w wz 16«2y Kor. J. Clin. Pharm., Vol. 16, No. 2. 2006 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, 162-90, Korea b Department of Pharmacy, Chungbuk National Hospital, Chungju, 361-163, Korea c College of Pharmacy, Chungbuk National University, Cheongju,361-763, 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 1.17. 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 361-763 12 Tel: 043-261-2822, Fax: 043-276-2754 E-mail: myklee@chungbuk.ac.kr š w, y w 1,4) w w w ACE- Inhibitor β-blocker w» w. 1975 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
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. 1999 1 2003 4 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
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 1999 1 2003 4 ¾ w û w 1 y 1 e z (follow-up) y 164 4 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 69 164. 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 ( : 18-83 ) 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# 14 19 62 69 Average Age (yrs) 57.8 69 62.2 66 Past medical History MI 2 1 6 7 Previous hospitalization History as HF 5 1 19 3 CABG surgery history 4 3 1 Stroke 2 6 HTN 6 8 21 28 Current medication Digoxin 7 11 46 54 ACE-I 12 13 43 46 ARB 3 1 8 Diuretics 10 17 49 61 Nitrates 3 1 6 4 Aspirin 5 12 17 28 Anticoagulants 3 2 9 9 Lipid-lowering agents 3 3 6 9 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
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( : 32-89 ) 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 ( : 25-89 ) š û ƒ 31, ƒ 37. y 7, w w x y 3, CABG y ƒ 1 š šx ƒ š y ƒ 28. 54 y ƒ digoxin wš š, ACE inhibitor y ƒ 46, y ƒ 61. 4 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 41 288. 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 0 1 0 3 numbers of hospitaliztion 6 15 10 32 hospital days on 1st admission 26 87 30 225 hospital days on 2nd admission 0 24 11 63 total hospital days 26 111 41 288
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).
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. 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
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 3 0 7 2 Nephrotoxicity: Scr 1 2 4 2 Nephrotoxicity: BUN 3 6 9 7 Hepatotoxicity: AST 2 1 7 4 Hepatotoxicity: ALT 2 0 5 4 Hepatotoxicity: Alkaline Phosphatase 0 0 0 1 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
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. 2006 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: 375-380. 2. 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: 1659-1667. 3. 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.
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