THE VALUE OF 24 H HEART RATE VARIABILITY IN PREDICTING THE MODE OF DEATH IN PATIENTS WITH HEART FAILURE AND SYSTOLIC DYSFUNCTION IN BETA-BLOCKING BLOCKING ERA Arbolishvili GN, Mareev VY Institute of Clinical Cardiology, Moscow, Russia ISHNE Heart Failure World-Wide Wide Internet Symposium,, 2006
Heart Rate Variability (HRV) LF 0,04-0,15 Hz HF 0,15-0,40 Hz SDNN Sympathetic/vagal modulation Parasympathetic modulation
Objectives: To assess the relationship between parameters of HRV and traditional clinical markers of unfavorable prognosis with total mortality and mode of death in pts with heart failure and LV dysfunction in beta-blocking blocking era.
Inclusion criteria Symptomatic heart failure (NYHA II-IV IV) Sinus rhythm Left ventricle systolic dysfunction (LVEF 40%) Stable clinical condition
Exclusion criteria non-sinus rhythm myocardial infarction (< < 3 months) diabetes mellitus SA and AV-block renal failure severe non-cardiac diseases (with poor prognosis)
Study design Prospective observational study
End points Primary endpoint all-cause mortality Secondary endpoints pump failure death (PFD) sudden death (SD)
Statistical analysis (stepwise regression analysis) Clinical variables HRV variables Univariable model p<0.1 Multivariable model p<0.05 Univariable model p<0.1 Multivariable model p<0.05 Final prognostic model based on forward stepwise Cox proportional hazard regression p<0.05 INDEPENDENT PREDICTORS
Baseline patients clinical characteristics Age, yrs Gender (m/f) Etiology (isch/nonisch) LVEF,, % NYHA VPCs (24h) NSVT (n) Characteristics NYHA II NYHA III NYHA IV Total (n=135) 52.4 ± 11.9 111/23 (82%/17%) 91/43 (68%/32%) 30.1 ± 6.7 2.9 ± 0.8 56 (42%) 55 (40%) 24 (18%) 219 (34-817)* 57 (35%( 35%) * Presented as median with 25th and 75th percentiles
Baseline treatment Diuretics Nitrates Treatment ACE Inhibitors Beta-blockers Digoxin Spironolactone Aspirin Amiodarone Warfarin % 90.3% 89.1% 79.4% 45.1% 68.6% 76.4% 11.1% 14.8% 5.6%
Heart Rate Variability in Heart Failure
HRV measures SDNN, ms SDANN, ms SD, ms RMSDD, ms pnn50,, % TP, ln ms 2 LF, ln ms 2 HF, ln ms 2 LF/HF VLF, ln ms 2 ULF, ln ms 2 Measures Value 107 ± 44.2 90.2 ± 29.1 38.1 ± 18.3 28.9 ± 14.8 3.9 ± 7.4 9.5 ± 2,5 5.9 ± 1.2 5.6 ± 1.4 2.0 ± 1.4 7.9 ± 1.4 9.8 ± 1.6
Changes of Heart Rate and SDNN by NYHA 120 100 80 60 40 75 112 77 106 86 * 69 * HR SDNN 20 0 NYHA II NYHA III NYHA IV *p value < 0.05
Changes of Frequency Domain HRV measures by NYHA 10 9 8 7 6 5 4 3 2 1 0 9,1 5,4 4,8 NYHA II 2,2 9,1 5,2 4,6 NYHA III 2,3 8,3 * * 4,64,5 NYHA IV 1,6 * TP (ln) LF (ln) HF (ln) LF/HF *p value < 0.05
TOTAL MORTALITY
135 patients Follow-up ~2.4 years Non- cardiac 3 pts (5%) 63 patients died 36 pts (57%) PUMP FAILURE DEATH 3 pts (5%) Myocardial Infarction 21 pts (33%) SUDDEN DEATH
Univariable predictors of total mortality among clinical variables Variable RR p 95% CI (cut-off value) NYHA, III-IV IV 3.5 0.003 1.2-4.25 NSVT 1.1 0.04 0.2 3.4 LVEF 30 % 1.5 0.03 0.8 1.7
Univariable predictors of total mortality among HRV measures Variable (cut-off value) RR p 95% CI RR 746 ms 1.5 0.01 0.9-1.9 SDNN < 90 ms 3.0 0.0003 1.3 4.2 SDANN < 70 ms 1.5 0.006 0.9 2.0 TP ln < 9.05 ms 2 1.7 0.002 02 1.1 2.5 LF ln < 5.1 ms 2 1.6 0.005 1.1 2.3 VLF ln < 6.35 ms 2 1.3 0.04 0.9 2.1 ULF ln < 8.1 ms 2 1.2 0.002 0.8 1.6
Multivariable predictors of total mortality Variable (cut-off value) NYHA, III-IV IV Clinical variables RR 2.0 p 0.02 95% CI 1.0-3.3 Variable (cut-off value) SDNN 90 мс HRV measures RR 1.5 p 0.002 02 95% CI 0.6-1.8
Final prognostic multivariable model for total mortality (forward stepwise Cox proportional hazard regression) Variable RR p 95% CI (cut-off value) NYHA, III-IV IV 1.8 0.001 01 0.7-2.8 SDNN 90 ms 1.2 0.002 02 0.2-1.9
Kaplan-Meier Survival by NYHA Cumulative Proportion Surviving (Kaplan-Meier) Complete Censored 1,0 Cumulative Survival Proportion Surviving 0,9 0,8 0,7 0,6 0,5 n=24 n=55 NYHA II NYHA IV NYHA III 0,4 0,3 Log-rank Total mortality 0 5 10 15 20 25 30 35 40 45 50 Months Time p<0.0001 Group 1 Group 2 Group 3
Kaplan-Meier Survival by SDNN Cumulative Proportion Surviving (Kaplan-Meier) Complete Censored 1,0 0,9 SDNN > 110 ms Cumulative Proportion Surviving Survival 0,8 0,7 0,6 0,5 0,4 SDNN 91-109 ms SDNN < 90 ms n=49 n=42 n=37 0,3 0,2 Log rank Total mortality 0 5 10 15 20 25 30 35 40 45 50 Months Time p<0.001 Group 1 Group 2 Group 3
PUMP FAILURE DEATH
Univariable predictors of pump failure death Variable (cut-off value) NYHA, III-IV IV NSVT LVEF 28 % Variable (cut-off value) RR 705 мс (85 ) SDNN 85 ms Clinical variables RR 9.5 1.3 1.6 HRV measures RR 2.3 1.3 p 0.0003 0.003 03 0.02 p 0.0004 004 0.03 95% CI 2.9-16.8 0.3 3.5 0.8 2.4 95% CI 1.2-3.3 0.7 2.2
Multivariable predictors of pump failure death Variable (cut-off value) NYHA, III-IV IV Clinical variables RR 8.1 p 0.001 01 95% CI 2.3-15.7 Variable (cut-off value) RR 705 ms (85 ) HRV measures RR 2.0 p 0.001 001 95% CI 1.1-3.0
Final prognostic multivariable model for pump failure death (forward stepwise Cox proportional hazard regression) Variable (cut-off value) NYHA, III-IV IV RR 8.0 p 0.001 01 95% CI 2.1-14.8 RR 705 ms (85 ) 1.5 0.002 02 0.6 3.8
Kaplan-Meier Survival by NYHA Cumulative Proportion Surviving (Kaplan-Meier) Complete Censored 1,0 NYHA II n=56 Cumulative Survival Proportion Surviving 0,9 0,8 0,7 0,6 n=42 NYHA IV NYHA III n=55 0,5 0,4 Log-rank Pump failure death 0 5 10 15 20 25 30 35 40 45 50 Months Time p<0.05 Group 1 Group 2 Group 3
Kaplan-Meier Survival by mean RR Cumulative Proportion Surviving (Kaplan-Meier) Complete Censored 1,0 Cumulative Proportion Surviving Выживаемость Survival 0,9 0,8 0,7 0,6 0,5 n=89 n=40 RR > 705 ms (<85 bpm ) RR 705 ms ( 85 bpm) 0,4 Log-rank Pump failure death p=0.0004 0,3 0 5 10 15 20 25 30 35 40 45 50 Months Time Group 2, Group 1,
Kaplan-Meier Survival in 2 independent risk factor model n=43 NYHA II + RR mean > 705 ms (<85 bpm ) Survival n=33 NYHA III-IV + RR mean 705 ms ( 85 bpm ) Pump failure death Months
SUDDEN DEATH
Univariable predictors of sudden cardiac death Variable (cut-off value) NYHA, II LVEF 26 % Clinical variables RR 6.5 2.4 p 0.0002 0.004 95% CI 2.4 9.5 1.1 3.6 Variable (cut-off value) LF< < 4.5, ln ms 2 LF/HF < 1.5 HRV measures RR 2.1 3.5 p 0.006 0.001 95% CI 0.9 5.5 1.45 4.49
Multivariable predictors of sudden cardiac death Variable (cut-off value) NYHA, II Clinical variables RR 2.0 p 0.002 02 95% CI 1.0-3.3 LVEF 26 % 1.1 0,04 0.2 4.6
Multivariable predictors of sudden cardiac death HRV measures Variable (cut-off value) RR p 95% CI LF/HF < 1.5 3.5 0.001 1.45 4.49
Final prognostic multivariable model for sudden cardiac death (forward stepwise Cox proportional hazard regression) Variable (cut-off value) NYHA, II RR 3.5 p 0.003 95% CI 2.0 9.5 LVEF 26 % 1.4 0,04 0.4 3.0 LF/HF < 1.5 1.5 0.001 0.5 2.9
1,05 Cumulative Proportion Surviving (Kaplan-Meier) Kaplan-Meier Complete Survival Censored by LF/HF 1.5 1,00 n=68 LF/HF > 1,5 Cumulative Proportion Surviving Survival 0,95 0,90 0,85 n=61 LF/HF 1.5 0,80 0,75 Log-rank Sudden death 0 5 10 15 20 25 30 35 40 45 50 Months Time p=0.001 Group 1, Group 2,
Kaplan-Meier Cumulative Survival Proportion in Surviving 3 independent (Kaplan-Meier) risk factor model Complete Censored 1,0 Cumulative Proportion Surviving Survival 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 LVEF<26%+LF/HF<1.5+NYHA II Log-rank LVEF>26% + LF/HF>1.5 + NYHA > II RR= = 9.5 (95% CI 4.4 14.4) 0 5 10 15 20 25 30 35 40 45 50 Months Time p=0,0001 Group 1 Group 2
Conclusions 1. The main HRV indices (both time- and frequency domain) are depressed in heart failure which relates to the severity of heart failure 2. III-IV IV NYHA and SDNN 90 ms are independent predictors of all-cause mortality. 3. III-IV IV NYHA and mean RR 705 ms (HR 85 ) are independent predictors of death from progressive pump failure. Their combination singles out pts at the most increased risk of pump failure death.
Conclusions (continued) 5. Patients in II NYHA, depressed LVEF 26%, and decreased LF/HF 1.5 are independent predictors of sudden death. Their combination singles out patients with heart failure at the most increased risk of sudden death. 6. HRV measures are advantageous over traditional markers of unfavorable prognosis (VPCs( VPCs,, NSVT) in identifying patients with heart failure at increased risk of sudden death.