Role of Heart rate in the management of HFrEF Waleed AlHabeeb, MD, - - PowerPoint PPT Presentation
Role of Heart rate in the management of HFrEF Waleed AlHabeeb, MD, MHA Consultant Heart Failure Cardiologist President of the Saudi Heart failure Society The role of heart rate in cardiovascular disease Elevated heart rate + +
Atherosclerosis Endothelial dysfunction↑ Oxidative stress↑ Plaque stability↓ Arterial stiffness↑ Ischemia Oxygen consumption↑ Duration of diastole↓ Coronary perfusion↓ Remodeling Cardiac hypertrophy↑ Chronic heart failure Oxygen demand↑ Ventricular efficiency ↓ Ventricular relaxation↑
+ + + +
Kaplan-Meier curves for the probability of all-cause mortality or all-cause hospitalization. This figure displays the Kaplan-Meier estimated event rate for all-cause mortality or all-cause hospitalization DeVore A. D., Schulte P. J., Mentz R. J., et al. Relation of elevated heart rate in patients with heart failure with reduced ejection fraction to one-year outcomes and
1-Year Mortality or hospitalization
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De Vo re AD e t a l. Am He a rt J 2015;0:1-7.
De spite tr e atme nt with
β- bloc ke r
s, 71% patie nts had a disc har ge he ar t r ate of
≥70 bpm,
inc luding 63%
disc ha rg e d o n 50% o f ta rg e t do se o r g re a te r
OPT IMIZE
e gistr y: analysis in 10,696 patie nts with L VSD and SR disc har ge for WHF
Logeart D, et al. European Heart Journal. 2012;33(Abst Suppl):485
N=1658 (170 hospitals) Survival (%)
Marti NC, Fonarow GC, Gheorghiade M, Bulter J. Circ Heart Fail 2013;6:1095-1101
Changes in risk profile after hospitalization. Hazard ratio of all-cause mortality after discharge from hospital for first hospitalization for heart failure after discharge.
Failure Outcome Study with Tolvaptan (EVEREST) program. Am Heart J. 2010;159:841-849.e1.
With each hospitalization, there is likely myocardial and renal damage that contributes to progressive LV
renal dysfunction, leading to an inevitable downward spiral.
Gheorghiade et al. Am J Cardiol .2005;96:11–17
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Data from nationwide Danish registries in 11880 HF patients with a first HF hospitalization (1997-2012)
Rø rth R e t a l. Circ ula tio n. 2016;134(14):999-1009
L
tant c onse que nc e of HF both for the individual and forthe soc ie ty
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COR LOE Recommendations Comment/ Rationale
IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are receiving GDEM*, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest. NEW: New clinical trial data. *In other parts of the document, the term “GDMT” has been used to denote guideline-directed management and therapy. In this
recommendation, however, the term “GDEM” has been used to denote this same concept in order to reflect the original wording
for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure”.
Effects of endotoxin on pacemaker current If (HCN channels) and adrenergic pacemaker current If stimulation in human atrial cardiomyocytes. Notes: Endotoxin not only inhibits If but also intensifies beta-adrenoceptor-mediated stimulation of If.36 If inhibition by endotoxin is not an unspecific effect, as the L-type calcium current is not inhibited by endotoxin. ⇑ indicates stimulation and ⇓ indicates inhibition. Abbreviations: AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; Gi, inhibitory G protein; Gs, stimulatory G protein; HCN, hyperpolarization-activated cyclic nucleotide-gated; ICa,T, T- type calcium current; ICa,L, L-type calcium current; If, “funny” current; IK, potassium current. Advances in the management of heart failure: the role of ivabradine Ursula Müller-Werdan, Georg Stöckl, Karl Werdan Vasc Health Risk Manag. 2016; 12: 453–470. Published online 2016 Nov 17. doi: 10.2147/VHRM.S9038
To evaluate whether the If inhibitor ivabradine improves cardiovascular
Ivabradine 5mg bd or placebo, titrated to 7.5mg/5mg/2.5mg according to tolerability
Swedberg K, et al. Lancet. 2010;376:875-885.
89 91 84 61 22 3 90 91 83 59 22 4
20 40 60 80 100
Beta-blockers ACEIs and/or ARBs Diuretics Aldosterone antagonists Digitalis ICD/CRT
Ivabradine Placebo
Patients (%)
6 12 18 24 30
Time from randomisation (months)
5 10
Ivabradine n=113 (1.9% PY) Placebo n=151 (2.6% PY)
HR = 0.74 [95% CI=0.58;0.94] p=0.014
Cumulative frequency (%)
Ivabradine Placebo
N at risk
COPD (pl) 372 298 250 209 110 COPD (iva) 358 312 266 216 124 NCOPD (pl) 2892 2570 2239 1852 979 NCOPD (iva) 2883 2616 2334 1957 1067
6 12 18 24 10 20 30 40 50 5 15 25 35 45
Patients (%) Time (months)
COPD (ivabradine) Non-COPD (ivabradine) COPD (placebo) Non-COPD (placebo)
6 12 18 24 30 10 20 30 40 50
Patients (%) Time (months)
Ivabradine, renal dysfunction Placebo,renal dysfunction
N at risk RD (pl) 799 706 612 488 261 95 RD (iva) 780 720 612 489 273 104 NRD (pl) 2293 2119 1847 1551 820 343 NRD (iva) 2288 2166 1963 1662 906 339
Placebo,no renal dysfunction Ivabradine,no renal dysfunction
Time (years)
10 20 30 40 50
1 2 3 Time (years) Time (years)
Placebo Ivabradine Placebo Ivabradine Placebo Ivabradine Komajda M et al. Eur J Heart Fail 2014; doi: 10.1002/ejhf.114
Baseline SBP <115 mm Hg
HR 0.84 (95% CI, 0.72 to 0.98), p=0.022 HR 0.86 (95% CI, 0.72 to 1.03), p=0.099
Baseline SBP 115 to <130 mm Hg
HR 0.77 (95% CI, 0.66 to 0.92), p=0.003
Baseline SBP≥130 mm Hg Rate of primary endpoint (cardiovascular mortality or hospitalization for worsening heart failure), %
10 20 30 40 50 1 2 3
10 20 30 40 50 1 2 3
52 54 56 58 60 62 64 66 68
Reil JC et al. J Am Coll Cardiol. 2013;62:1977-1985.
Ivabradine or placebo is given on top of guideline-recommended therapy including ACE inhibitor, β-blocker, mineralocorticoid receptor antagonist
P<0.0001
Stroke volume (mL)
Baseline Month 8
Ivabradine (n=143)
Baseline Month 8
Placebo (n=132) +9± 17 mL
50 75 70 65 60 55
∆ - 7.0 mL/m2 ∆ - 0.9 mL/m2 ∆∆= -5.8; p = 0.0002
Baseline M 8
Baseline M 8
LVESVI, mL/m2
Tardif JC, et al. Eur Heart J 2011; 32:2507-2515.
Tardif JC et al; Ear Heart J. 2011;32(20):2507-2515
LVEF (%)
P≤0.001
Ivabradine or placebo is given on top of guideline-recommended therapy including ACE inhibitor, β-blocker, mineralocorticoid receptor antagonist
Δ 2.4 Δ -0.1
Ivabradine Placebo
Baseline Month 8 Baseline Month 8
Komajda M et al. Eur J Heart Fail. 2016; doi: 10.1002/ejhf.582
Difference between baseline and 12 months Placebo (n= 839) Ivabradine (n=842)
Physical & Social Limitations, symptoms, quality of life Overall Summary Score (OSS) Physical Limitations & symptoms Clinical Summary Score (CSS)
ΔΔ 1.8 P =0.018 ΔΔ 2.4 P <0.001 3 6 9
4.3 6.7 3.3 5.0 Ekman I, et al. Eur Heart J. 2011;32:2395–2404.
Bagriy AE et al. Adv Ther. 2015;32:108-119.
Bagriy AE et al. J Am Coll Cardiol. 2013;61(10_S). doi:10.1016/S0735-1097(13)60700-7.
Combining Procoralan as the first step of treatment with β-blocker provides better and quicker uptitration
1. PROCORALAN Summary of Product Characteristics. http://emc.medicines.org.uk / 2. Data on file 12MDA0004 SHIFT endpoint analysis HR≥75bpm / 3. Data on file 12PRC0011 SHIFT baseline characteristics HR≥75bpm
main SHIFT cohort with heart rate ≥75bpm
months 3
Cardiovascular death or hospitalisation for worsening heart failure
1.1 0.4 0.5 0.6 0.7 0.8 0.9 1.0
Cardiovascular death
ARR 2.6% HR 0.83 p=0.0166
NNT 38 All cause mortality -17%
ARR 2.8% HR 0.83 p=0.0109
NNT 36 Death from heart failure
ARR 2.2% HR 0.61 p=0.0006
NNT 45
HR (95% CI) Favours ivabradine Favours placebo
Primary composite
end point
ARR 6.2% HR 0.76 p<0.0001
NNT 16