Dobutamine-induced increase in heart rate is blunted by ivabradine treatment in patients with acutely decompensated heart failure Yuksel Cavusoglu, KU Mert, A Nadir, F Mutlu, E Gencer, T Ulus, A Birdane Eskisehir Osmangazi University, Faculty of Medicine, Cardiology Department, Eskisehir, Turkey. ESC Congress 2012 Munich, Germany, 25 Aug 2012
Presenter Disclosure Information Presenter: Yuksel Cavusoglu, MD, FESC Co-authors: KU Mert, A Nadir, F Mutlu, E Gencer, T Ulus, A Birdane THE AUTHORS HAVE NOTHING TO DISCLOSE ESC Abstract No. 81910: Dobutamine-induced increase in heart rate is blunted by ivabradine treatment in patients with acutely decompensated heart failure ESC Congress 2012, Munich, Germany, 25 Aug 2012
Background Elevated Heart Rate shortens diastole, impairs ventricular loading, decreases ventricular efficiency, reduces myocardial blood supply, increases myocardial oxygen consumption, increases oxidative stress leads to endothelial dysfunction impairs plaque stability increases arterial stiffness High resting HR is associated with poor clinical outcomes.
Resting heart rate and mortality in patients with CAD CASS Registry (24 959 patients with CAD) Resting HR is an independent predictor for mortality in patients with CAD Diaz A et al. Eur Heart J 2005; 26: 967-74.
Resting heart rate and mortality in patients with chronic heart failure CIBIS-II(2539 patients with NYHA III-IV heart failure) Resting HR is also a strong marker for mortality and rehospitalization in patients with HF, particularly in those with sinus rhythm Lechat P et al. Circulation 2001; 103: 1428-33.
Resting heart rate and mortality in patients with chronic heart failure BEAUTIFUL (Placebo arm, 5438 patients with stable CAD and LVSD) Resting HR is a strong predictor of cardiovascular death. Fox K et al. Lancet 2008; 372: 817-21.
Resting heart rate and in-hospital mortality in patients with acute decompensated HF ADHERE Risk of in-hospital mortality is significantly increased in patients with Heart Rate >84 bpm Abraham WT et al. J Am Coll Cardiol 2005; 46: 57-64
Heart rate reduction and mortality in heart failure Metaanalysis from beta blocker trials Mortality reduction was linear with the reduction of heart rate. BHAT Circulation 1986; CIBIS I Circulation 1994; US Carvedilol NEJM; CIBIS II Lancet 1999; MERIT Lancet 1999; BEST NEJM 2001; COPERNICUS NEJM 2001; CAPRICORN Lancet 2001; COMET Lancet 2003; SENIORS Eur Heart J 2005; MDC Lancet 1993; ANZHF Circulation 1995; Precise Circulation 1996; MOCHA Circulation 1996.
Inotropic stimulation with dobutamine enhance myocardial contractility, increase HR, increase energy expenditure, precipitate ischemia and myocardial necrosis
Dobutamin may cause ischemic myocardial injury Dobutamine-induced redistribution of blood flow and the increased energy expenditure during the dobutamine infusion contribute to impair the development of myocardial hibernation and to precipitate myocardial infarction. Dobutamin might reduce subendocardial blood flow and enhance infarct size in anesthetized open-chest pigs. Schulz R et al. Circulation 1993; 88: 684-695.
Dobutamine increases myocardial oxygen consumption 70 Increase in Oxygen Consumption, % 60 50 40 30 20 10 58% 12% 0 Dobutamine Levosimendan Ukkonen H, et al. Clin Pharmacol Ther. 1997;61:596-607.
The LIDO Study Dobutamine may cause myocardial ischemia Angina pectoris or myocardial ischemia P=0.013 Follath F et al. Lancet 2002; 360: 196-202.
SHIFT 6505 patients with NYHA II-IV, EF %35, sinus rhythm, HR >70 bpm HR reduction with ivabradine, a specific inhibitor of the I f current in the sino-atrial node, has been shown to improve clinical outcomes in chronic HF.
Purpose The aim of this prospective, randomized study was to evaluate whether ivabradine treatment prevents DOB-induced increase in HR.
Methods Fifty eight acutely decompensated HF patients who were in need of inotropic support, LVEF <35% and in sinus rhythm were randomized (in a 1:1 design) to ivabradine (n=29) or placebo (n=29). All patients underwent holter recording for 6 h before the initiation of 18-h DOB infusion. Following baseline recording, DOB was administered at incremental doses of 5, 10 and 15 µgr/kg/min, with 6-h steps.
Methods Holter monitoring was continued during 18 h of DOB infusion. Ivabradine 7.5 mg was given at the time of the initiation of DOB and readministered at 12 h of DOB infusion in ivabradine group. Control group did not receive ivabradine. Holter recordings were analyzed for mean HR change for each step of study protocol.
Methods Inclusion criteria Age >20 years NYHA III-IV decompanseted HF Ischemic/nonischemic etiology Sinus rhythm LVEF <35% Resting heart rate >70 bpm
Methods Exclusion criteria Atrial fibrillation or flutter Acute coronary syndromes Beta blocker therapy Hypertrophic cardiomyopathy Renal failure Systolic blood pressure <90 mmhg Cardiogenic shock Pregnancy Hypo/hyperthyroidism
Results Patient Demographics Control (n=29) Ivabradine (n=29) p Age, years 67±12 64±8.4 0.076 Male gender, n 21(72%) 19 (65%) 0.777 Height, cm 167±7.5 167±8.1 0.904 Weight, kg 75.2±16 75.6±19 0.815 Diabetes, n 13 (44%) 17 (58%) 0.431 Hypertension, n 23 (79%) 21 (72%) 0.759 Hyperlipidemia, n 9 (31%) 12 (41%) 0.581 Family history, n 3 (10%) 4 (13%) 1.0 Ischemic heart failure, n 24 (82%) 24 (82%) 1.0
Results Clinical and laboratory data Control (n=29) Ivabradine (n=29) p NT-proBNP, pg/ml 6964±6806 7145±7634 0.930 Hgb, gr/dl 12.7±1.9 12.8 ± 2.1 0.765 Cr, mg/dl 1.26±0.5 1.25±0.7 0.405 Na, mg/dl 139±4.2 139±3.6 1.0 K, mg/dl 4.69±0.65 4.63±0.67 0.723 LVEF, % 27.52±5.31 25.69±5.95 0.222 6-MWD, m 106±51 123±79 0.406 Medication ACEI/ARB, n Nitrate, n Diuretic, n Spironolactone, n Digoxin, n 18 (62%) 17 (58%) 20 (69%) 18 (62%) 3 (10%) 21 (72%) 10 (35%) 22 (75%) 17 (58%) 3 (10%) 0.576 0.114 0.769 1.0 1.0
Results Changes in laboratory parameters after inotropic therapy Control (n=29) Ivabradine (n=25) Before After p Before After p Hgb, gr/dl 12.7±1.9 12.7 ± 1.6 0.955 12.8 ±2.1 13.0±1.6 0.483 K, mg/dl 4.6±0.6 4.7±0.4 0.893 4.6±0.6 4.6±0.5 0.709 Na, mg/dl 139±4.2 137± 5.1 0.073 139± 3.6 137±5.3 0.085 Cr, mg/dl 1.26±0.5 1.32±0.7 0.509 1.25±0.7 1.32±0.6 0.107 NT-proBNP, pg/ml 6964±6806 3777±2652 0.048 7145±7634 4312±5724 0.01 LVEF, % 27.5±5.3 28.4±4.9 0.014 25.6±5.9 26.4±5.3 0.013 6-MWD, m 106±51 166±52 0.001 123±79 195±96 0.001
Results The increase in heart rate during DOB infusion Control Group Mean HR, bpm Ivabradine Group Mean HR, bpm p Baseline 81.9±11.7 82.1±17.3 0.958 DOB 5 µg/kg/min 90.3±16.6* 82.4±15.7 0.069 DOB 10 µg/kg/min 97.7±14.8*# 85.1±14.9 0.002 DOB 15 µg/kg/min 101.7±16.9 83.5±12.4 0.001 p (Two way ANOVA) 0.001 0.439 *p=0.001 and p=0.0001 compared with baseline. #p=0.006 and p=0.0001 compared with DOB 5 µg/kg/min.
*P <0.009 F:7.328 *p value of overall repeated-measures analysis of variance estimated by Two Way Repeated Measures ANOVA
P <0.001 P <0.0001 P <0.007
P <0.002 P <0.001 P <0.012
Conclusions This study suggested that dobutamine-induced increase in HR was blunted by ivabradine treatment, which may be very important in reducing deleterious effects of dobutamine. However, further studies will be necessary to determine whether preventing dobutamine-induced increase in HR by ivabradine treatment also provides better clinical outcomes.