with certain caveats, including ACE inhibitors, angiotensin receptor antagonists, and aldosterone blockade agents. These agents require careful attention to potassium and creatinine levels and any ongoing changes in renal function, meaning that early monitoring of these values is essential.
4. The choice of intravenous antithrombotic therapy, essential in the care of patients with ACS, requires attention to relevant labelling recommendations for dosing modifications and contraindications. Intravenous anticoagulant therapy is indicated in patients with CKD and ACS, although enoxaparin is associated with higher rates of bleeding with greater renal function impairment and is not a recommended agent for this indication (despite a Class I indication for the overall ACS population), while fondaparinux and bivalirudin treatment is associated with lower rates of bleeding in patient with stage III and stage IV CKD and may be preferred for these patients. Glycoprotein IIb/IIIa receptor antagonists may also be used in this patient population, although a higher associated bleeding risk must be considered along with dosing adjustments for renally cleared agents.

While the scope of this work is intentionally limited to the pharmacological management of ACS, one cannot ignore the importance of invasive strategies in the treatment of these patients and the resulting impact on administered medical therapies. In both those with and without CKD, the decision to perform angiography and/or intervene is complex and has a major impact on medication choice, dosing, and duration. This is particularly true for patients with CKD, as renal function changes that frequently occur after angiography can impact medication clearance and may affect bleeding risk and outcome. Indeed, the risk of angiography and revascularization is heightened in patients with CKD, whether in the acute⁶ or elective⁷ setting.

Greater focus on this interaction would be an ideal addition to this statement to supplement ACS guidelines that impact the choice of reperfusion in this population, albeit with limited supporting data and incomplete consensus. Along with Class I procedural recommendations, including support for adequate preparatory hydration and contrast-sparing techniques, the most recent NSTEMI guideline statement provides a Class IIa recommendation for an invasive strategy in patients with Stage 2 and 3 CKD (Level of Evidence: B).⁸ These limited recommendations reflect the uncertainty inherent in the lack of prospective data available to guide clinical decision-making. While numerous studies have suggested a correlation between greater degrees of renal impairment and worse outcome, the relationship between coronary revascularization and improved outcome is less linear in patients with ACS. Non-randomized and retrospective studies or meta-analyses have supported an association between an early invasive strategy and improved survival⁹ or reduced adverse events¹⁰ in patients with mild or moderate CKD, but not in those with more severe renal dysfunction. As a result, in the absence of sufficient data, there are no specific recommendations regarding early revascularization for patients with ACS and more severe degrees of renal dysfunction. This represents a clear focus for future research.

In uncharted territory, it is easy to get lost. Without a map or suitable guidance, even the most experienced of travelers can only approximate a reasonable course and, despite ample skill and experience, may end up far from the intended destination. This paper by Washam and colleagues provides a compass to chart an initial course in the medical care of ACS patients with CKD. A detailed map based on robust research is needed to ensure we arrive reliably at our destination of optimal outcome in these patients.