Elsevier

American Heart Journal

Volume 258, April 2023, Pages 49-59
American Heart Journal

Clinical Investigations
Outcomes in patients with cardiometabolic disease who develop hyperkalemia while treated with a renin-angiotensin-aldosterone system inhibitor

https://doi.org/10.1016/j.ahj.2023.01.002Get rights and content

Background

Many patients with indications for renin-angiotensin-aldosterone system inhibitor (RAASi) therapy are not receiving these medications. Concern about hyperkalemia is thought to contribute to this lack of evidence-based therapy.

Methods

A retrospective cohort study included adult patients in primary care practices affiliated with an integrated health care delivery system treated with RAASi between 2000 and 2019 for any of the following indications: (a) coronary artery disease (CAD); (b) heart failure (HF) with a left ventricle ejection fraction ≤ 40%; (c) diabetes mellitus (DM) with proteinuria; or (d) chronic kidney disease (CKD) with proteinuria. Relationship between hyperkalemia (K > 5.0 mEg/L) over the first 12 months of follow-up and a composite end point of cardiovascular events, renal dysfunction, and all-cause mortality was evaluated.

Results

Among 82,732 study patients, 7,727 (9.34%) developed hyperkalemia. Patients with hyperkalemia were older (69.0 vs 64.6) and more likely to have CAD (57.8 vs 53.7%), CKD (57.3 vs 51.1%), HF (19.3 vs 9.7%), and DM (45.3 vs 33.3%) (P < .001 for all). Five-year cumulative risk of the primary outcome was higher in patients who did (63.9%; 95% CI: 62.8%-65.1%) versus did not (37.2%; 95% CI: 36.8%-37.6%) develop hyperkalemia. Five-year cumulative risk of ED visit or hospitalization for hyperkalemia was 15.6% (14.7%-16.6%) for patients with versus 2.7% (95% CI: 2.6-2.9) for patients without hyperkalemia, rising to 25.9% (95% CI: 22.4-29.9) for patients with severe (K > 6.0 mEq/dL) hyperkalemia. Patients who experienced hyperkalemia were more likely (34.4%) than patients who did not (29.2%) to deintensify RAASi therapy (P < .001). Five-year cumulative risk of the primary outcome was higher in patients who lowered RAASi dose (50.4%; 95% CI: 48.5%-52.4%) or stopped RAASi therapy completely (49.3%; 95% CI: 48.5%-50.1%), compared to patients who continued RAASi therapy (36.1%; 95% CI: 25.7-36.5). Similar findings were observed in multivariable analyses and for individual components of the primary outcome.

Conclusions

Hyperkalemia is a common complication of RAASi therapy and is associated with an increased risk of multiple adverse outcomes. Patients who have their RAASi medications deintensified after a hyperkalemic event have higher incidence of cardiovascular events, renal dysfunction and death.

Section snippets

Study design

We performed a retrospective cohort study to assess the relationship of hyperkalemia with treatment and outcomes of patients being treated with RAASi.

Participants

Study participants included adults (≥18 years old) who were treated with a RAASi and received their primary care from a provider affiliated with Mass General Brigham. Patients were required to have a baseline creatinine level available and at least one of the following indications for RAASi therapy: (a) diabetes mellitus (DM) and proteinuria; (b)

Sources of funding

This study was funded in part by Astra-Zeneca. The study funder contributed to the study design and manuscript review. The study funder had no role in conduct of the study; collection, management, analysis, and interpretation of the data; and decision to submit the manuscript for publication.

Results

We identified 94,280 adult patients who had indications for RAASi therapy and were treated with a RAASi. After excluding patients with history of angioedema, advanced CKD or were missing demographic or baseline potassium information (Figure 1), 82,732 patients were included in analysis (Table 1). Of these, 24,467 (29.6%) patients had DM and proteinuria; 7,224 (8.7%) had heart failure with LVEF ≤ 40%; 44,737 (54.1%) had CAD; and 39,073 (27.2%) CKD stage I-IV and proteinuria (some patients had

Discussion

In this large population-based study of patients treated with RAASi for evidence-based indications, we found that hyperkalemia was common and was associated with an increased risk of adverse outcomes. Many patients who developed hyperkalemia had their RAASi deintensified (stopped or dose decreased); RAASi deintensification was linked to a higher risk of adverse outcomes.

The present study showed that hyperkalemia was linked to an increased risk to a broad range of adverse outcomes, including

Conclusions

In conclusion, the present study found that patients treated with RAASi commonly develop hyperkalemia. Deintensification of RAASi therapy remains a widespread approach to prevention of hyperkalemia recurrence in this patient population and is associated with a significantly increased risk of adverse clinical outcomes. Broad implementation of safe and effective treatments for prevention of hyperkalemia that would enable continuation of RAASi therapy could make a significant impact on quality of

Conflict of Interest

Dr McMahon has received personal fees from Apellis and grant support from Alexion and Allena. Dr Turchin has equity in Brio Systems; has received personal fees from Covance and Proteomics International; and received grant support from Eli Lilly, Edwards, and Novo Nordisk. None of the other authors have any conflicts of interest.

References (55)

  • S Gilligan et al.

    Hyperkalemia and hypokalemia in CKD: prevalence, risk factors, and clinical outcomes

    Adv Chronic Kidney Dis

    (2017)
  • Y Xu et al.

    Stopping renin-angiotensin system inhibitors after hyperkalemia and risk of adverse outcomes

    Am Heart J

    (2022)
  • N Vasavada et al.

    A double-blind randomized crossover trial of two loop diuretics in chronic kidney disease

    Kidney Int

    (2003)
  • I Lazich et al.

    Prediction and management of hyperkalemia across the spectrum of chronic kidney disease

    Semin Nephrol

    (2014)
  • S Yusuf et al.

    Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure

    N Engl J Med

    (1991)
  • EJ Lewis et al.

    The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group

    N Engl J Med

    (1993)
  • S Yusuf et al.

    Telmisartan, ramipril, or both in patients at high risk for vascular events

    N Engl J Med

    (2008)
  • MA Pfeffer et al.

    Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both

    N Engl J Med

    (2003)
  • R Kunz et al.

    Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin–angiotensin system on proteinuria in renal disease

    Ann Intern Med

    (2008)
  • B Pitt et al.

    The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators

    N Engl J Med

    (1999)
  • SD Navaneethan et al.

    Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis

    Clin J Am Soc Nephrol

    (2009)
  • HOPES. Investigators

    Effects of an angiotensin-converting–enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients

    New Engl J Med

    (2000)
  • DT Ko et al.

    Regional differences in process of care and outcomes for older acute myocardial infarction patients in the United States and Ontario, Canada

    Circulation

    (2007)
  • CE Cooke et al.

    Physician conformity and patient adherence to ACE inhibitors and ARBs in patients with diabetes, with and without renal disease and hypertension, in a medicaid managed care organization

    J Managed Care Pharm

    (2006)
  • CD Chu et al.

    Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use among hypertensive US adults with albuminuria

    Hypertension

    (2021)
  • G Savarese et al.

    Factors associated with underuse of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: an analysis of 11 215 patients from the Swedish Heart Failure Registry

    Eur J Heart Fail

    (2018)
  • JP Ferreira et al.

    Mineralocorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: findings from BIOSTAT-CHF

    Eur J Heart Fail

    (2017)
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