title: Clinical significance of incident hypokalemia and hyperkalemia in treated hypertensive patients in the antihypertensive and lipid-lowering treatment to prevent heart attack trial.
abstract: Concerns exist that diuretic-induced changes in serum potassium may have adverse effects in hypertensive patients. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, a large practice-based clinical trial, made it possible to examine consequences of observed changes in potassium during care in conventional practice settings. Normokalemic participants randomized to chlorthalidone (C) versus amlodipine or lisinopril as a first-step drug were stratified by year-1 potassium. Postyear-1 outcomes among hypokalemics (potassium, <3.5 mmol/L) and hyperkalemics (potassium, >5.4 mmol/L) were compared with normokalemics (potassium, 3.5-5.4 mmol/L). Year-1 hypokalemia incidence was 6.8%; incidence in C (12.9%) differed from amlodipine (2.1%; P<0.001) and lisinopril (1.0%; P<0.01). Hyperkalemia incidence (2.0%) was greater in lisinopril (3.6%) than in C (1.2%; P<0.01) or amlodipine (1.9%; P<0.01). Coronary heart disease occurred in 8.1% with hypokalemia, 8.0% with normokalemia, and 11.1% with hyperkalemia. Overall, mortality was higher in hypokalemics than in normokalemics (Cox hazard ratio, 1.21 [95% CI, 1.02-1.44]) with statistically significant (interaction, P<0.01) disparity in hazard ratios for the 3 treatment arms (hazard ratios, C=1.21, amlodipine=1.60, lisinopril=3.82). Hyperkalemia was associated with increased risk of combined cardiovascular disease (hazard ratio, 1.58 [95% CI, 1.15-2.18]) without significant treatment interactions. In conventional practice settings, the uncommon appearance of hyperkalemia was associated with increased cardiovascular disease risk. Hypokalemia was associated with increased mortality; however, the statistically significant heterogeneity in hazard ratios across treatment groups strongly suggests that the observed increase in mortality is unrelated to the specific effects of C. Thus, for most patients, concerns about potassium levels should not influence the clinician's decision about initiating hypertension treatment with low-moderate doses of thiazide diuretics (12.5-25.0 mg of C).
authors.affiliation: Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Alderman
authors.forename: Linda B
authors.initials: LB
authors.lastname: Piller
authors.forename: Charles E
authors.initials: CE
authors.lastname: Ford
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Probstfield
authors.forename: Suzanne
authors.initials: S
authors.lastname: Oparil
authors.forename: William C
authors.initials: WC
authors.lastname: Cushman
authors.forename: Paula T
authors.initials: PT
authors.lastname: Einhorn
authors.forename: Stanley S
authors.initials: SS
authors.lastname: Franklin
authors.forename: Vasilios
authors.initials: V
authors.lastname: Papademetriou
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Ong
authors.forename: John H
authors.initials: JH
authors.lastname: Eckfeldt
authors.forename: Curt D
authors.initials: CD
authors.lastname: Furberg
authors.forename: David A
authors.initials: DA
authors.lastname: Calhoun
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davis
mesh_terms: D000368:Aged; D017311:Amlodipine / Q000008:administration & dosage / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001774:Blood Chemical Analysis; D002318:Cardiovascular Diseases / Q000401:mortality / Q000517:prevention & control; D002752:Chlorthalidone / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced* / Q000401:mortality; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D007008:Hypokalemia / Q000139:chemically induced* / Q000453:epidemiology; D015994:Incidence; D053208:Kaplan-Meier Estimate; D017706:Lisinopril / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000401:mortality / Q000517:prevention & control*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D017311:Amlodipine; D017706:Lisinopril; D002752:Chlorthalidone