ACEIs More Likely Than Other Antihypertensive Drugs to Cause Hyperkalemia; Overall Risk Low in Nondiabetic Kidney Disease

Laurie Barclay, MD

October 08, 2009

October 8, 2009 ( UPDATED October 23, 2009 ) — Angiotensin-converting enzyme inhibitors (ACEIs) are more likely than other antihypertensive drugs to cause hyperkalemia, according to the results of a study reported in the September 28 issue of the Archives of Internal Medicine. However, the risk for hyperkalemia is small in nondiabetic patients with hypertensive chronic kidney disease (CKD) treated with ACEIs, particularly if baseline and follow-up glomerular filtration rate (GFR) exceed 40 mL/minute/1.73 m2 and if patients receive a diuretic.

"Hyperkalemia from ACEI use has been frequently described, and ACEIs are often underprescribed in patients with CKD because of concerns of hyperkalemia," write Joy M. Weinberg, MD, from Lenox Hill Hospital in New York, NY, and colleagues from the African American Study of Hypertension and Kidney Disease Collaborative Research Group. "The incidence and factors associated with hyperkalemia in patients with...CKD treated with...ACEIs and other antihypertensive drugs was investigated using the African American Study of Kidney Disease and Hypertension (AASK) database."

In the AASK trial, 1094 nondiabetic adults with hypertensive CKD (GFR, 20 - 65 mL/minute/1.73 m2) were observed for 3.0 to 6.4 years and randomly assigned to treatment with an ACEI, beta-blocker, or dihydropyridine calcium channel blocker. For this analysis, the main endpoints were a serum potassium level greater than 5.5 mEq/L (to convert to millimoles per liter, multiply by 1.0), or a clinical center–initiated hyperkalemia stop point.

Among 6497 potassium measurements, 80 hyperkalemic events were identified in 51 participants, including 76 events identified by a central laboratory result and 4 events identified by a clinical center–initiated hyperkalemia stop point.

The hazard ratio (HR) for hyperkalemia in patients with a GFR between 31 and 40 mL/minute/1.73m2 vs a GFR higher than 50 mL/minute/ 1.73 m2 after multivariable adjustment was 3.61 (95% confidence interval [CI], 1.42 - 9.18; P = .007). For a GFR lower than 30 mL/minute/1.73 m2, HR was 6.81 (95% CI, 2.67 - 17.35; P < .001). Risk for hyperkalemia was not increased if GFR was 41 to 50 mL/minute/1.73 m2.

There were more episodes of hyperkalemia with ACEI use vs calcium channel blocker use (HR, 7.00; 95% CI, 2.29 - 21.39; P < .001) or with beta-blocker use (HR, 2.85; 95% CI, 1.50 - 5.42; P = .001). Risk for hyperkalemia was decreased by 59% when diuretics were used.

"In nondiabetic patients with hypertensive CKD treated with ACEIs, the risk of hyperkalemia is small, particularly if baseline and follow-up GFR is higher than 40 mL/min/1.73 m2," the study authors write. "Including a diuretic in the regimen may markedly reduce risk of hyperkalemia."

Limitations of this study include probably insufficient power to detect a difference in the rate of hyperkalemia between dose levels of ACEIs and limited generalizability to other drugs in the classes studied, to ethnic groups other than African Americans, and to a general routine care setting. In addition, the number of hyperkalemic events in the group with a GFR of less than 20 mL/minute/1.73m2 was probably underestimated.

"In the setting of nondiabetic, hypertensive CKD, the risk of hyperkalemia is inversely related to GFR and BMI [body mass index], regardless of antihypertensive treatment," the study authors conclude. "After initiation of antihypertensive therapy, the risk of hyperkalemia is greatest with ACEI use, intermediate with BB [beta-blocker]use, and lowest with CCB [calcium channel blocker] use."

When asked for independent comment for Medscape Nephrology, Franz H. Messerli, MD, FACC, FACP, director of the Hypertension Program and professor of clinical medicine, Columbia University College of Physicians and Surgeons, and Division of Cardiology, St. Luke's-Roosevelt Hospital in New York, described this study as "thorough" and "from a well-established group."

"The authors attempt to reassure practicing physicians that in nondiabetic patients with chronic kidney disease, the risk of hyperkalemia induced by ACE inhibitor therapy is small, particularly if GFR remains higher than 40 mL per minute," Dr. Messerli told Medscape Nephrology. "Not surprisingly, diuretic use was associated with a substantial decrease in risk of hyperkalemia. However, in their enthusiasm, the authors forget to emphasize that these findings only hold true in African Americans, as 100% of their patients were African Americans."

Dr. Messerli cited the Atherosclerosis Risk in Communities (ARIC) Study (Andrew ME, et al., Am J Hypertens. 2002 Jul;15[7 Pt 1]:594-599), which documented that unprovoked hypokalemia for African Americans was more than 5 times more common vs European Americans.

"African Americans are well known to have a tendency to hypokalemia that is not shared by white patients," Dr. Messerli said. "Thus, any extrapolation from these findings to a general hypertensive population is not appropriate."

"The clinical implications are that when African American patients with chronic kidney disease don't have a GFR above 40, physicians can be less vigilant in monitoring potassium with ACE inhibitor therapy, [but] white patients with chronic kidney disease and a low GFR need to be closely monitored when a blocker of the renin-angiotensin system is initiated," Dr. Messerli concluded. "Given the racial difference in the risk of hypokalemia and in potassium metabolism, a comparative study looking at the risk of hyperkalemia with renin-angiotensin blockade should be done in a biracial population. Until then, physicians should remain vigilant with regard to hyperkalemia with the addition of an ACE inhibitor or ARB in patients with low GFR."

The AASK trial was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases and received additional financial support from the Office of Research in Minority Health and drug donations from Pfizer Inc, AstraZeneca Pharmaceuticals, and King Pharmaceuticals. The study authors and Dr. Messerli have disclosed no relevant financial relationships.

Arch Intern Med. 2009;169:1587-1594. Abstract