Adverse clinical outcomes associated with RAAS inhibitor discontinuation: analysis of over 400 000 patients from the UK Clinical Practice Research Datalink (CPRD)

Abstract

Background Users of guideline-recommended renin-angiotensin-aldosterone system (RAAS) inhibitors may experience disruptions to their treatment, for example due to hyperkalaemia, hypotension or acute kidney injury. The risks associated with treatment disruption have not been comprehensively assessed; therefore, we evaluated the risk of adverse clinical outcomes in RAAS inhibitor users experiencing treatment disruptions in a large population-wide database. Methods This exploratory, retrospective analysis utilized data from the UK’s Clinical Practice Research Datalink, linked to Hospital Episodes Statistics and the Office for National Statistics databases. Adults (≥18 years) with first RAAS inhibitor use (defined as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) between 1 January 2009 and 31 December 2014 were eligible for inclusion. Time to first occurrence of adverse clinical outcomes (all-cause mortality, all-cause hospitalization, cardiac arrhythmia, heart failure hospitalization, cardiac arrest, advancement in chronic kidney disease [CKD] stage and acute kidney injury) was compared between RAAS inhibitor users with and without interruptions or cessations to treatment during follow-up. Associations between baseline characteristics and adverse clinical outcomes were also assessed. Results Among 434 027 RAAS inhibitor users, the risk of first occurrence of all clinical outcomes, except advancement in CKD stage, was 8–75% lower in patients without interruptions or cessations versus patients with interruptions/cessations. Baseline characteristics independently associated with increased risk of clinical outcomes included increasing age, smoking, CKD, diabetes and heart failure. Conclusions These findings highlight the need for effective management of factors associated with RAAS inhibitor interruptions or cessations in patients for whom guideline-recommended RAAS inhibitor treatment is indicated.

Discontinuation of Renin-Angiotensin-Aldosterone System Inhibitors Secondary to Hyperkalemia Translates into Higher Cardiorenal Outcomes

“…Most prior studies have reported increased cardiovascular events following RAASi discontinuation [12–15, 17]. In contrast, our study did not find differences in cardiovascular outcomes associated with RAASi discontinuation, similar to the report from Hundemer et al [16] Again, it is important to note that our population did not include patients with prior heart failure hospitalizations and was not limited to patients with proteinuria.…”

Cost effectiveness of sodium zirconium cyclosilicate for the treatment of hyperkalaemia in patients with CKD in Norway and Sweden

“…Therefore, RAASi therapy is frequently downtitrated or discontinued in patients who experience hyperkalaemia, contributing to significant discrepancies between guideline recommendations and real-world practice regarding RAASi treatment [13][14][15][16]. Failure to achieve guideline-recommended doses of RAASi has been associated with adverse outcomes [8, 13,17]. Thus, there is an established need for safe and effective treatment of hyperkalaemia, in particular to permit maintenance of RAASi therapy.…”

“…Recent KDIGO guidance on hyperkalaemia management in kidney disease highlighted that evidence supporting low-potassium diet is weak and that it may deprive patients of the benefits of a plant-rich diet [1]. Similarly, downtitration or discontinuation of RAASi deprives patients of the benefits of RAAS inhibition and is associated with an increased risk of adverse outcomes [8, 13,17]. The evidence for the efficacy of SPS/CPS is modest; one small, short-term, singleblinded RCT has been published comparing SPS to CPS, [34] however no comparison with placebo was performed and no studies have evaluated longer term efficacy or safety.…”

Effect of SGLT2 Inhibitors on Discontinuation of Renin–angiotensin System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials

“…Third, these results were generated from well-designed trials involving experienced investigators who were encouraged to continue guideline-directed background care wherever possible, and thus, persistent use of RAS blockade was high. Whether these findings translate into more pronounced effects on RAS blockade discontinuation in real-world settings—where this occurs much more frequently than in clinical trials 27,28 —should be examined in future work, leveraging routinely collected data.…”