Hyperkalemia after the Publication of RALES
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《新英格兰医药杂志》
To the Editor: The data presented by Juurlink et al. (Aug. 5 issue)1 regarding hyperkalemia that was attributed to spironolactone do not justify the conclusion that the rate of admission for hyperkalemia increased. The authors identified "all hospital admissions involving a diagnosis of hyperkalemia," and their database included "up to 16 diagnoses for each admission." They did not review individual records. Therefore, they could not distinguish admissions for hyperkalemia from admissions for other diagnoses that involved hyperkalemia. They should have excluded patients with other primary indications for admission before concluding that the rate of admissions for hyperkalemia increased.2 Since no data on the serum potassium concentration are offered, it is likely that most of the patients in these hyperkalemia-related admissions were patients with potassium concentrations only minimally greater than the normal range, and perhaps as low as 5.2 to 5.4 mmol per liter. For the same reasons, deaths in the hospital cannot be decisively attributed to hyperkalemia. These deaths are referred to both as "associated with hyperkalemia" and as "hyperkalemia-related," but they cannot be designated as "deaths caused by hyperkalemia." Most patients with hyperkalemia in these circumstances are easily treated and would rarely die, if treated properly, while in a hospital.3
David S. Goldfarb, M.D.
New York Harbor Veterans Affairs Medical Center
New York, NY 10010
dsgold@verizon.net
References
Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-551.
Charytan D, Goldfarb DS. Indications for hospitalization of patients with hyperkalemia. Arch Intern Med 2000;160:1605-1611.
Paice B, Gray JM, McBride D, Donnelly T, Lawson DH. Hyperkalaemia in patients in hospital. Br Med J (Clin Res Ed) 1983;286:1189-1192.
To the Editor: Juurlink et al. report dramatic increases in the incidence of hyperkalemia-induced hospitalizations and deaths after publication of the Randomized Aldactone Evaluation Study (RALES).1 Their results provide an important and provocative message to clinicians who care for elderly patients: however, because the authors lacked access to serum creatinine levels, a recognized limitation of their analysis is their inability to adjust for kidney function. Though unavoidable because of their study design, this is an important clinical omission, given the frequently overlooked age-related decrement in kidney function among elderly patients,2 who make up a rapidly growing segment of the U.S. population. We would like to emphasize the importance of considering and assessing kidney function in elderly patients, preferably with the abbreviated Modification of Diet in Renal Disease equation,3 which requires only the serum creatinine concentration, sex, and age for calculation. Adjustment of medication dosages and judicious prescription decisions based on kidney function rather than just the serum creatinine concentration in this population may help to minimize adverse outcomes such as those observed by Juurlink et al.
Britt B. Newsome, M.D., M.P.H.
David G. Warnock, M.D.
University of Alabama at Birmingham
Birmingham, AL 35205
bnewsome@uab.edu
References
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;341:709-717.
Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004;351:585-592.
Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 1999;11:A0828-A0828. abstract.
To the Editor: Juurlink et al. outline six factors to explain the increased rate of hospitalization for hyperkalemia after publication of RALES. With our data set of spironolactone use in patients with heart failure1 we are able to adjust for all the factors except differences in the patient population. We prescribed spironolactone only to those patients strictly fulfilling the RALES inclusion criteria, used the same mean dose of spironolactone as that in RALES, monitored our patients closely, and paid attention to baseline characteristics. Despite these precautions, hyperkalemia necessitating the discontinuation of spironolactone developed in 10 percent of our patients, as opposed to 2 percent in RALES. Fortunately, none of the patients in our cohort were hospitalized because of hyperkalemia.
A substantial number of patients have hyperkalemia even if spironolactone therapy is used and monitored appropriately, although close monitoring may prevent the dire consequences of this condition. The other lesson surely must be to enroll more representative groups of patients in trials of heart failure than are currently enrolled.2 To know how typical patients respond to therapy, one has to study typical patients.
Miles D. Witham, B.M., B.Ch.
Neil D. Gillespie, M.D.
Allan D. Struthers, M.D.
University of Dundee
Dundee DD1 9SY, United Kingdom
m.witham@dundee.ac.uk
References
Witham MD, Gillespie ND, Struthers AD. Tolerability of spironolactone in patients with chronic heart failure -- a cautionary message. Br J Clin Pharmacol 2004;58:554-557.
Masoudi FA, Havranek EP, Wolfe P, et al. Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure. Am Heart J 2003;146:250-257.
To the Editor: In their report of hospital admissions for hyperkalemia after the publication of RALES, Juurlink et al. do not describe the racial distribution of their patient population. We have reported racial differences in potassium concentrations during spironolactone therapy for heart failure.1 In a more recent, prospective study of 35 patients at our heart-failure center, serum potassium concentrations increased to a greater degree in whites than in blacks after the initiation of spironolactone therapy (unpublished data). There were no significant differences between the groups at baseline in terms of the severity of heart failure, medical therapy, or renal function. Despite the use of similar doses of spironolactone (median dose, 25 mg), the median increase in the serum potassium concentration was 0.9 mmol per liter (range, 0.2 to 1.6) in whites, but only 0.1 mmol per liter (range, –0.5 to 1.2) in blacks (P=0.003 by the Mann–Whitney U test). We are interested in the racial background of the patients in the study by Juurlink et al. and would like to know whether the authors observed any racial differences in the incidence of hyperkalemia-related hospitalizations.
Larisa Cavallari, Pharm.D.
Paul Vaitkus, M.D.
Vicki Groo, Pharm.D.
University of Illinois at Chicago
Chicago, IL 60612
humma@uic.edu
References
Cavallari LH, Fashingbauer LA, Beitelshees AL, et al. Racial differences in patients' potassium concentrations during spironolactone therapy for heart failure. Pharmacotherapy 2004;24:750-756.
The authors reply: Goldfarb reiterates an important aspect of our study: namely, that hyperkalemia may have been a nonfatal coexisting condition in many cases. Therefore, these admissions are best considered as having been complicated by hyperkalemia rather than having been caused by it. We have reanalyzed our data by examining hospitalizations in which hyperkalemia was the primary diagnosis and found a similar and statistically significant increase in these admissions between early 1999 and early 2000 (P=0.008).
The corollary of Goldfarb's point merits emphasis. Patients with severe hyperkalemia may die suddenly outside the hospital, with no opportunity for diagnosis, and such deaths will probably be mistakenly attributed to heart disease. This undetected cause of death may partly explain why the widespread prescribing of spironolactone did not have a large beneficial effect on overall mortality or on the rate of readmission for heart failure at the population level. We encourage further research on this issue with the use of laboratory data; however, the true number of deaths resulting from hyperkalemia cannot be known with certainty.
We agree with Newsome and Warnock that renal dysfunction is often overlooked and that creatinine values alone may be misleading in older patients. Their assertion that adjustment for renal disease might have altered our conclusions is incorrect, however, given the ecologic design of our study. Even if the prevalence of renal dysfunction among patients with heart failure rose abruptly after the publication of RALES, diuretic-associated worsening of renal insufficiency is simply another mechanism by which the drug interaction between spironolactone and angiotensin-converting–enzyme (ACE) inhibitors can be mediated.
Witham and colleagues provide further evidence that hyperkalemia occurs more frequently in practice than is predicted by clinical trials. Their findings are consistent with data from other studies indicating that, even in an ideal setting, discontinuation of spironolactone is frequently necessary because of hyperkalemia.1,2 Moreover, because spironolactone dosing at their institution mirrored that in RALES, some patients may have received 50 mg per day — a dose associated with hyperkalemia in 20 percent of patients in a previous study of spironolactone therapy in heart failure.3
Eighty-seven percent of the patients who were treated with spironolactone in RALES were white. Although we have no information regarding the racial background of patients admitted to Ontario hospitals, we agree with Cavallari and colleagues that racial differences in the response to drugs are underappreciated and especially relevant in patients with heart failure.4 Whether the interaction between ACE inhibitors and spironolactone is modulated by race warrants further study, but clinicians should exercise caution with this drug combination in all patients.
David N. Juurlink, M.D., Ph.D.
Sunnybrook and Women's College Health Sciences Centre
Toronto, ON M4N 3M5, Canada
dnj@ices.on.ca
Muhammad M. Mamdani, Pharm.D., M.P.H.
Institute for Clinical Evaluative Sciences
Toronto, ON M4N 3M5, Canada
Donald A. Redelmeier, M.D.
University of Toronto
Toronto, ON M4N 3M5, Canada
References
Bozkurt B, Agoston I, Knowlton AA. Complications of inappropriate use of spironolactone in heart failure: when an old medicine spirals out of new guidelines. J Am Coll Cardiol 2003;41:211-214.
Sligl W, McAlister FA, Ezekowitz J, Armstrong PW. Usefulness of spironolactone in a specialized heart failure clinic. Am J Cardiol 2004;94:443-447.
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;78:902-907.
Taylor JS, Ellis GR. Racial differences in responses to drug treatment: implications for pharmacotherapy of heart failure. Am J Cardiovasc Drugs 2002;2:389-99.
David S. Goldfarb, M.D.
New York Harbor Veterans Affairs Medical Center
New York, NY 10010
dsgold@verizon.net
References
Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-551.
Charytan D, Goldfarb DS. Indications for hospitalization of patients with hyperkalemia. Arch Intern Med 2000;160:1605-1611.
Paice B, Gray JM, McBride D, Donnelly T, Lawson DH. Hyperkalaemia in patients in hospital. Br Med J (Clin Res Ed) 1983;286:1189-1192.
To the Editor: Juurlink et al. report dramatic increases in the incidence of hyperkalemia-induced hospitalizations and deaths after publication of the Randomized Aldactone Evaluation Study (RALES).1 Their results provide an important and provocative message to clinicians who care for elderly patients: however, because the authors lacked access to serum creatinine levels, a recognized limitation of their analysis is their inability to adjust for kidney function. Though unavoidable because of their study design, this is an important clinical omission, given the frequently overlooked age-related decrement in kidney function among elderly patients,2 who make up a rapidly growing segment of the U.S. population. We would like to emphasize the importance of considering and assessing kidney function in elderly patients, preferably with the abbreviated Modification of Diet in Renal Disease equation,3 which requires only the serum creatinine concentration, sex, and age for calculation. Adjustment of medication dosages and judicious prescription decisions based on kidney function rather than just the serum creatinine concentration in this population may help to minimize adverse outcomes such as those observed by Juurlink et al.
Britt B. Newsome, M.D., M.P.H.
David G. Warnock, M.D.
University of Alabama at Birmingham
Birmingham, AL 35205
bnewsome@uab.edu
References
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;341:709-717.
Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004;351:585-592.
Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 1999;11:A0828-A0828. abstract.
To the Editor: Juurlink et al. outline six factors to explain the increased rate of hospitalization for hyperkalemia after publication of RALES. With our data set of spironolactone use in patients with heart failure1 we are able to adjust for all the factors except differences in the patient population. We prescribed spironolactone only to those patients strictly fulfilling the RALES inclusion criteria, used the same mean dose of spironolactone as that in RALES, monitored our patients closely, and paid attention to baseline characteristics. Despite these precautions, hyperkalemia necessitating the discontinuation of spironolactone developed in 10 percent of our patients, as opposed to 2 percent in RALES. Fortunately, none of the patients in our cohort were hospitalized because of hyperkalemia.
A substantial number of patients have hyperkalemia even if spironolactone therapy is used and monitored appropriately, although close monitoring may prevent the dire consequences of this condition. The other lesson surely must be to enroll more representative groups of patients in trials of heart failure than are currently enrolled.2 To know how typical patients respond to therapy, one has to study typical patients.
Miles D. Witham, B.M., B.Ch.
Neil D. Gillespie, M.D.
Allan D. Struthers, M.D.
University of Dundee
Dundee DD1 9SY, United Kingdom
m.witham@dundee.ac.uk
References
Witham MD, Gillespie ND, Struthers AD. Tolerability of spironolactone in patients with chronic heart failure -- a cautionary message. Br J Clin Pharmacol 2004;58:554-557.
Masoudi FA, Havranek EP, Wolfe P, et al. Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure. Am Heart J 2003;146:250-257.
To the Editor: In their report of hospital admissions for hyperkalemia after the publication of RALES, Juurlink et al. do not describe the racial distribution of their patient population. We have reported racial differences in potassium concentrations during spironolactone therapy for heart failure.1 In a more recent, prospective study of 35 patients at our heart-failure center, serum potassium concentrations increased to a greater degree in whites than in blacks after the initiation of spironolactone therapy (unpublished data). There were no significant differences between the groups at baseline in terms of the severity of heart failure, medical therapy, or renal function. Despite the use of similar doses of spironolactone (median dose, 25 mg), the median increase in the serum potassium concentration was 0.9 mmol per liter (range, 0.2 to 1.6) in whites, but only 0.1 mmol per liter (range, –0.5 to 1.2) in blacks (P=0.003 by the Mann–Whitney U test). We are interested in the racial background of the patients in the study by Juurlink et al. and would like to know whether the authors observed any racial differences in the incidence of hyperkalemia-related hospitalizations.
Larisa Cavallari, Pharm.D.
Paul Vaitkus, M.D.
Vicki Groo, Pharm.D.
University of Illinois at Chicago
Chicago, IL 60612
humma@uic.edu
References
Cavallari LH, Fashingbauer LA, Beitelshees AL, et al. Racial differences in patients' potassium concentrations during spironolactone therapy for heart failure. Pharmacotherapy 2004;24:750-756.
The authors reply: Goldfarb reiterates an important aspect of our study: namely, that hyperkalemia may have been a nonfatal coexisting condition in many cases. Therefore, these admissions are best considered as having been complicated by hyperkalemia rather than having been caused by it. We have reanalyzed our data by examining hospitalizations in which hyperkalemia was the primary diagnosis and found a similar and statistically significant increase in these admissions between early 1999 and early 2000 (P=0.008).
The corollary of Goldfarb's point merits emphasis. Patients with severe hyperkalemia may die suddenly outside the hospital, with no opportunity for diagnosis, and such deaths will probably be mistakenly attributed to heart disease. This undetected cause of death may partly explain why the widespread prescribing of spironolactone did not have a large beneficial effect on overall mortality or on the rate of readmission for heart failure at the population level. We encourage further research on this issue with the use of laboratory data; however, the true number of deaths resulting from hyperkalemia cannot be known with certainty.
We agree with Newsome and Warnock that renal dysfunction is often overlooked and that creatinine values alone may be misleading in older patients. Their assertion that adjustment for renal disease might have altered our conclusions is incorrect, however, given the ecologic design of our study. Even if the prevalence of renal dysfunction among patients with heart failure rose abruptly after the publication of RALES, diuretic-associated worsening of renal insufficiency is simply another mechanism by which the drug interaction between spironolactone and angiotensin-converting–enzyme (ACE) inhibitors can be mediated.
Witham and colleagues provide further evidence that hyperkalemia occurs more frequently in practice than is predicted by clinical trials. Their findings are consistent with data from other studies indicating that, even in an ideal setting, discontinuation of spironolactone is frequently necessary because of hyperkalemia.1,2 Moreover, because spironolactone dosing at their institution mirrored that in RALES, some patients may have received 50 mg per day — a dose associated with hyperkalemia in 20 percent of patients in a previous study of spironolactone therapy in heart failure.3
Eighty-seven percent of the patients who were treated with spironolactone in RALES were white. Although we have no information regarding the racial background of patients admitted to Ontario hospitals, we agree with Cavallari and colleagues that racial differences in the response to drugs are underappreciated and especially relevant in patients with heart failure.4 Whether the interaction between ACE inhibitors and spironolactone is modulated by race warrants further study, but clinicians should exercise caution with this drug combination in all patients.
David N. Juurlink, M.D., Ph.D.
Sunnybrook and Women's College Health Sciences Centre
Toronto, ON M4N 3M5, Canada
dnj@ices.on.ca
Muhammad M. Mamdani, Pharm.D., M.P.H.
Institute for Clinical Evaluative Sciences
Toronto, ON M4N 3M5, Canada
Donald A. Redelmeier, M.D.
University of Toronto
Toronto, ON M4N 3M5, Canada
References
Bozkurt B, Agoston I, Knowlton AA. Complications of inappropriate use of spironolactone in heart failure: when an old medicine spirals out of new guidelines. J Am Coll Cardiol 2003;41:211-214.
Sligl W, McAlister FA, Ezekowitz J, Armstrong PW. Usefulness of spironolactone in a specialized heart failure clinic. Am J Cardiol 2004;94:443-447.
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;78:902-907.
Taylor JS, Ellis GR. Racial differences in responses to drug treatment: implications for pharmacotherapy of heart failure. Am J Cardiovasc Drugs 2002;2:389-99.