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 Chronic heart failure Endothelial dysfunction ↑ Oxygen demand ↑ Oxidative stress ↑ Ventricular efficiency ↓ Plaque stability ↓ Ventricular relaxation ↑ Arterial stiffness ↑ + + Ischemia Remodeling Oxygen consumption ↑ Cardiac hypertrophy ↑ Duration of diastole ↓ Coronary perfusion ↓

Relationship of Elevated Heart Rate in Patients with Heart Failure with Reduced Ejection Fraction 1-Year Mortality or hospitalization 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 costs. The American Journal of Cardiology . 2016;117(6):946–951. doi: 10.1016/j.amjcard.2015.12.031.

 β -blockers are known to improve prognosis proportionally to HR reduction and to significantly decrease through different mechanisms  A reduction in HR to reach values lower than 70 bpm improves survival in patients with HF- REF treated with β -blockers  For every increase in HR by 5bpm, there was an 8% increase in cardiovascular death and a 16% increase in admissions to hospital

11 OPT IMIZE - HFr e gistr y: analysis in 10,696 patie nts with L VSD and SR disc har ge for WHF 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% o f pa tie nts disc ha rg e d o n 50% o f ta rg e t do se o r g re a te r De Vo re AD e t a l. Am He a rt J 2015;0:1-7.

Elevated Heart Rate at hospital discharge is a predictor of one-year mortality (OFICA) Survival (%) 41% increase in the risk of death (p = 0.01) N=1658 (170 hospitals) Logeart D, et al. European Heart Journal. 2012;33(Abst Suppl):485

Mortality is particularly high in the early phase after hospitalization Changes in risk profile after hospitalization. Hazard ratio of all-cause mortality after discharge from hospital for first hospitalization for heart failure after discharge. Marti NC, Fonarow GC, Gheorghiade M, Bulter J. Circ Heart Fail 2013;6:1095-1101

Rehospitalisation is particularly high in the early phase after hospitalization 50% The highest rate of death & up to 24% of hospital readmissions occur during the first month after discharge 1,2 1. O’Connor et al. Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program. Am Heart J. 2010;159:841-849.e1. 2. Marti NC, Fonarow GC, Gheorghiade M, Bulter J. Circ Heart Fail 2013;6:1095-1101

Heart failure patients have recurrent hospitalization With each hospitalization, there is likely myocardial and renal damage that contributes to progressive LV or renal dysfunction, leading to an inevitable downward spiral. Gheorghiade et al. Am J Cardiol .2005;96:11–17

9 L oss of e mployme nt is an impor tant c onse que nc e of HF both for the individual and forthe soc ie ty Data from nationwide Danish registries in 11880 HF patients with a first HF hospitalization (1997-2012) 9 Rø rth R e t a l. Circ ula tio n. 2016;134(14):999-1009

Guidelines

Pharmacological Treatment for Stage C HF With Reduced EF Ivabradine Comment/ COR LOE Recommendations Rationale Ivabradine can be beneficial to reduce NEW: New clinical trial HF hospitalization for patients with data. symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are IIa B-R 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. * 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 of the recommendation that initially appeared in the “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure”.

Controlling Heart Rate

HCN channels in the sinoatrial node 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

Clinical Benefits of Heart rate control

Primary objective To evaluate whether the I f inhibitor ivabradine improves cardiovascular outcomes in patients with: 1. Moderate to severe chronic heart failure 2. Left ventricular ejection fraction ≤ 35% 3. Heart rate ≥ 70 bpm in sinus rhythm 4. Best recommended therapy Ivabradine 5mg bd or placebo, titrated to 7.5mg/5mg/2.5mg according to tolerability

HF background treatment Patients (%) 100 Ivabradine 91 91 90 89 Placebo 84 83 80 61 59 60 40 22 22 20 4 3 0 Beta-blockers ACEIs and/or ARBs Diuretics Aldosterone Digitalis ICD/CRT antagonists Swedberg K, et al. Lancet. 2010;376:875-885.

Death from heart failure 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 (%) 10 Ivabradine Placebo - 26% 5 0 0 6 12 18 24 30 Time from randomisation (months)

Effect of ivabradine on composite of CV death or HF hospitalization 50 45 40 COPD (placebo) COPD (ivabradine ) 35 Patients (%) 30 Non-COPD (placebo ) 25 Non-COPD (ivabradine) 20 15 10 5 0 0 6 12 18 24 Time (months) 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

Effect of ivabradine on composite of CV death or HF hospitalization 50 Placebo,renal dysfunction 40 Ivabradine, renal dysfunction Patients (%) Placebo,no renal dysfunction 30 Ivabradine,no renal dysfunction 20 10 0 0 6 12 18 24 30 Time (months) 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

Ivabradine improves outcomes irrespective of the level of blood pressure Rate of primary endpoint (cardiovascular mortality or hospitalization for worsening heart failure), % Baseline SBP <115 mm Hg Baseline SBP≥130 mm Hg Baseline SBP 115 to <130 mm Hg HR 0.84 (95% CI, 0.72 to 0.98), HR 0.86 (95% CI, 0.72 to 1.03), HR 0.77 (95% CI, 0.66 to 0.92), 50 p=0.022 p=0.099 p=0.003 50 50 Placebo 40 40 40 Placebo Placebo 30 Ivabradine 30 30 20 20 20 Ivabradine Ivabradine 10 10 10 0 0 0 0 1 2 3 0 1 2 3 0 1 2 3 Time (years) Time (years) Time (years) Komajda M et al. Eur J Heart Fail 2014; doi: 10.1002/ejhf.114

Ivabradine increases stroke volume Stroke volume (mL) P <0.0001 68 +9 ± 17 mL 66 64 62 -1 ± 16 mL 60 58 56 54 52 Baseline Month 8 Baseline Month 8 Placebo Ivabradine (n=132) (n=143) Ivabradine or placebo is given on top of guideline- recommended therapy including ACE inhibitor, β -blocker, mineralocorticoid receptor antagonist Reil JC et al. J Am Coll Cardiol. 2013;62:1977-1985.

Primary endpoint: change ( ∆ ) in LV End Systolic Volume Index (LVESVI) LVESVI, mL/m 2 ∆∆ = -5.8; p = 0.0002 75 70 ∆ - 7.0 mL/m 2 ∆ - 0.9 mL/m 2 65 60 55 50 0 Baseline M 8 Baseline M 8 Placebo (n=203) Ivabradine (n=208) Tardif JC, et al. Eur Heart J 2011 ; 32:2507-2515.

Ivabradine improves LV ejection fraction P≤0.001 LVEF (%) Δ 2.4 Δ -0.1 Baseline Month 8 Baseline Month 8 Ivabradine Placebo Ivabradine or placebo is given on top of guideline- recommended therapy including ACE inhibitor, β -blocker, mineralocorticoid receptor antagonist Tardif JC et al; Ear Heart J. 2011;32(20):2507-2515

Effect of Ivabradine on all-cause hospitalizations over 3 months after first hospital admission for HF

Effect of Ivabradine on all-cause hospitalizations over 3 months after a first hospital admission for HF Komajda M et al. Eur J Heart Fail. 2016; doi: 10.1002/ejhf.582