Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) are first-line antihypertensives for individuals with albuminuria, and are among the few clinically-proven therapies to delay chronic kidney disease (CKD) progression in patients with albuminuria.1-5 ACE-Is and ARBs may also provide benefits post myocardial infarction, with improvement in myocardial performance and survival compared with placebo.6-11 On the other hand, ACE-Is, ARBs, or their combination (ACE-I/ARB) may predispose to hyperkalemia and acute kidney injury (AKI), risks that are particularly high among patients with low estimated glomerular filtration rate (eGFR) or albuminuria.12,13
Currently, there is equipoise in the safety and efficacy of ACE-I/ARB use in advanced CKD, which motivated ongoing clinical trials such as the STOP-ACEi trial.14,15 The STOP-ACEi trial is a multi-center randomized controlled trial, which randomizes users of ACE-I/ARB with advanced progressive CKD to either discontinue or continue to receive ACE-I/ARB.14,15 Clinical guidelines reflect the uncertainty, and remain vague as to when ACE-I/ARB needs to be discontinued in patients with advanced CKD, leaving providers and patients to navigate these questions without clear scientific guidance. For example, the Kidney Disease Improving Global Outcomes (KDIGO) guideline recommends “temporary discontinuation” of ACE-I/ARB “in people with a GFR <60 ml/min/1.73 m2 (GFR categories G3a-G5) who have serious intercurrent illness that increases the risk of AKI”; yet also states “do not routinely discontinue [ACE-I/ARB therapy] in people with GFR <30 ml/min/1.73 m2 as they remain nephroprotective”.16 Although clinical trials suggest the rate of discontinuation of ACE-Is and ARBs is low,17 less is known about real-world practice in the setting of CKD progression.
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The goal of this study was to describe ACE-I/ARB discontinuation patterns in a real-world setting using over ten years of data from a large, integrated healthcare delivery network, with a particular focus on patterns in the setting of CKD. As a secondary objective, we identified additional factors associated with ACE-I/ARB discontinuation, hypothesizing that hypotension, elevated potassium levels, low bicarbonate level, and recent AKI-related hospitalization would be among the strongest risk factors for discontinuing ACE-I/ARB therapy. Additionally, we assessed how ACE-I/ARB discontinuation was affected by concurrent use of loop and thiazide diuretics, two medication classes known to be associated with decreased risk of hyperkalemia.18 Finally, among discontinued users, we assessed antecedent events as well as the frequency of restarting ACE-I/ARB within six months of therapy discontinuation.
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