Abstract
BACKGROUND
Renin-angiotensin-aldosterone system (RAAS) inhibitors are associated with hyperkalemia, but there is little evidence demonstrating patients who receive potassium monitoring have a lower rate of hyperkalemia.
OBJECTIVE
To evaluate the association between potassium monitoring and serious hyperkalemia-associated adverse outcomes among patients with diabetes newly initiating RAAS inhibitor therapy.
DESIGN
Retrospective observational study.
PARTICIPANTS
Patients with diabetes without end-stage renal disease initiating RAAS inhibitor therapy between 2001 and 2006 at three integrated health care systems.
MEASUREMENTS
Potassium monitoring and first hyperkalemia-associated adverse event during the initial year of therapy. Hyperkalemia-associated adverse events included hospitalizations, emergency department visits or deaths within 24 h of hyperkalemia diagnosis and/or diagnostic potassium ≥6 mmol/l. Incidence rates were calculated in person-years (p-y). We used inverse probability propensity score weighting to adjust for differences between patients with and without monitoring; Poisson regression was used to obtain adjusted relative risks.
RESULTS
A total of 19,391 of 27,355 patients (71%) received potassium monitoring. Serious hyperkalemia-associated events occurred at an incidence rate of 10.2 per 1,000 p-y. Compared to patients without monitoring, adjusted relative risk of hyperkalemia-associated adverse events among all patients with monitoring was 0.50 (0.37, 0.66); in the subset of patients who also had chronic kidney disease (n = 2,176), adjusted relative risk was 0.29 (0.18, 0.46).
CONCLUSIONS
Patients prescribed RAAS inhibitors who have both diabetes and chronic kidney disease and receive potassium monitoring are less likely to experience a serious hyperkalemia-associated adverse event compared to similar patients who did not receive potassium monitoring. This evidence supports existing consensus-based guidelines.
References
Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.
Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet. 2002;359:1004–10.
HOPE (Heart Outcomes Prevention Evaluation) Study Investigators. Effects of an angiotensin converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–53.
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709–17.
Chobanian AV, Bakris GI, Black HR, Cushman WC, Green LA, Izzo JL. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. 2003;39(suppl 1):S94–8.
Cohn JN, Tognoni G. for the Valsartan heart failure trial investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–75.
McMurray JJV, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767–71.
Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893–906.
Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.
Pfeffer MA. ACE inhibition in acute myocardial infarction. N Engl J Med. 1995;332:118–20.
Pfeffer MA, Braunwald E, Moye LA. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement trial. N Engl J Med. 1992;327:669–77.
Gruppo Italiano per lo Studio della Sopravvivenza nell'infart Miocardico. GISSI-3: effects of lisinopril and transfermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after myocardial infarction. Lancet. 1994;343:1115–22.
Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001;38:2101–13.
Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: Pathophysiology and indications. Kidney Int. 2005;67:799–812.
The RALES Investigators. Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the randomized aldactone evaluation study [RALES]). Am J Cardiol. 1996;78:902–7.
Palmer BF. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what to do if the serum creatinine and/or serum potassium concentration rises. Nephrol Dial Transplant. 2003;18:1973–5.
Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med. 2004;351:585–92.
Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med. 2004;351:543–51.
Ahuja TS, Freeman D Jr, Mahnken JD, Agraharkar M, Siddiqui M, Memon A. Predictors of the development of hyperkalemia in patients using angiotensin-converting enzyme inhibitors. Am J Nephrol. 2000;20:268–72.
Desai AS, Swedberg K, McMurray JJV, et al. Incidence and predictors of hyperkalemia in patients with heart failure: An analysis of the CHARM program. J Am Coll Cardiol. 2007;50:1959–66.
Ramadan FH, Masoodi N, El-Solh AA. Clinical factors associated with hyperkalemia in patients with congestive heart failure. J Clin Pharm Therapeutics. 2005;30:233–9.
Bakris G, Williams M, Dworkin L. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36:646–61.
Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160:685–93.
Schepkens H, Vanholder R, Billiouw JM, Lameire N. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med. 2001;110:438–41.
Schaefer TJ, Wolford RW. Disorders of potassium. Emerg Med Clin N Am. 2005;23:723–47.
Berry C, McMurray J. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone. Am J Med. 2001;111:587.
Knight EL, Avorn J. Quality indicators for appropriate medication use in vulnerable elders. Ann Intern Med. 2001;135:703–10.
Lloyd SJ, Mauro VF. Spironolactone in the treatment of congestive heart failure. Ann Pharmacother. 2000;34:1336–40.
Shah KB, Rao K, Sawyer R, Gottlieb SS. The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure. J Am Coll Cardiol. 2005;46:845–9.
Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112:e154–235.
de Denus S, Tardif J-C, White M, et al. Quantification of the risk and predictors of hyperkalemia in patients with left ventricular dysfunction: A retrospective analysis of the Studies of Left Ventricular Dysfunction (SOLVD) trials. Am Heart J. 2006;152:705–12.
Stevens LA, Fares G, Fleming J, et al. Low rates of testing and diagnostic codes usage in a commercial clinical laboratory: evidence for lack of physician awareness of chronic kidney disease. J Am Soc Nephrol. 2005;16:2439–48.
Duru OK, Vargas RB, Kermah D, Nissenson AR, Norris KC. High prevalence of stage 3 chronic kidney disease in older adults despite normal serum creatinine. J Gen Intern Med. 2009;24:86–92.
Miller WG. Reporting estimated GFR from serum creatinine: Recommendations from the laboratory working group of the National Kidney Diabetes Education Program. Oral presentation from the 2006 annual meeting of the American Association of Clinical Chemistry. 2006. Available from: http://www.aacc.org/events/expert_access/2006/kidneydisease/Pages/default.aspx Accessed Dec. 2009.
Winkelmayer WC, Schneeweiss S, Mogun H, Patrick AR, Avorn J, Solomon DH. Identification of Individuals with CKD from Medicare Claims Data: a validation study. Am J Kidney Dis. 2005;46:225–32.
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1–S266.
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med. 1999;130:461–70.
Cockcroft Dw, Gault MH. Prediction o f creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.
Clark DO, Von Korff M, Saunders K, Baluch WM, Simon GE. A chronic disease score with empirically derived weights. Med Care. 1995;33:783–95.
Raebel MA, McClure DL, Simon SR, et al. Laboratory monitoring of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in ambulatory patients. Pharmacoepidemiol Drug Saf. 2007;16:55–64.
Raebel MA, McClure DL, Andrade SE, et al. Laboratory evaluation of potassium and creatinine among ambulatory patients prescribed spironolactone: are we monitoring for Hyperkalemia? Ann Pharmacother. 2007;41:193–200.
Raebel MA, Lyons EE, Andrade SE, et al. Laboratory monitoring of high risk drugs at initiation of therapy in ambulatory care. J Gen Intern Med. 2005;20:1120–6.
Rosenbaum PR, Rubin DB. The central role of propensity score in observational studies for causal effects. Biometrika. 1983;70:41–55.
Robins JM, Herman MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiol. 2000;11:550–60.
Rosenbaum PR. Model-Based Direct Adjustment. J Am Stat Assoc. 1987;82:387–94.
Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Sturmer T. Variable selection for propensity score models. Am J Epidemiol. 2006;163:1149–56.
Xu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value in Health. doi:10.1111/j.1524-4733.2009.00671.x.
Arruda J, Batlle D, Sehy J, Roseman M, Baronowski R, Kurtzman NA. Hyperkalemia and renal insufficiency: role of selective aldosterone deficiency and tubular unresponsiveness to aldosterone. Am J Nephrol. 1981;1:160–7.
DeFronzo RA. Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int. 1980;17:118–34.
Schaefer TJ, Wolford RW. Disorders of potassium. Emerg Med Clin N Am. 2005;23:723–47.
Chiu TF, Bullard MJ, Chen JC, Liaw SJ, Ng CJ. Rapid life-threatening hyperkalemia after addition of amiloride HCl/hydrochlorothiazide to angiotensin-converting enzyme inhibitor therapy. Ann Emerg Med. 1997;30:612–5.
Kurata C, Uehara A, Sugi T, Yamazaki K. Syncope caused by nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors. Jpn Circ J. 1999;63:1002–3.
Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA. 2003;289:1652–8.
Maddirala S, Khan A, Vincent A, Lau K. Effect of angiotensin converting enzyme inhibitors and angiotensin receptor blockers on serum potassium levels and renal function in ambulatory outpatients: risk factors analysis. Am J Med Sci. 2008;336:330–5.
Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. Arch Intern Med. 1998;158:26–32.
Shah KB, Rao K, Sawyer R, Gottlieb SS. The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure. J Am Coll Cardiol. 2005;46:845–9.
NCQA. Annual monitoring for patients on persistent medications: new measure for HEDIS 2006. NCQA . 2006. Available from: http://www.ncqa.org/Portals/0/HEDISQM/Archives/2006/MeasuresList.pdf Accessed December 2009.
Acknowledgements
“Diabetes and Drug-Associated Hyperkalemia: Effect of Laboratory Monitoring” was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under the following grant number: R21DK075076. NIDDK did not participate in any of the following: design and conduct of the study; collection, management, analysis and interpretation of the data; and preparation, review or approval of the manuscript.
We thank Xiuhai Yang, MS, Hans Petersen, MS, and Junling Ren, MEd, for programming efforts, and Leslie A. Wright, MA, and Jill Mesa for project management.
Conflicts of Interest Disclosure
Marsha Raebel reports being a co-investigator in a research study funded by Sanofi-Aventis. This study does not involve the evaluation of any commercial product. Dr. Raebel also owns ≤400 shares of stock in each of Merck, Genentech, Teva, Biogen and Pfizer. Douglas Roblin reports receiving research grants within the last 3 years from GlaxoSmithKline and Gilead. Craig Cheetham reports being a co-investigator on a research study funded by Merck, owns stock in Allergan Pharmaceuticals and has a family member employed by Allergan Pharmaceuticals. Christopher Blanchette was previously employed by GlaxoSmithKline, during which time he owned stock in that company. He has received research grants from GlaxoSmithKline, AstraZeneca, Wyeth, Amgen and Premier, Inc., and serves as a consultant for NovoNordisk, GlaxoSmithKline, AstraZeneca, Sepracor and Viostat. David Smith has received research grants from Genzyme, Sanofi-Aventis, Amgen and Abbott. These research grants do not involve the evaluation of any commercial product. Colleen Ross, Stanley Xu and Gwyn Saylor report no potential conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Raebel, M.A., Ross, C., Xu, S. et al. Diabetes and Drug-Associated Hyperkalemia: Effect of Potassium Monitoring. J GEN INTERN MED 25, 326–333 (2010). https://doi.org/10.1007/s11606-009-1228-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11606-009-1228-x