Difficulties in Maintaining Potassium Homeostasis in Patients with Heart Failure

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1 4686g-dursun 8/14/06 11:14 AM Page 1 Clin. Cardiol. 29, (2006) Difficulties in Maintaining Potassium Homeostasis in Patients with Heart Failure IHSAN DURSUN, M.D., AND MAHMUT SAHIN, M.D. Ondokuz Mayis University Medical School, Department of Cardiology, Samsun, Turkey Summary: Potassium (K) concentration plays a significant role in cell metabolism and membrane excitability. The imbalance of serum potassium is important because it can lead to life-threatening events. Potassium balance may be lost both through the neurohormonal mechanisms involved in cardiovascular diseases and through the drugs used in the treatment of this illness. Avoiding both hypo- and hyperkalemia is beneficial in several cardiovascular diseases, especially heart failure. Electrolyte abnormalities are frequently seen complications in subjects with heart failure. Malignant ventricular arrhythmias and sudden cardiac death are particularly feared complications in K + instability. Key words: potassium imbalance, potassium and heart failure, potassium and drugs Potassium Homeostasis Address for reprints: Dr. Ihsan Dursun Ondokuz Mayis Universitesi Tip Fakultesi Kardiyoloji Anabilim Dali Samsun, Turkey ihsandursun@mynet.com Received: November 20, 2005 Accepted with revision: February 16, 2006 Total body potassium (K + ) is 4,000 mmol, of which 98% is intracellular and only mmol is extracellular in an adult. The different distribution of K + is the basis of transmission in muscle and nerve cells. The ratio of intra- to extracellular K + reflects the resting membrane potential. 1, 2 Potassium homeostasis is preserved by oral intake under physiologic conditions. The mean daily dietary intake of K + is mmol; when the dietary intake of K + is reduced to < 25 mmol per day, depletion of K + and hypokalemia are seen. 3 Normal transcellular distribution of K + is maintained by two major hormones. Insulin increases the entry of sodium (Na + ) ions through cells by stimulating the membrane Na + - H + exchanger. Sodium ions exit and K + ions enter the cells by activation of Na + -K + adenosine triphosphate (ATPase). Betaadrenergic catecholamines stimulate cell membrane Na + - K + ATPase. Thus, both insulin and beta-adrenergic catecholamines increase cellular potassium uptake. There is a positive feedback system valid for insulin, in which hyperkalemia stimulates insulin secretion; however, no feedback systems have been identified for beta-adrenergic catecholamines. 2, 3 Aldosterone is the major regulator hormone of body stores of potassium. Its main effect is on the excretion of potassium from the kidneys and therefore on preserving the K + balance. There is a feedback system for aldosterone: hyperkalemia stimulates the release of aldosterone and hypokalemia inhibits it. 3 A serum potassium increase by 0.25 mmol/l elevates serum aldosterone concentrations by 50 to 100%. 1 Heart Failure and Potassium Electrolyte abnormalities are frequently seen complications in subjects with heart failure (HF). The pathophysiologic changes and renal dysfunction that develop in HF and cause neurohormonal activation (stimulation of the renin-angiotensin-aldosterone system, sympathoadrenergic stimulation), affect the potassium balance. 4 All causes of potassium disturbances are presented in Table I. Abnormalities in cardiac conduction are extremely unusual in patients without heart disease, even when the serum K + concentration is < 3.0 mmol/l. Nevertheless, even mild to moderate hypokalemia increases the likelihood of cardiac arrhythmias in patients with cardiac ischemia, HF, or left ventricular hypertrophy. 3 As many as 50% of HF deaths are sudden death due to malignant ventricular tachyarrhythmias. Hypokalemia is a potent and independent predictor of mortality in HF. Myocardial potassium levels were found to be significantly lower in subjects with sudden death than in controls. 5 Maintenance of the serum potassium levels > 4 mmol/l is recommended in HF. 1 It is recommended in the guidelines for the diagnosis and treatment of chronic HF that the treatment begin with angiotensin-converting enzyme inhibitors (ACE-I) in asymptomatic subjects in New York Heart Association (NHYA) II and continue with diuretics and beta blockers (also indicated in asymptomatic subjects after acute myocardial infarction); spironolactone and cardiac glycosides should be added in subjects in NYHA class III IV. 6 These drugs either alter the serum potassium balance or are affected by the potassium balance (Fig. 1).

2 4686g-dursun 8/14/06 11:14 AM Page 389 I. Dursun and M. Sahin: Potassium homeostasis in HF 389 TABLE I All causes of potassium disturbances Hypokalemia Hyperkalemia Potassium loss in stool Transcellular movement of potassium Infectious diarrhea, tumors (vipoma, Zollinger-Ellison Metabolic acidosis, exercise, hyperglycemia, insulin deficiency, syndrome), Jejunoileal bypass, enteric fistula, chemotherapy, acute tumor lysis, intravascular hemolysis, rhabdomyolysis, malabsorption, geophagia hyperkalemic familial periodic paralysis Potassium loss in urine Total body potassium excess Primer hyperaldosteronism, metabolic alkalosis, congenital Acute or chronic renal failure, burns, bleeding into gastrointestinal adrenal hyperplasia, renin-secreting tumors, Cushing s syndrome, tract, adrenal insufficiency, oral or parenteral potassium therapy, renovascular hypertension, Bartter s syndrome, tissue injury, hyporeninemic hypoaldosteronism (type 4 renal Gitelman s syndrome tubular acidosis), fasting (suppression of insulin secretion) Drug-induced hypokalemia Drug-induced hyperkalemia Beta-adrenergic agonists, tocolytic agents, theophylline, thiazide Beta-blockers, ACE-I, A-II RB, digital intoxication, NSAIDs, and loop diuretics, verapamil intoxication, mineralocorticoids, heparin, tacrolimus, ketoconazole, trimethoprim, potassium-sparinsulin overdose, antibiotics ing diuretics, pentamidine, cyclosporine Abbreviations: ACE-I = angiotensin-converting enzyme inhibitor, A-II RB = angiotensin-ii receptor blocker, NSAIDs = nonsteroidal antiinflammatory drugs. Potassium and Drugs in Hypokalemia Diuretics Both hypokalemia secondary to diuretics which increases K + excretion and hyperkalemia secondary to potassium-sparing diuretics, contribute to mortality and morbidity in subjects with HF. The most frequent cause of hypokalemia is the use of diuretics. Hypokalemia is seen as the result of the use of hydrochlorthiazides and loop diuretics in 5 30% and 5 20% of cases, respectively. 7 Renal K + loss due to the use of the diuretics may be increased even more because of hyperaldosteronism in patients with HF who have not been treated. The risk of developing ventricular arrhythmias secondary to the use of diuretics is high, particularly in elderly patients with organic heart disease who receive high doses of diuretics. 8 Both thiazide and loop diuretics may cause hypomagnesemia, providing the basis for ventricular arrhythmias. 5 Magnesium (Mg) is a cofactor of the activation of Na + -K + ATPase, 9 and although it affects the K + balance, it is not measured routinely. Hypomagnesemia leads to refractory hypokalemia. Magnesium deficiency makes it difficult to correct K + deficiency (particularly when Mg < 0.5 mmol/l) and Mg should be replaced first. 3 Intravenous Mg sulfate is the agent of choice for immediate treatment of torsade de pointes (Fig. 2). How Mg prevents the recurrences of torsade de pointes is not clear, but it is able to inhibit both early afterdepolarizations and tachyarrhythmias Potassium and Drugs in Hyperkalemia Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers The ACE-Is are used in 10 38% of patients hospitalized with hyperkalemia. 14 The risk of increased serum potassium levels reported in randomized trials of patients with congestive heart failure varies from 1.2 to 4.9% (Table II). 15, 16 Discontinuation of ACE-I therapy was necessary in very few patients, however. Hyperkalemia induced by ACE-I or angiotensin-ii receptor (A-II R) blockers may result from decreased sodium absorption from the distal nephron, which impairs K + excretion; from aldosterone deficiency; or because of abnormal functioning of Hypokalemia 1-Loop diuretics Hyperkalemia 2-Thiazide diuretics 1-ACE-I 2-A-II RB 3-K + sparing diuretics 4-Beta blockers 5-Heparin Heart failure FIG. 1 Drugs affecting the potassium balance in treatment of heart failure. ACE-I = angiotensin-converting enzyme inhibitor, A-II RB = angiotensin-ii receptor blocker, K + = potassium. (A) (B) FIG. 2 Torsade de pointes due to hypokalemia: (A) Electrocardiogram showed sinus rhythm with multifocal ventricular extrasystoles and prolonged QT interval. Potassium level was 2.3 mmol/l; (B) 4.5 h later, typical torsade de pointes. 13

3 4686g-dursun 8/14/06 11:14 AM Page Clin. Cardiol. Vol. 29, September 2006 TABLE II Hyperkalemia rates in randomized controlled trials of angiotensin-converting enzyme inhibitors in patients with heart failure No. of Trials (Ref. No.) patients Therapy Disease Hyperkalemia rate SOLVD (15) 6,797 Enalapril or placebo Heart failure 1.2 vs. 0.4% TRACE (16) 1,749 Trandolapril or placebo Recent MI 4.9 vs. 2.6% ATLAS (17) 3,164 Low- and high-dose lisinopril Heart failure 4 vs. 6% NETWORK (18) 1, , 5, or 10 mg enalapril Heart failure 1.6, 2.2, and 3.3% Abbreviations: MI = myocardial infarction, SOLVD = Studies Of Left Ventricular Dysfunction, TRACE = Trandolapril Cardiac Evaluation, ATLAS = Assessment of Treatment with Lisinopril and Survival, NETWORK = Network of general practitioners and hospital physicians involved in the study of low versus high doses of enalapril in patients with heart failure trial. the cortical collecting tubules. Reduction of aldosterone synthesis through ACE-I in patients with normal renal function does not result in a clinically significant increase in serum potassium concentrations; 19 severe hyperkalemia that develops during ACE is seen mainly in patients with diabetes and renal failure. The risk of hyperkalemia increases with high doses and combinations of these drugs, and this risk is further increased when an aldosterone antagonist is also added. In addition, afterload-reducing effect of ACE-Is or A-II R blockers may contribute to the development of hyperkalemia in patients with HF. 14 The fact that ACE-I and A-II R blockers decrease mortality rates in HF despite their hyperkalemic effects has been demonstrated in randomized trials (Tables II and III) , Beneficial effects of ACE-I on mortality may also be due to the fact that they decrease ventricular arrhythmias by increasing serum potassium. 1 If treatment with an ACE-I or an AlI-R blocker is initiated in patients at risk of hyperkalemia, the initial dose should be low and their renal function should first be evaluated by calculation of the glomerular filtration rate (GFR) (rather than serum creatine levels). The risk is high in patients with GFR < 30 ml/min. Serum potassium concentrations should be checked within 1 week following the initial treatment or after increasing the dose of the drug. If potassium increases to 5.5 mmol/l, the drug dose should be decreased or the patient withdrawn from the combination of aldosterone receptor blockers (if applicable). Use of this combination should be avoided when the GFR is < 30 ml/min. If despite all these precautions potassium is still > 5.5 mmol/l, the drugs should be discontinued. 14 TABLE III Changes in serum potassium in randomized controlled trials of angiotensin-ii receptor blockers in patients with heart failure Trials No. of (Ref. No.) patients Duration Therapy Disease Comment CHARM- 7, Years Candesartan Heart failure Potassium > 6 mmol/l: Overall (20) vs. placebo Candesartan 2%, placebo 1% (p = 0.017) CHARM- 2, Years Candesartan Heart failure Potassium > 6 mmol/l: Added (21) vs. placebo Candesartan 3%, placebo 1% (p = 0.089) VALIANT (22) 14, Years Valsartan, Recent MI Requiring dose reduction due captopril, and to hyperkalemia: Valsartan 1.3%, combination captopril 0.9%, and combination 1.2% OPTIMAAL (23) 5, Years Losartan Recent MI Change from baseline potassium: vs. captopril Losartan 0.19 mmol/l, captopril 0.22 mmol/l (p = 0.01) Val-HEFT (24) 5, Years Valsartan Heart failure Mean change serum potassium: vs. placebo Valsartan, increase 0.12 mmol/l; placebo, decrease 0.07 mmol/l (p < 0.001) ELITE (25) Weeks Losartan Heart failure Withdrawals due to hyperkalemia: vs. captopril Losartan 0.6%, captopril 1.6% Abbreviations: MI = myocardial infarction, CHARM = Candesartan cilexitil (Atacand ) in Heart failure Assessment of Reduction Mortality and morbidity, VALIANT = VALsartan In Acute myocardial infarction Trial, OPTIMAAL = Optimal Trial in Myocardial infarction with the Angiotensin-II Antagonist Losartan, Val-HEFT = VALsartan Heart Failure Trial, ELITE = Evaluation of Losartan In the Elderly.

4 4686g-dursun 8/14/06 11:14 AM Page 391 I. Dursun and M. Sahin: Potassium homeostasis in HF 391 Beta Blockers Beta-blocking agents are recommended for the treatment of HF. 6 They decrease hypokalemia by inhibition of both Na + -K + ATPase and renin secretion, and this contributes to their beneficial effects in prevention of sudden cardiac death. 14, 26 Although nonselective and beta 2 -selective blockers are believed to protect patients from hypokalemia secondary to high levels of catecholamines, beta 1 -selective blockers do not have this protective effect. 7, 27 Adrenaline stimulates the Na + -K + ATPase pump via beta 2 - receptors and shifts intracellular potassium. 28 Serum potassium shows negative correlation with plasma renin activity and noradrenalin in HF, and patients who respond to treatment show increases in intracellular potassium concentration. Therefore, the neurohormonal activation contributes significantly to potassium consumption in HF. Since catecholamines increase arrhythmia risk by causing hypokalemia, beta-blocker treatment has beneficial effects on mortality in HF. 1 Potassium-Sparing Diuretics Aldosterone antagonists: It has been proven that the addition of spironolactone to ACE-I treatment in patients with HF decreases mortality. 29 However, the risk of developing hyperkalemia due to ACE-I increases even more with the addition of spironolactone. In healthy individuals, aldosterone has a generally transient effect on sodium reabsorption, but it results in continuous sodium retention in the presence of HF and hypertension. Thus, it causes loss of K + and Mg, which contributes to the development of ventricular arrhythmia. 30 Many researchers have found that the incidence of clinical hyperkalemia due to spironolactone involving HF treatments is 10%. 31 However, this rate was smaller than the rate determined (2%) in the Randomized Aldactone Evaluation Study (RALES), which demonstrated the benefits of spironolactone in the treatment of HF. 29 In RALES, mean K + concentration increased by 0.3 mmol/l in the spironolactone group compared with the placebo group. Although this rate was statistically significant, it was clinically unimportant. No difference in occurrence of severe hyperkalemia was found between the two groups. However, the K + levels of the patients recruited in the study were < 5.0 mmol/l and their mean creatine levels were 1.2 mg/dl. Although hyperkalemia was observed less in RALES, the risk of developing hyperkalemia due to the ACE-I and spironolactone combination was found to be high in studies performed later, particularly in subjects with renal dysfunction. 32 According to a recently published study performed to investigate the effects of the publication of RALES on the use of this combination, hospitalization rates of patients with HF due to hyperkalemia were 0.2% prior to RALES, and increased significantly to 1.1% after completion of the study. 33 In-hospital deaths due to hyperkalemia had increased seven-fold to 0.2%. It is interesting that, although the prescription rate of spironolactone had increased five-fold after RALES, there was no relationship between the decrease in rehospitalization due to HF and deaths due to all causes. 33 TABLE IV Administration and dosing considerations with spironolactone in patients with heart failure Check serum potassium (< 5.0 mmol/ l) and creatinine (< 250 µmol/l) Add 25 mg spironolactone daily Check serum potassium and creatinine after 4 6 days If at any time serum potassium mmol/l, reduce dose by 50%. Stop if serum potassium > 5.5 mmol/l If after 1 month symptoms persevere and normokalemia exists, increase to 50 mg daily. Check serum potassium/creatinine after 1 week According to the guidelines for the diagnosis and treatment of chronic HF, K + levels should be < 5 mmol/l to warrant the addition of spironolactone to standard treatment in patients with HF (Table IV). 6 Caution is advised in patients with abnormal renal function and diabetes mellitus with hyporeninemic hypoaldosteronism because severe hyperkalemia may ensue. 7 The addition of eplerenone, a selective aldosterone blocker, to the standard treatment in patients with HF and hypertension has increased the risk of hyperkalemia significantly. While the rate of hyperkalemia was 2% in RALES, it was found to be 5% in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). 34 Amiloride and triamterene: Triamterene and amilorid block the epithelial sodium channel in the collecting duct, thereby removing a major driving force for the secretion of potassium. 14 At present, potassium-sparing diuretics should only be considered if there is persisting diuretic-induced hypokalemia despite concomitant ACE-I therapy, or in severe HF, despite concomitant ACE inhibition plus low-dose spironolactone. 6 Cardiac Glycosides Cardiac glycosides are indicated in atrial fibrillation and any class of symptomatic HF. 6 They inhibit the Na + -K + ATPase enzyme by binding reversibly. Under physiologic conditions, these drugs bind the enzyme through phosphorylation. Extracellular K + facilitates the dephosphorylation of the enzyme and thus decreases the binding affinity of digoxin to the enzyme. This effect of K + explains its use in digital intoxication. 5 Hypokalemia facilitates digital intoxication by both decreasing the renal clearance and facilitating the myocardial binding of the drug. Hyperkalemia depolarizes the myocytes and strengthens the suppressive effect of digoxin on the atrioventricular node. 1 Hyperkalemia may be due to digitalis toxicity, and it is believed to result from inhibition of the Na + -K + ATPase enzyme by digitalis. 7 Digoxin directly limits the renal tubular reabsorption of Mg and increases its excretion. 4 Hypomagnesemia reduces intracellular potassium by decreasing the membrane concentration of the Na + -K + ATPase pump, thus increasing the tendency toward digital intoxication. 1 Hypokalemia and hypomagnesemia should be avoided in patients receiving digitalis. Potas-

5 4686g-dursun 8/14/06 11:14 AM Page Clin. Cardiol. Vol. 29, September 2006 sium chloride used in the treatment of digital intoxication should not be administered in cases of incomplete heart blocks. Atropine or transient pacemaker should be applied in these patients. 35 Dysrhythmias associated with digitalis intoxication have been found to be very sensitive to magnesium sulfate therapy. This may be due to the effect of Mg on Na + -K + ATPase or on calcium or potassium transport. 10 Treatment of digitalis intoxication with digoxin-specific Fab antibody fragments is effective for the management of life-threatening arrhythmias refractory to conventional therapy. The treatment is especially useful in the presence of hyperkalemia. 7 Heparin Patients with HF are at high risk of thromboembolic events. Heparin can cause hyperkalemia by blocking the synthesis of aldosterone. However, severe hyperkalemia occurs in the presence of additional factors affecting potassium homeostasis. While the principle of the treatment is to discontinue the heparin, it is first recommended to discontinue other potassium-elevating drugs (ACE-I, spironolactone) if heparin therapy is vital. 36 Conclusion Changes in potassium ion may cause life-threatening arrhythmias. Although healthy individuals are affected less, patients with HF receiving cardiac medications are susceptible to these effects of potassium. Close follow-up of patients at risk of developing potassium imbalance is very important in the prevention of cardiac events. References 1. Macdonald JE, Struthers AD: What is the optimal serum potassium level in cardiovascular patients? J Am Coll Cardiol 2004;43: Halperin ML, Kamel KS: Potassium. Lancet 1998;352: Gennari FJ: Hypokalemia. N Engl J Med 1998;339: Schwinger RH, Erdmann E: Heart failure and electrolyte disturbances. Methods Find Exp Clin Pharmacol 1992;14: Bristow MR, Port JD, Kelly RA: Treatment of heart failure: Pharmacological methods. In Heart Disease. A Textbook of Cardiovascular Medicine, 6th ed. (Eds. Braunwald E, Zipes DP, Libby P), pp Philadelphia: W.B. Saunders, Remme WJ, Swedberg K: Task force for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22: Khan MG: Cardiac Drug Therapy, 6th ed. Philadelphia: W.B. Saunders, He FJ, MacGregor GA: Beneficial effects of potassium. Br Med J 2001;323: Sheehan JP, Seelig MS: Interactions of magnesium and potassium in the pathogenesis of cardiovascular disease. Magnesium 1984;3: Tong GM, Rude RK: Magnesium deficiency in critical illness. J Intens Care Med 2005;20(1): Vester EG: Clinico-electrophysiologic effects of magnesium, especially in supraventricular tachycardia. Herz 1997;22(suppl 1): Khan IA: Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am J Med 2002;112(1): Eriksson JW, Carlberg B, Hillön V: Life-threatening ventricular tachycardia due to liquorice-induced hypokalemia. J Intern Med 1999;245: Palmer BF: Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004;351: Kostis JB, Shelton B, Gosselin G, Goulet C, Hood WB Jr, Kohn RM, Kubo SH, Schron E, Weiss MB, Willis PW III, Young JB, Probstfield J: Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). SOLVD Investigators. Am Heart J 1996;131(2): Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, Videbaek J, Cole DS, Auclert L, Pauly NC: A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995;333(25): Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, Ryden L, Thygesen K, Uretsky BF: Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999;100(23): The NETWORK Investigators: Clinical outcome with enalapril in symptomatic chronic heart failure: A dose comparison. Eur Heart J 1998;19(3): Brunner HR, Weaber B, Nussberger J: Angiotensin-converting enzyme inhibitors. In Cardiovascular Drug Therapy, 2nd ed. (Ed. Messerli FH), pp Philadelphia: W. B. Saunders, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Ostergren J, Yusuf S, Pocock S, for the CHARM Investigators and Committees: Effects of candesartan on mortality and morbidity in patients with chronic heart failure. The CHARM-Overall programme. Lancet 2003;362: McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA, for the CHARM Investigators and Committees: Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin converting-enzyme inhibitors: The CHARM-Added trial. Lancet 2003;362: Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM, for the Valsartan in Acute Myocardial Infarction Trial Investigators: Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349: Dickstein K, Kjekshus J, and the OPTIMAAL Steering Committee for the OPTIMAAL Study Group: Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: The OPTIMAAL randomized trial. Lancet 2002;360: Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators: A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345: Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, Deedwania PC, Ney DE, Snavely DB, Chang PI: Randomized trial of losartan versus captopril in patients over 65 with heart failure: Evaluation of Losartan in Elderly Study (ELITE). Lancet 1997;349: Podrid PJ: Potassium and ventricular arrhythmias. Am J Cardiol 1990;65: 33E 44E;discussion 52E 27. Madias JE, Shah B, Chintalapally G, Chalavarya G, Madias NE: Admission serum potassium in patients with acute myocardial infarction: Its correlates and value as a determinant of in-hospital outcome. Chest 2000;118: Foo K, Sekhri N, Deaner A, Knight C, Suliman A, Ranjadayalan K, Timmis AD: Effect of diabetes on serum potassium concentrations in acute coronary syndromes. Heart 2003;89: Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341: Struthers AD, MacDonald TM: Review of aldosterone- and angiotensin llinduced target organ damage and prevention. Cardiovasc Res 2004;61: Gross P, Pistrosch F: Hyperkalemia: Again. Nephrol Dial Transplant 2004; 19: Schepkens H, Vanholder R, Billiouvv JM, Lameire N: Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: An analysis of 25 cases. Am J Med 2001;110: Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA: Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med 2004;351: Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M, for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators: Eplerenone, selective aldosterone blocker in patients with left-ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348: Mason DT, Zelis R, Lee G, Hughes JL, Spann JF, Amsterdam EA: Current concepts and treatment of digitalis toxicity. Am J Cardiol 1971;27: Day JRS, Chaudhry AN, Hunt I, Taylor KM: Heparin-induced hyperkalemia after cardiac surgery. Ann Thorac Surg 2002;74: