Remote ischemic preconditioning for renal and cardiac protection in congestive heart failure (RICH) trial

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Contrast-associated acute kidney injury (CA-AKI) is a common complication of intravenous, iodinated contrast media, that is widely used for coronary angiography and percutaneous coronary intervention (PCI) in patients with coronary artery disease (CAD) and heart failure (HF). An estimated 38 million people worldwide suffer from HF most frequently as a consequence of CAD, the number one killer of all adults in the US. The expected growth of the elderly population including Veterans is estimated to be paralleled by a significant increase (50% in the US) in the number of patients diagnosed with HF every year. Although PCI restores blood flow to the heart and improves myocardial function in patients with HF, the contrast media used for the procedure can cause CA-AKI, possibly mediated by contrast–induced vasoconstriction of renal blood vessels and free radical–mediated direct renal tubular toxicity. The incidence of CA-AKI is estimated to range between 10 and 50% in patients undergoing coronary angiography and PCI with higher rates in patients with HF with reduced left ventricular ejection fraction (LVEF). In the U.S, approximately 1.4 million coronary angiogram procedures are performed each year. Among the U.S Veterans alone, approximately 30,000 coronary angiograms are performed annually, and over 1 million contrast-enhanced imaging studies are performed for other various purposes. This estimate is expected to increase exponentially in the next few decades. With increasing use of contrast media, the prevalence of CA-AKI is also expected to rise. CA-AKI predicts elevated risk of heart attack, longer hospital stay, more complicated hospitalization course, and higher in-hospital mortality. Although, periprocedural administration of isotonic saline intravenous fluid (IVF) has been the standard intervention to prevent CA- AKI, patients with HF with reduced LVEF may not tolerate IVF. Unfortunately, all the major clinical trials evaluating prophylactic IVF and other agents excluded patients with HF. Currently, there is no alternative preventive therapy for CA-AKI in patients with congestive HF with reduced LVEF who cannot tolerate IVF. This study proposes remote ischemic pre-conditioning (RIPC) elicited by application of one or more, brief episodes of ischemia and reperfusion of a limb, as a promising alternative therapy for preventing or attenuating CA-AKI. Given that renal ischemic injury and tubular toxicity are the most common pathophysiological concepts of CA-AKI, it stands to reason that RIPC may prevent CA-AKI via nitrite-induced vasodilation and damage associated molecular protein -mediated renal cell protection. In the preliminary analysis of data of patients with heart attack, an association of RIPC with lower rate of CA-AKI and in-hospital mortality was observed. In the subgroup with HF with reduced LVEF, RIPC was associated with lower incidence of CA-AKI, HF symptoms and lower level of plasma brain natriuretic peptide (BNP). Taken together, these observational data suggest a role for RIPC in renal protection and improvement in HF symptoms in a population of patients who may not tolerate the standard therapy, isotonic saline IVF. Therefore, this study is intended to fill a critical void in the prevention of CA-AKI in a population of Veterans with congestive HF undergoing life-saving coronary angiography and/or PCI. This study proposes a randomized clinical trial (RCT) to determine the effect of RIPC on CA-AKI (primary outcome), and to characterize the effect of RIPC on BNP, functional capacity determined by 6-minute walk test distance, and major adverse kidney events at 90 days (MAKE-90, secondary outcomes) in patients with congestive HF and LVEF <50% undergoing coronary angiography and/or PCI. This research project will determine the effect of RIPC on CA-AKI in Veterans with HF with reduced LVEF who cannot tolerate IVF. The findings from this study will inform the design of a larger multi-center RCT to determine the long-term effects of RIPC on morbidity/mortality in HF population. It will help develop new therapies for AKI and HF.