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1 w wz 16«2y Kor. J. Clin. Pharm., Vol. 16, No w y wcfubcmpdlfs z sƒ BÁ DÁ DÁ CÁ D B z C w D w w w Retrospective Evaluation for Efficacy and Tolerance of beta-blocker in Heart Failure Patients with Concomitant Diabetes Sun Mi Jang a, Min Hee Kang c, Sung Cil Lim c, Jun Seop Lee b, and Myung Koo Lee c a Department of Pharmacy, Chungju, , Korea b Department of Pharmacy, Chungbuk National Hospital, Chungju, , Korea c College of Pharmacy, Chungbuk National University, Cheongju, , Korea Purpose: A retrospective study was performed to assess the efficacy and tolerance of β-blocker administration in patients with heart failure and diabetes. Method: Records of 164 patients who were treated for the heart failure condition more than a year were studied retrospectively. Patients were divided into 4 groups based on their diabetes(dm) status and the administration of β-blockers (DM+β-blocker group: 14, DM w/o β-blocker: 19, No DM + -blocker: 62, No DM + no β-blocker: 69). All patients had been receiving conventional therapy such as digoxin, ACE-I, ARB, diuretics, nitrates, aspirin, anticoagulants or lipid-lowering agents. The primary endpoints (death and hospital admission) were recorded during 1 year period and hemodynamic factors (HR, LVEF, SBP, DBP) were obtained from all patient groups before and after 12 months of β-blocker treatment. To evaluate toxicity of β-blocker, SCr, BUN, AST, ALT and Alkaline phosphatase were obtained. Result: There were less death and hospital admission in DM + β-blocker group than in DM without β-blocker group (p=0.014). Relative risk of hospital admission for DM+β-blocker group over no DM group was Long term β-blocker administration was associated with an improvement of heart rate in patients with DM (P< 0.02) with no significant improvement of LVEF, SBP, DBP. in DM patient. In patient without DM, β-blocker was associated with improvement in LVEF, HR and DBP (P<0.01, P<0.03), but not in SBP. The incidence of toxicity was similar between the four group with no significant difference. Conculsion: Treatment of heart failure patients with β-blocker appears to be beneficial in terms of hospital admission event and several hemodynamic factors. The toxicities of β-blocker treatment were not significant and the treatment is generally well-tolerated in most of the heart failure patients. ý Key words CHF, DM, β-blocker efficacy, Toxicity y» w» ƒ» v w x œ w k w k w. j y, y, q y, ƒ» x y š v w. Renin-Angiotensin-Aldosterone (RAA) system w y w w Correspondence to : w w w Tel: , Fax: myklee@chungbuk.ac.kr š w, y w 1,4) w w w ACE- Inhibitor β-blocker w» w β- practolol alprenolol y (dilated cardiomyopathy) y x (exercise tolerance)» w k š», β-blocker w ƒ, x, y β-blocker n w, w û š. x z ƒ 3) β-blocker Metoprolol, Bisoprolol š Carvedilol, Metoprolol Bisoprolol β 1 -adrenergic receptor k š, Carvedilol β 1 -, β 2 -, α 1 -adrenergic receptor 113

2 114 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 k ùkü. β-blocker 4,5,6) w e w ùkü. k w x wù. ƒ š y w y w { ù z š y ùkü. 7) Framingham study šx ù xx y ƒ š ƒ û y k y ƒ y w 2.4 š y 5.0. w 8) šx, š x, y y ùš w. 8) w» w ƒ», y Neurohormonal Activation, Endothelial Dysfuction, Oxidative Stress k œ wš. y e β-blocker 9) x, x y, Insulin Resistance w» ù, 10) The United Kingdom Prospective Diabetes Study(UKPDS) β-receptor y w. w x ww š ƒ y Carvedilol, Metoprolol Bisoprolol β-blocker n w n w y w y x k. ¾ w β-blocker y n ƒ y ƒ y ùký d ù, US Carvedilol trial, Australia and New Zealand (ANZ)-carvedilol trial, COPERNICUS sww 6 x w meta-analysis β-blocker, ƒ y Mortality ƒ y w x j w š š. 11) β-blocker y y wš, z w x meta analysis w ƒ š š, w β-blocker y q» w z sƒwš w. w û w e š y ƒ β-blockerƒ w x» w w» m w ¾ w û w 1 y 1 e z (follow-up) y 164 w, ù x y w ù, w w y. ü» mw zw k 164 y ƒ š β-blocker» 4 group w z v w w. Group 1(DM+β-blocker) y ƒ ƒ e w β-blocker n, Group 2(DM w/o β-blocker) y ƒ š, e w β-blocker n, Group 3(No DM +β-blocker) y ƒ w š e β-blocker n, Group 4(No DM+no β-blocker) y ƒ w š e β-blocker n w. y w β-blocker Carvedilol( p / )R Bisoprolol(gg / j)r Carvedilol 12.5 mg w 25 mg bid/day w š, Bisoprolol 1.25 mg/1z w ƒw 5 mg/day w. w y Conventional therapy Digoxin, ACE inhibitor,, Aspirin, Anticoagulant, Lipid-lowering agents wš. w y,,, j, (BMI: body mass index),, (stroke), šx coronary artery bypass graft(cabg), x wš,, y ƒ y š (DOE: dyspnea on exertion) Class w. z q w ƒ w Primary end point, z, w, x w w z sƒ e ƒ 1» w (left ventricular ejection fraction),,»x y» x» ü d e w ƒ y mw. ó β-blocker ùkú sƒw» w,, w. 1» e e z heart rate e», w Heart Rate eƒ β-blocker n β-blocker n z e w(hr<60 bpm) û y» w. w β-blocker n d» 1 w w ƒ z

3 w y w beta-blocker z sƒ 115 e w û y d w. 1» e e z Scr, BUN e w. e» ü baseline w e z e w y w. e e z AST, ALT, Alkaline phosphate e w. e» ü baseline w e z AST, ALT, Alkaline phosphatase eƒ e w y w. m SAS system for Window V8 w y ƒ baseline e w. (LVEF: Left Ventricular Ejection Fraction), (HR: Heart Rate),»x (SBP: Systolic Blood Pressure),»x (DBP: Diastolic Blood Pressure) sƒw» w Wilcoxon rank sum test mwš, e z w sƒ w t-test w. w w» w v Kruskal-Wallis test w. m p valueƒ 0.05 w š q w. y p ¾ w û w 1 y 1 e z (follow-up) y w w, y r DM+β-blocker group 14, DM w/o β-blocker group 19, No DM+β-blocker group 62, No DM w/o β-blocker group DM+βblocker group s³ 57.8 ( :34-82) š û ƒ 9, ƒ 5. y ƒ 2, w w x y ƒ 5, CABG w y ƒ 4, šx ƒ š y ƒ 6. x w Conventional therapy digoxin w y ƒ 7, ACE inhibitor w y ƒ 12, w y ƒ 10, aspirin w y ƒ 5. DM w/o β-blocker group s³ 69 ( : ) š û ƒ 11, ƒ 8. ƒ y ƒ 1 š w x y ƒ 1, stroke ƒ y Table 1. Demographic Characteristics of Patients DM + β-blocker group DM w/o β-blocker group No DM + β-blocker group No DM w/o β-blocker group Pt n# Average Age (yrs) Past medical History MI Previous hospitalization History as HF CABG surgery history Stroke 2 6 HTN Current medication Digoxin ACE-I ARB Diuretics Nitrates Aspirin Anticoagulants Lipid-lowering agents Previous Highest DOE class (I/II/III/IV) 0/0/1/0 0/1/4/0 0/1/3/0 1/13/10/0 MI: myocardiac infarction CABG: coronary artery bypass graft HTN: hypertension DM: diabetes DOE: dyspnea on exertion HF: heart failure

4 116 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 ƒ 2, šx ƒ š y ƒ 8. cux digoxin y ƒ 11, ACE inhibitor y ƒ 13, y ƒ 17, aspirin y ƒ 12. DM y p Table 1» w. No DM+β-blocker s³ 62.2( : ) š, û ƒ 32, ƒ 23. xw y ƒ 6, w x y ƒ 19, CABG w y ƒ 3, stroke xw y ƒ 6, šx ƒ š y ƒ 21. x wš Digoxin 46, ACE inhibitor 43, 49, Aspirin 17. No DM w/o β-blocker group s³ 66 ( : ) š û ƒ 31, ƒ 37. y 7, w w x y 3, CABG y ƒ 1 š šx ƒ š y ƒ y ƒ digoxin wš š, ACE inhibitor y ƒ 46, y ƒ y ƒ ACE inhibitor wš (Table 1). 1SJNBSZFOEQPJOU 4 DM+β-blocker group 0, DM w/o β-blocker group 1, No DM+β-blocker group 0, No DM w/o β-blocker group 3 ù β-blockern ƒ ùkû. z, No DM+β-blocker group w DM+β-blocker group relative riskƒ 1.17 DM+ β-blocker group x j ùkû. ƒ y z ƒ DM+βblocker group 6z, DM w/o β-blocker group 15z β-blocker n z ƒ ùkû š(p=0.014), No DM+β-blocker group 30, No DM w/o β-blocker group 225 β-blocker n x ùkû (p=0.05). w ƒ β-blocker n y 14 y ƒ 26 y β-blocker n y 19 y ƒ 111. ƒ y β-blocker group(n=62) non β-blocker group Fig. 2. Left ventricular ejection fraction (LVEF) before and after a year treatment in non-diabetic patients who has been taking β-blocker. LVEF was significantly improved after a year in this group of patients (p<0.01). (n=69) ƒ ƒƒ ƒ, z š Table 2 w. y β-blocker n y Bisoprolol n Carvedilol n β-blocker primary end point ƒ (Table 2). x w )FNPEZOBNJDGBDUPS w w (LVEF) w w 1 e» zw LVEF e w, ƒ group β-blocker w w Table 2. Differences of occurrences in each groups DM + β-blocker group (n=14) DM w/o β-blocker group (n=19) No DM + β-blocker group (n=62) No DM w/o β-blocker group(n=69) death numbers of hospitaliztion hospital days on 1st admission hospital days on 2nd admission total hospital days

$w y w beta-blocker z sƒ 117 Fig. 2. Left ventricular ejection fraction (LVEF) before and after a year treatment in non-diabetic patients who has been taking β-blocker.$ $Left ventricular ejection fraction (LVEF) before and after a year treatment in non-diabetic patients who has not been taking β-blocker.$ No significant LVEF was observed after a year in this group of patients (p=0.61). yƒ (Fig. 1). w ƒ group β-blocker w LVEFƒ x w š (p<0.01 Fig. 2) β-blocker w yƒ (Fig. 3).

No significant LVEF was observed after a year in this group of patients (p=0.61). yƒ (Fig. 1). w ƒ group β-blocker w LVEFƒ x w š (p<0.01 Fig. 2) β-blocker w yƒ (Fig. 3).

5 w y w beta-blocker z sƒ 117 Fig. 2. Left ventricular ejection fraction (LVEF) before and after a year treatment in non-diabetic patients who has been taking β-blocker. LVEF was significantly improved after a year in this group of patients (p<0.01). Fig. 4. Changes in heart rate after a treatment of congestive heart failure. Top: HF with DM patients treated with a β-blocker. Bottom: HF with DM patients who were not treated with a β-blocker. Fig. 3. Left ventricular ejection fraction (LVEF) before and after a year treatment in non-diabetic patients who has not been taking β-blocker. No significant LVEF was observed after a year in this group of patients (p=0.61). yƒ (Fig. 1). w ƒ group β-blocker w LVEFƒ x w š (p<0.01 Fig. 2) β-blocker w yƒ (Fig. 3). y β-blocker n y bisoprolol n carvedilol n β-blocker LVEFƒ e z ƒ. w w ƒ group β-blocker ƒ w š(p=0.02, Fig. 4), w group ƒ (Fig. 3). ƒ group Fig. 5. Heart rate before and after a year treatment in non-diabetic patients who has been taking β-blocker. HR was significantly reduced after a year in this group of patients (p<0.01).

6 118 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 Fig. 6. Heart rate (HR) before and after a year treatment in nondiabetic patients who has not been taking β-blocker. HR was not significantly changed after a year in this group of patients (p=0.05). Fig. 8. Systolic blood pressure (SBP) before and after a year treatment in non-diabetic patients who has been taking β-blocker. SBP was not affected by β-blocker treatment in this group of patients (p=0.22). Fig. 9. Systolic blood pressure (SBP) before and after a year treatment in non-diabetic patients who has not been taking β-blocker. SBP was not significantly different before and after treatment in this group of patients (p=0.21). Fig. 7. Changes in SBP after a year treatment of heart failure Top: CHF with DM patients treated with a β-blocker. Bottom: HF with DM patients who were not treated with a β-blocker. β-blocker w group ƒ x w š(p<0.01, Fig. 5), w group yƒ (Fig. 6).»x (SBP) w w ƒ group β-blocker w group w group yƒ š(fig. 7), ƒ group β-blocker w group w group yƒ (Fig. 8 and Fig. 9).»x (DBP: Diastolic Blood Pressure) w w ƒ group β-blocker w group w group

w y w beta-blocker z sƒ 119 Fig. 12. Diastolic blood pressure (DBP) before and after the one year treatment in non diabetic patients who has not been taking β-blocker.

7 w y w beta-blocker z sƒ 119 Fig. 12. Diastolic blood pressure (DBP) before and after the one year treatment in non diabetic patients who has not been taking β-blocker. DBP was similar to that of before treatment in this group of patients (p=0.89). yƒ ù(fig. 10), ƒ group β-blocker»x w (p=0.03, Fig. 11). β-blocker w y (No DM: Non-diabetic group) yƒ (Fig. 12). Fig. 10. Changes in DBP after a year treatment of heart failure Top: HF with DM patients treated with a β-blocker. Bottom: HF with DM patients who were not treated with a β-blocker. wsƒ (bradycardia) 4 group y DM+β-blocker group 3, DM w/o β-blocker group 0, No DM+β-blocker group 7, No DM w/o β-blocker group 2 β-blocker n w group ùkû ù, n w group ƒ (Table 3). e» 1 zw SCr BUN eƒ e w y w β-blocker n w group ù m (Table 3). AST, ALT, Alkaline Phosphates eƒ e» 1 w e w w 3ƒ ƒ (Table 3). w AST y ALT y 2 ƒw w (Table 3). š Fig. 11. Diastolic blood pressure (DBP) before and after a year treatment in non-diabetic patients who has been taking β- blocker. DBP was significantly reduced by β-blocker treatment in this group of patients (p=0.03). y w β-blocker e x, y w w», 1970 z 20 ù

8 120 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 Table 3. Toxicities due to HF treatments in each groups DM + β-blocker group (n=14) DM w/o β-blocker group (n=19) No DM + β-blocker group (n=62) No DM w/o β-blocker group (n=69) Bardycardia Nephrotoxicity: Scr Nephrotoxicity: BUN Hepatotoxicity: AST Hepatotoxicity: ALT Hepatotoxicity: Alkaline Phosphatase w wì w, ü ùkù e. x ³ mw 2,6,12) z ƒ, y x 1/3 w j z ƒ Bisoprolol, Metoprolol, Carvedilol, w e z. 6,13,14) Heart Failure Society of America w e Guideline NYHA class II~III» w y t e (Standard therapy) β-blocker «w š,» Carvedilol, Metoprolol Bisoprolol sw. 15) p, Carvedilol Metoprolol succinate Extended Release x e. 13,16) w j β-blockerƒ, y k w x ƒ» w, wù» β-receptor w w», wù β-receptor l (Resensitization)». β-receptor w β-blocker, z, s w, ³x, Metoprolol Bisoprolol β 1 - k, Inverse Agonist, Carvedilol k š 30,31) Inverse Activity Receptor l ƒ š, Alpha1-receptor e z wì. ƒ z w ù COMET Carvedilol w ƒ ùkû. ù w wš, β 2 -receptor yz w w y Carvedilol w ƒ v w. 17) y Cardiovascular event { ùküš, Cardiovascular event ù ƒ š y x ƒw ù z ùkü.» w y œ wš». 7) x ACE inhibitor, Aldosterone antagonists, β-blocker w y y y w Cardiovascular event ù ƒ y e v š. w e 18) t x jš w wš j ƒ y ù ƒ š y w š, e w» w w ƒ y w y w ùkû. ƒ y 3) β-blocker Insulin Resistance ƒ jš Triglyceride ƒ k ù type II y j ùkù x. 19) ¾ š ùkù e w β- blocker w ƒ w, mw y β-blockere z sƒw š w š. p, w w sƒw š y» z w w. y 164 š ƒ š y 33 y 20%ƒ wš. Primary end point y ƒ y β-blocker y ƒ ùkû, w y β-blocker w w š, z β-blocker y ùkü. w ƒ y β-blocker z ƒ š,, z ù ƒ w. β-blocker y (morbidity) j. β-blocker e z ƒ w z w Relative Riskƒ 1.17 ƒ x ùkù š

9 w y w beta-blocker z sƒ 121 w, w y β-blocker w e zw. w LVEF x w x» ùkü r LVEFƒ 60%. x β-blocker NYHA class II - III» y z, Class IV y w z ƒ. y 9,15,20,21) w» y DOE class yw» w».22,23 y LVEF e» e eƒ 20% w ƒ w y 1 β-blocker ƒ y ù ƒ y e ùkû. w y y y (Heart Rate)ƒ ƒw y w β-blocker y ƒ y g y 80z/ yw e. β-blocker w y y ƒ y LVEF, HR, SBP, DBP eƒ e» j w. Primary end point x w (Hemodynamic factors) w k β-blocker e y (Morbidity) jš,» w g y y k. 24,25) w y ƒ y w β-blocker z w x w x w w w w y LVEF, HR, DBP w g ù, ƒ y HR w k z ƒ y ƒ y j y w. ƒ y w 6,14,21,24,25) β-blocker e ƒ j ùkù, β-blocker y y ƒ ùkû. ù x 27,28) ùkù β-blocker e w y 9% š β-blocker w ƒ ùkû. β- blocker y y w y ALT, AST, Alkaline phosphate e w sƒw ù e j y ƒ š β-blocker w y. y ü. ¾ r w β-blocker e z x w (Hemodynamic Factor) y z ùkü w ù β-blocker e w zw. ù β-blocker p w p ƒ, w ƒ w w» y p,, (compliance) š w, k w w. w { ù z ùküš w y w x e w» w x. y β-blocker e ƒ y z ƒ y j, z x w w y e w ùkû. w β-blocker w ƒ w y ü. ù y» w w x y β-blocker w w w.. š x 1. Australia/New zealand Heart Failure Research Collaborative Group. Randomized, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischemic heart disease. Lancet 1997; 349: β- Blocker Evaluation of Survival Trial Investigators. A trial of the β- blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001; 344: Goldstein S et al, Clinical studies on β- blockers and heart failure preceding the MERIT-HF trial. Am J Cardiol 1997; 80(9B): 50J-53J. 4. Bristow MR. Pathophysiologic and pharmacologic rationales for clinical management of chronic heart failure with β-blocking agents. Am J cardiol 1993; 71: 12C-22C. 5. CIBIS II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II(CIBIS II): a randomized trial.

10 122 Kor. J. Clin. Pharm., Vol. 16, No. 2, 2006 Lancet 1999; 353: Frishman WH. Carvedilol. NEJM 1998; 339(24): Levy D, Larson MG, Vasan RS et al, The progression from hypertension to congestive heart failure. JAMA. 1996; 275: Kannel WB, McGee DL et al, Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979; 241: Lechat P, Packer M, Chalon S, Cuchrat M, et al. Clinical Effects of β-adrenergic Blockade in Chronic Heart Failure. A meta-analysis of Double-Blind, placebo-controlled, Randomized Trials. Circulation 1998; 98: Sheu WH, Swislocki AL, Hoffman B, Chen YD, Reaven GM. Comparison of the effects of atenolol and nifedipine on glucose, insulin, and lipid metabolism in patients with hypertension. Am J Hypertens Mar; 4(3 Pt 1): Hori M, Sasayama S, et al, for MUCHA Investigators. Lowdose carvedilol improves left ventricular function and reduces cardiovascular hospitalization in Japanese patients with chronic heart failure: the Multicenter Carvedilol Heart Failure Dose Assessment (MUCHA) trial. Am Heart J 2004; 147: Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic approach. 4th edition. Stamford, CT: Appleton and Lange; p Genth-Zotz S, Zotz RJ, Sigmund M, et al. MIC trial: metoprolol in patients with mild to moderate heart failure: effects on ventricular function and cardiopulmonary exercise testing. Eur J Heart Fail 2000; 2: Packer M, Coats AJ, Fowler MB, et al, for the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344: Gattis WA, O Connor CM, Gallup DS, et al, for IMPACT- HF Investigators and Coordinators. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. J Am Coll Cardiol 2004; 43: Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure. Results of the Carvedilol Or Metoprolol European Trial. Lancet 2003; 362: Petrofski JA, Koch WJ. The β-adrenergic receptor kinase in heart failure. J Mol Cell Cardiol. 2003; 35(10): Francis GS, Cohn JN et al, Heart failure: mechanisms of cardiac and vascular dysfunction and the rationale for pharmacologic intervention. FASEB J. 1990; 4(13): Douglas S. Lee, Muhammad M, Mamdani, et al. Trends in Heart Failure Outcomes and Pharmacotherapy: 1992 to Am J Med 2004; 116: Manesh R, Patel MD, Wendy Gattis, et al. Which β-blocker for heart failure? Am Heart J 2004; 147: MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure(MERIT-HF). Lancet 1999; 353: Cleland JG, Pennell DJ, et al, for CHRISTMAS investigators. Myocardial viability as a determinant of the ejection fraction response to carvedilol in patients with heart failure (CHRISTMAS trial): randomized controlled trial. Lancet 2003; 362: Colucci WS, Packer M, Bristow MR, et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation 1996; 94: Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: Michael R. Bristow, et al, for the MOCHA Investigators. Carvedilol Produces Dose-Related Improvements in Left Ventricular Function and Survival in Subjects With Chronic Heart Failure. Circulation 1996; 94: Waagstein F, Brisow MR, Swedberg K, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy: metoprolol in dilated cardiomyopathy (MDC) trial study group. Lancet 1991; 342: Joglar JA, Acusta AP, Shusterman NH, et al. Effect of carvedilol on survival and hemodynamics in patients with atrial fibrillation and left ventricular dysfunction: retrospective analysis of the US Carvedilol Heart Failure Trials Program. Am Heart J 2001; 142: Marrick L, Kukin, et al. β-blockers in Chronic Heart Failure: Considerations for Selecting an Agent. Mayo Clin Pro 2002; 77:

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16(1)-3(국문)(p.40-45).fm w wz 16«1y Kor. J. Clin. Pharm., Vol. 16, No. 1. 2006 x w$btf3fqpsu'psn û w m w Department of Statistics, Chonnam National University Eunsik Park College of Natural Sciences, Chonnam National University