title: The effect of ramipril and telmisartan on serum potassium and its association with cardiovascular and renal events: results from the ONTARGET trial.
abstract: OBJECTIVE
  In the Ongoing Telmisartan Alone and in Combination with Ramipril Trial (ONTARGET), dual agent renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) did not reduce the risk of renal and cardiovascular outcomes compared with the single use of either agent. Dual therapy however increased the incidence of hyperkalemia. We examined risk factors for hyper- and hyokalemia and hypothesized that both would be associated with worse cardiovascular and renal outcomes.
  
  
  METHODS
  A post-hoc analysis of the ONTARGET trial comparing dual therapy (ramipril and telmisartan) vs monotherapy (ramipril or telmisartan) was performed. The association between serum potassium at week 6 on cardiovascular and renal outcomes during the 56 months follow-up was assessed by multivariate Cox analysis. The main cardiovascular outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The renal outcome was defined as the composite of a doubling of serum creatinine or chronic dialysis.
  
  
  RESULTS
  Six weeks after randomization, hyperkalemia developed in 210 (2.7%) patients on dual therapy vs. 264 (1.6%) patients on monotherapy (p < 0.001 vs. dual therapy). Hypokalemia developed in 87 (1.1%) patients on dual therapy vs. 200 (1.2%)patients on monotherapy. Serum potassium was nonlinearly associated with cardiovascular and renal events with a nadir between 4.0-5.0 mmol/l for cardiovascular and 4.0-4.5 mmol/l for renal events such that subjects above or below these values exhibited higher risks. This association was independent of age, gender, diabetes, estimated glomerular filtration rate, systolic blood pressure and diuretic use.
  
  
  CONCLUSIONS
  With the precautions stipulated by the protocol of the ONTARGET trial, hypokalemia and hyperkalemia were infrequent events. Nevertheless, both high and low serum potassium were associated with an increased risk of cardiovascular and renal disease.
authors.affiliation: Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hiddo J Lambers
authors.initials: HJ
authors.lastname: Heerspink
authors.forename: Peggy
authors.initials: P
authors.lastname: Gao
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.forename: Catherine
authors.initials: C
authors.lastname: Clase
authors.forename: Gilles R
authors.initials: GR
authors.lastname: Dagenais
authors.forename: Peter
authors.initials: P
authors.lastname: Sleight
authors.forename: Eva
authors.initials: E
authors.lastname: Lonn
authors.forename: Koon T
authors.initials: KT
authors.lastname: Teo
authors.forename: Salim
authors.initials: S
authors.lastname: Yusuf
authors.forename: Johannes F
authors.initials: JF
authors.lastname: Mann
mesh_terms: D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D000959:Antihypertensive Agents / Q000009:adverse effects*; D001562:Benzimidazoles / Q000009:adverse effects*; D001565:Benzoates / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000209:etiology / Q000628:therapy; D006760:Hospitalization; D006801:Humans; D006947:Hyperkalemia / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D006973:Hypertension / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D007008:Hypokalemia / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D007674:Kidney Diseases / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000097:blood / Q000209:etiology; D017711:Nonlinear Dynamics; D016017:Odds Ratio; D011188:Potassium / Q000097:blood*; D016016:Proportional Hazards Models; D017257:Ramipril / Q000009:adverse effects*; D006435:Renal Dialysis; D012084:Renin-Angiotensin System / Q000187:drug effects; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000209:etiology; D000077333:Telmisartan; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001565:Benzoates; D003404:Creatinine; D017257:Ramipril; D011188:Potassium; D000077333:Telmisartan
keywords: Dual RAAS blockade; cardiovascular; hyperkalemia; nephropathy; potassium