Journal of Clinical Pharmacy and Therapeutics, 2014, 39, 61–68
doi: 10.1111/jcpt.12109
Onset time of hyperkalaemia after angiotensin receptor blocker initiation: when should we start serum potassium monitoring? I.-W. Park*2 MD PhD, S. S. Sheen†2 MD PhD, D. Yoon‡ MD MS, S.-H. Lee§ PharmD PhD, G.-T. Shin* MD FASN, H. Kim* MD PhD and R. W. Park‡¶** MD PhD *Department of Nephrology, Ajou University School of Medicine, †Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, ‡Department of Biomedical Informatics, Ajou University School of Medicine, §College of Pharmacy, Ajou University, Suwon, Korea, ¶Center for Clinical Epidemiology, and Biostatistics, and Department of Biostatistics & Epidemiology, Perelman School of Medicine at the University of Pennsylvania, and **Center for Pharmacoepidemiololgy Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Received 11 October 2013, Accepted 14 October 2013
Keywords: adverse effects, angiotensin receptor blockers, hyperkalaemia, potassium
SUMMARY
WHAT IS KNOWN AND OBJECTIVE
What is known and objective: Angiotensin receptor blockers (ARBs) frequently induce hyperkalaemia in high-risk patients. Early detection of hyperkalaemia can reduce the subsequent harmful effects. This study was performed to examine the onset time of hyperkalaemia after ARB therapy. Methods: We carried out a retrospective analysis to determine the onset time of hyperkalaemia (serum potassium >55 mM) among hospitalized patients newly starting ARB therapy between 2004 and 2012, in a tertiary teaching hospital. Predefined possible risk factors and concomitant medications were evaluated. Results and discussion: During the 97-month study period, a total of 4267 hospitalized patients started ARBs as new drugs and 225 patients showed hyperkalaemia. A significantly increased risk of hyperkalaemia was detected among patients with a high baseline potassium [odds ratio (OR) 60] and those who took non-potassium-sparing diuretics (OR 22) or potassium supplements (OR 16). A high glomerular filtration rate (GFR) was associated with a lower risk of hyperkalaemia (OR 0992). Fifty-two percentage of hyperkalaemic events occurred within the first week after initiation of ARB therapy. The highest frequency of hyperkalaemia occurred on the first day after initiation of ARBs. Hyperkalaemia occurred earlier in patients with a high baseline serum potassium level, reduced GFR, diabetes and in those without heart failure. What is new and conclusion: Hyperkalaemia occurs most frequently at the beginning of ARB therapy in hospitalized patients. Monitoring of serum potassium and estimated GFR after initiation of ARBs should be started within a few days or not later than 1 week, especially in patients with risk factors.
The use of angiotensin receptor blockers (ARBs) is increasing, and ARBs are now the most widely used antihypertensive drugs.1 ARBs have shown positive therapeutic results in patients with hypertension, heart dysfunction or diabetic nephropathy independent of their effect on blood pressure.2 However, ARBs are known to increase the risk of hyperkalaemia in some patient populations. Although ARB-associated hyperkalaemia is rare in low-risk patients, patients with risk factors such as renal insufficiency, diabetes or heart failure show increased risk of hyperkalaemia, ranging from 2% to 31%.3–7 Our previous study also showed that hyperkalaemia occurred in 54% of hospitalized patients receiving ARBs.8 Taking into consideration of the frequent occurrence of hyperkalaemia, proper monitoring strategies are critical for the safety of patients given ARBs, especially those at high risk. Raebel et al.9 reported that patients with diabetes who underwent serum potassium monitoring during their first year of therapy with renin– angiotensin–aldosterone system inhibitors were less likely to experience hyperkalaemia-associated adverse events than those who did not undergo monitoring. This protective effect of monitoring was evident in patients who also had advanced chronic kidney disease.9 Despite widespread agreement that potassium monitoring is a component of good clinical care for ARB administration, potassium monitoring has been performed in only a subset of patients.10 Although the reasons for lack of monitoring are incompletely understood, several factors may contribute, such as clinician and patient non-adherence to test ordering and completion, inconsistent recommendations for potassium-monitoring timing and frequency, consensus-based rather than evidence-based monitoring guidelines and a lack of guidelines tailored to patient-specific risks.3 There is a paucity of evidence regarding the onset time of hyperkalaemia after initiation of ARBs. This study was performed to examine the onset time of hyperkalaemia after ARB initiation in a cohort of hospitalized patients with different risk profiles, and to provide evidence for evidence-based establishment of potassium-monitoring recommendations for patients newly receiving ARBs.
Correspondence: Rae Woong Park, Department of Biomedical Informatics, Ajou University School of Medicine, Wonchon-dong, Yeongtong-gu, Suwon, Gyeonggi-do 442-749, Korea. and Center for Clinical Epidemiology and Biostatistics, and Department of Biostatistics & Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Tel.: +82-31-219-4471; fax: +82-31-219-4472; e-mail: [email protected] 2 The first two authors contributed equally to this work.
© 2013 John Wiley & Sons Ltd
METHODS Study population The data sources used for this study have been reported and described previously.8,11–16 The practice research database consists
61
I.-W. Park et al.
When does hyperkalaemia occur after ARB initiation?
from June 1994 to June 2012. The database contains 1056 million prescriptions, 1416 million laboratory tests and 17 million admissions. The Institutional Review Board of Ajou University Hospital approved this study. Patient selection and definition of events A retrospective cohort study with incident (new) user design was performed (Fig. 1). The cohort consisted of hospitalized patients newly prescribed ARBs (including ARB combination products) aged 18 years or more during the study period, which started on 12 April 2004 and ended on 31 May 2012. New ARB users were defined as patients who took ARBs during the hospitalization period for the first time without a history of having been prescribed these drugs previously in the hospital. The ARBs were introduced to the drug formulary of the institute in 2004. Candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan were available in the formulary of the institution. We excluded patients with baseline serum potassium at the time of admission outside the upper reference range (>55 mM). Patients with a short period of ARB administration (55 mM) at the time of admission were excluded. The observation period began at the first serum potassium measurement, 24 h after initiation of angiotensin receptor blockers (ARBs) until the last serum potassium measurement, within 48 h after the last ARB administration or within 30 days after ARB initiation during the period of hospitalization. First hyperkalaemia during the observation period was used as an indication of an event.
of clinical, prescribing, laboratory and administrative data from clinical records of about 23 million people from a Korean tertiary teaching hospital (Ajou University Hospital) over the 18 years Table 1. Characteristics of the study participants
Hyperkalaemic event Characteristics
All study participants
Yes
No
P-valuea
N Age Male Baseline K+b Maximal K+b Baseline creatinine Baseline GFRc GFR ≥ 60 30 ≤ GFR
doi: 10.1111/jcpt.12109
Onset time of hyperkalaemia after angiotensin receptor blocker initiation: when should we start serum potassium monitoring? I.-W. Park*2 MD PhD, S. S. Sheen†2 MD PhD, D. Yoon‡ MD MS, S.-H. Lee§ PharmD PhD, G.-T. Shin* MD FASN, H. Kim* MD PhD and R. W. Park‡¶** MD PhD *Department of Nephrology, Ajou University School of Medicine, †Department of Pulmonary and Critical Care Medicine, Ajou University School of Medicine, ‡Department of Biomedical Informatics, Ajou University School of Medicine, §College of Pharmacy, Ajou University, Suwon, Korea, ¶Center for Clinical Epidemiology, and Biostatistics, and Department of Biostatistics & Epidemiology, Perelman School of Medicine at the University of Pennsylvania, and **Center for Pharmacoepidemiololgy Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Received 11 October 2013, Accepted 14 October 2013
Keywords: adverse effects, angiotensin receptor blockers, hyperkalaemia, potassium
SUMMARY
WHAT IS KNOWN AND OBJECTIVE
What is known and objective: Angiotensin receptor blockers (ARBs) frequently induce hyperkalaemia in high-risk patients. Early detection of hyperkalaemia can reduce the subsequent harmful effects. This study was performed to examine the onset time of hyperkalaemia after ARB therapy. Methods: We carried out a retrospective analysis to determine the onset time of hyperkalaemia (serum potassium >55 mM) among hospitalized patients newly starting ARB therapy between 2004 and 2012, in a tertiary teaching hospital. Predefined possible risk factors and concomitant medications were evaluated. Results and discussion: During the 97-month study period, a total of 4267 hospitalized patients started ARBs as new drugs and 225 patients showed hyperkalaemia. A significantly increased risk of hyperkalaemia was detected among patients with a high baseline potassium [odds ratio (OR) 60] and those who took non-potassium-sparing diuretics (OR 22) or potassium supplements (OR 16). A high glomerular filtration rate (GFR) was associated with a lower risk of hyperkalaemia (OR 0992). Fifty-two percentage of hyperkalaemic events occurred within the first week after initiation of ARB therapy. The highest frequency of hyperkalaemia occurred on the first day after initiation of ARBs. Hyperkalaemia occurred earlier in patients with a high baseline serum potassium level, reduced GFR, diabetes and in those without heart failure. What is new and conclusion: Hyperkalaemia occurs most frequently at the beginning of ARB therapy in hospitalized patients. Monitoring of serum potassium and estimated GFR after initiation of ARBs should be started within a few days or not later than 1 week, especially in patients with risk factors.
The use of angiotensin receptor blockers (ARBs) is increasing, and ARBs are now the most widely used antihypertensive drugs.1 ARBs have shown positive therapeutic results in patients with hypertension, heart dysfunction or diabetic nephropathy independent of their effect on blood pressure.2 However, ARBs are known to increase the risk of hyperkalaemia in some patient populations. Although ARB-associated hyperkalaemia is rare in low-risk patients, patients with risk factors such as renal insufficiency, diabetes or heart failure show increased risk of hyperkalaemia, ranging from 2% to 31%.3–7 Our previous study also showed that hyperkalaemia occurred in 54% of hospitalized patients receiving ARBs.8 Taking into consideration of the frequent occurrence of hyperkalaemia, proper monitoring strategies are critical for the safety of patients given ARBs, especially those at high risk. Raebel et al.9 reported that patients with diabetes who underwent serum potassium monitoring during their first year of therapy with renin– angiotensin–aldosterone system inhibitors were less likely to experience hyperkalaemia-associated adverse events than those who did not undergo monitoring. This protective effect of monitoring was evident in patients who also had advanced chronic kidney disease.9 Despite widespread agreement that potassium monitoring is a component of good clinical care for ARB administration, potassium monitoring has been performed in only a subset of patients.10 Although the reasons for lack of monitoring are incompletely understood, several factors may contribute, such as clinician and patient non-adherence to test ordering and completion, inconsistent recommendations for potassium-monitoring timing and frequency, consensus-based rather than evidence-based monitoring guidelines and a lack of guidelines tailored to patient-specific risks.3 There is a paucity of evidence regarding the onset time of hyperkalaemia after initiation of ARBs. This study was performed to examine the onset time of hyperkalaemia after ARB initiation in a cohort of hospitalized patients with different risk profiles, and to provide evidence for evidence-based establishment of potassium-monitoring recommendations for patients newly receiving ARBs.
Correspondence: Rae Woong Park, Department of Biomedical Informatics, Ajou University School of Medicine, Wonchon-dong, Yeongtong-gu, Suwon, Gyeonggi-do 442-749, Korea. and Center for Clinical Epidemiology and Biostatistics, and Department of Biostatistics & Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Tel.: +82-31-219-4471; fax: +82-31-219-4472; e-mail: [email protected] 2 The first two authors contributed equally to this work.
© 2013 John Wiley & Sons Ltd
METHODS Study population The data sources used for this study have been reported and described previously.8,11–16 The practice research database consists
61
I.-W. Park et al.
When does hyperkalaemia occur after ARB initiation?
from June 1994 to June 2012. The database contains 1056 million prescriptions, 1416 million laboratory tests and 17 million admissions. The Institutional Review Board of Ajou University Hospital approved this study. Patient selection and definition of events A retrospective cohort study with incident (new) user design was performed (Fig. 1). The cohort consisted of hospitalized patients newly prescribed ARBs (including ARB combination products) aged 18 years or more during the study period, which started on 12 April 2004 and ended on 31 May 2012. New ARB users were defined as patients who took ARBs during the hospitalization period for the first time without a history of having been prescribed these drugs previously in the hospital. The ARBs were introduced to the drug formulary of the institute in 2004. Candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan and valsartan were available in the formulary of the institution. We excluded patients with baseline serum potassium at the time of admission outside the upper reference range (>55 mM). Patients with a short period of ARB administration (55 mM) at the time of admission were excluded. The observation period began at the first serum potassium measurement, 24 h after initiation of angiotensin receptor blockers (ARBs) until the last serum potassium measurement, within 48 h after the last ARB administration or within 30 days after ARB initiation during the period of hospitalization. First hyperkalaemia during the observation period was used as an indication of an event.
of clinical, prescribing, laboratory and administrative data from clinical records of about 23 million people from a Korean tertiary teaching hospital (Ajou University Hospital) over the 18 years Table 1. Characteristics of the study participants
Hyperkalaemic event Characteristics
All study participants
Yes
No
P-valuea
N Age Male Baseline K+b Maximal K+b Baseline creatinine Baseline GFRc GFR ≥ 60 30 ≤ GFR
