Cardiovascular Outcome Trials in Patients With Advanced Kidney Disease

idney disease is prevalent among patients with cardiovascular disease, and its presence is associated with an increased risk of cardiovascular events or death.Despite widespread acceptance of this tenet, patients with kidney disease, especially advanced kidney disease, are frequently excluded from cardiovascular outcome trials.Systematic reviews published in 2006 1,2 reported that 56% to 80% of major randomized trials in chronic heart failure, acute myocardial infarction, or coronary artery disease excluded patients with kidney disease.Despite a call by these authors >10 years ago encouraging greater enrollment of patients with kidney disease in cardiovascular trials, 1,2 a later systematic review (updated to reflect clinical trials published between 2006 and 2013 in the top 10 medical journals ranked by impact factor) found persistent exclusion of these patients from the majority (57%) of heart failure or acute coronary syndrome cardiovascular outcome trials SPRINT [Systolic Blood Pressure Intervention Trial] allowed an estimated glomerular filtration rate of ≥20 mL•min -1 •1.73 m -2 ; and SHARP [Study of Heart and Renal Protection] required serum creatinine ≥1.5 mg/dL [women] or ≥1.7 mg/dL [men] with or without dialysis for inclusion) are worth noting for their enrollment of patients with kidney disease, but, in general, these patients remain underrepresented in cardiovascular outcome trials.As a result, the best treatment approaches for patients with kidney disease remain shrouded by uncertainty.Insufficient data impair physician and patient decision making in terms of both safety and efficacy.When patients with advanced kidney disease are not well represented in cardiovascular outcome trials, dosing recommendations for these patients are often based on pharmacokinetic modeling and simulations that describe the relationship between estimated renal function and pharmacokinetic parameters.These models are used to predict drug exposure according to renal function and to select doses expected to produce serum concentrations matching patients with normal renal function.However, it is unknown whether these doses will lead to similar safety and efficacy as demonstrated in outcome trials.In the absence of data, physicians may avoid potentially life-prolonging therapies because of safety concerns.Many reasons (eg, potential for diminished treatment effects, high risk of unmodifiable clinical events, complex pathophysiology with many potential mechanisms contributing to cardiovascular disease, safety concerns, difficult recruitment and retention in trials) contribute to the exclusion of patients with advanced kidney disease from trials.Cardiovascular disease is a leading cause of death in patients with advanced kidney disease, but cancer, infectious disease, and pulmonary disease also account for a substantial proportion of mortality.These competing risks may discourage enrollment of patients with advanced kidney disease in cardiovascular outcome trials because of concerns that cardiovascular therapies are unlikely to show a treatment effect on noncardiovascular events.Thus, large, potentially prohibitively so, study populations are required to either overcome the noise of no effect when all-cause mortality is the primary end point or to accrue an adequate Cardiovascular Outcome Trials in Patients With Advanced Kidney Disease Time for Action