Optimizing Heart Failure Treatment :

If Not Now.. When ?

SUSI HERMININGSIH, MD FIHA

Department of Cardiology and Vascular Medicine
Dr. Kariadi General Central Hospital
 INCHF
Last decades in chronic heart failure -
outstanding reduction in mortality
Evidence from everyday clinical practice
Mortality of patients with chronic HF (Italy 1995-2010)

Courtesy A. Maggioni
 Optimizing heart failure management Goals to achieve
• Relieve signs &
Diagnosis symptoms
Guidelines-recommended
of HF therapy • Prevent hospital
confirmed admission
• Improve survival
• Improve QoL

Therapy optimization:
• dose-adjustment
maximal recommended dose ?
maximize target effect ?
• timing of intervention
• adherence & education
• future – individualized therapy (profiling)
 Optimizing heart failure
management
Acute setting
(patient hospitalized for HF)

Appropriate „timing” of each intervention

Initial phase In-hospital Discharge

(ED/ICU/CCU) phase phase

Clinical tasks:
• Defining goals of treatment
• Characterizing patient’ clinical profile
• Strategizing care
• Monitoring effects of treatment
 Optimizing heart failure
management
Acute setting
(patient hospitalized for HF)

Appropriate „timing” of each intervention

•Initiate and up-titrate disease-modifying therapy
•Consider device therapy in appropriate patients
•Plan follow-up strategy

Initial phase In-hospital Discharge

(ED/ICU/CCU) phase phase

Clinical tasks:
• Defining goals of treatment
• Characterizing patient’ clinical profile
• Strategizing care
• Monitoring effects of treatment
Evolution of Heart Failure Management

Kidney disease Cardiovascular disease Neuroendocrine disease

Back/forward story Inotropism, pre/after load Evidence based medicine,
Digitalis, diuretics, rest Inotrops, vasodilators prognosis vs. symptoms
ACEi, B-Blockers, MRA,
Ivabradine training

Epidemic syndrome
Remodelling, heart rate
Devices, HF/transplant centres
 HR as a predictor of
CARDIOVASCULAR DEATH HOSPITALISATION FOR HF

HOSPITALISATION FOR MI REVASCULARISATION

 The faster the heart rate :
• The greater the number of systoles that generate
force per minute and
– the greater the myocardial oxygen demand

• The greater the time per minute that myocardial

blood vessels are compressed to prevent
coronary blood flow and

• The less diastolic time is available in diastole

to allow coronary blood flow
– the lower the myocardial oxygen supply
 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↓
 Rationale for treating stable CAD patients
recommendations to reduce HR: the guidelines …

In the new ESC guidelines on the management of stable CAD released in September 2013,

heart rate is presented among the risk factors aggravating the prognosis:
“An elevated resting heart rate is also indicative of a worse prognosis in those with suspected
or proven CAD”
and a target heart rate of 60 bpm is clearly recognized:
“lowering the heart rate <60 bpm is an important goal in the treatment of SCAD.”

Last but not least, ivabradine is recommended in combination with -blockers:

Adding Ivabradine twice daily to Beta Blocker

gives better control of heart rate and angina symptoms

4. Deedwania PC, Nelson JR. Pathophysiology of silent myocardial ischemia during daily life. Hemodynamic evaluation by simultaneous electrocardiographic and blood pressure monitoring.
Circulation. 1990;82:1296-1304. 5. Montalescot G, et al. 2013 ESC guidelines on the management of stable coronary artery disease. The Task Force on the management of stable coronary artery
disease of the European Society of Cardiology. Eur Heart J. 2013;34,2949-3003.
 Rationale for treating stable CAD patients
24 hour HR control is important …
In most ischemic episodes in CAD patients, significant increases in heart rate and blood
pressure precede the onset of ST-segment depression and must play a significant role in
the genesis of these events.

4. Deedwania PC, Nelson JR. Pathophysiology of silent myocardial ischemia during daily life. Hemodynamic evaluation by simultaneous electrocardiographic and blood pressure monitoring.
Circulation. 1990;82:1296-1304. 5. Montalescot G, et al. 2013 ESC guidelines on the management of stable coronary artery disease. The Task Force on the management of stable coronary artery
disease of the European Society of Cardiology. Eur Heart J. 2013;34,2949-3003.
 Heart rate in recent HF registries…
IMPACT RECO III HF OUTCOME* ESC PILOT HF**
1407 patients 3480 patients 2450 patients

54.6 55.6
53.4
Patients (%)

31 33.7
29.7
22.5
20.7
17.2

HR 70 bpm HR >75 bpm HR >80 bpm

*Courtesy of Prof Tavazzi
**Courtesy of Prof Maggioni
…including patients on beta-blocker

HF OUTCOME* ESC HF PILOT**

Beta-blocker (%) Beta-blocker (%)
100
90

80
80
70

60
60
50

40
40

30

20 20

10

0 0

HR 70 bpm HR >75 bpm HR >80 bpm

*Courtesy of Prof Tavazzi
**Courtesy of Prof Maggioni
 Ivabradine
A new concept for a drug
providing anatomical
(sinus node cells)
and functional
(If channel)
selectivity
 If current in the sinus node:
the determinant of HR
Sinus node action
Sinus node potential and currents

0 500 ms
mV

-50

pA I
f
-50
50
IK
Sinus node channels Beta Receptor I CaL
-50
I CaT
Ca channel -50
T- type
f-channel I NaCa
-50
Ca channel K channel
L- type

Robinson RB, DiFrancesco D. Fundamental and Clinical Cardiology; NY; Marcel Decker; 2001:151-170.
 Suppresssion of If current
RR

0 mV
Heart rate
reduction
exclusively

-40 mV

-70 mV
Ivabradine

• 30% reduction of diastolic slope

• other currents maintain pacemaker activity
• safety factor of ivabradine
 Ivabradine interacts internaly with the If
channel: a safety valve
Closed Open Inihibited

Extracelular Side

Intracelular Side
Na+ K+ Ivabradine

When the channel is in closed state (bradycardia)

ivabradine is inactive.

Bucchi A, Baruscotti M, DiFrancesco D. J Gen Physiol. 2002;120:1-13

 Goals of therapy for heart failure

• Improve survival

• Reduce HF hospitalisations and,

thus, the very high economic burden
of the disease

• Improve quality of life

 Mean Heart Rate reduction

Heart rate (bpm)

Mean Procoralan dose: 6.4 mg bid at 1 month
90 Coralan
Placebo
6.5 mg bid at 1 year

80 80
75
75
70
67

60
64

50
0 2 weeks 1 4 8 12 16 20 24 28 32
Swedberg K, et al. Lancet. 2010 Months
 Primary composite endpoint

Cumulative Primary Composite Endpoint =

frequency (%) •Cardiovascular death
40 •Hospitalization for worsening Heart Failure (HF)
Coralan
Placebo

30 - 18%

20
p<0.0001
Procoralan n=793
(14.5%PY) Placebo n=937
10 (17.7%PY)
HR = 0.82

0 Months
0 6 12 18 24 30

Swedberg K, et al. Lancet. 2010

 Hospitalization for HF

Cumulative
frequency (%)
30
Coralan
Placebo
- 26%
20

p<0.0001
Procoralan n=514
10 (9.4%PY) Placebo n=672
(12.7%PY)
HR = 0.74

0 Months
0 6 12 18 24 30

Swedberg K, et al. Lancet. 2010

 Reduces Recurrent Hospitalization for
Heart Failure

p-value

hospitalization p<0.001

Benefit for Patients

p<0.001
hospitalization

p=0.012 Free from Fear and

hospitalization Social Isolation
0.4 0.6 0.8 1.0 1.2
Standard : BB, ACE, MR Antagonist Favours Coralan Favours standard

Borer JS et al. Eur Heart J. 2012;33:2813-2820.

 Pre-specified subgroups
Test for interaction
Age
<65 years
≥65 years
Sex
Male
Female
Beta-blockers
No
Yes
Aetiology of heart failure
Non-ischaemic
Ischaemic
NYHA class
NYHA class II
NYHA class III or IV
Diabetes
No
Yes
Hypertension
No
Yes
Baseline heart rate
<77 bpm p=0.029
≥77 bpm

0.5 1.0 1.5

Hazard ratio
Favours ivabradine Favours placebo
 Clinical implications
• The NNT for 1 year to prevent
•One primary endpoint is 26
•One hospitalisation for HF is 27

• Ivabradine should be added to HF

therapy if HR is ≥ 70 bpm
 Further questions

• Is the HF outcome related to HR?

• Is the benefit of ivabradine
related to the achieved HR
reduction?
 Patients with at least 50%
BB target dose (n=3 181)

Favours Favours
Coralan placebo
Hazard ratio p value
Procoralan Placebo

Primary composite 330 362 ns

0.90
endpoint (11.9 PY) (13.3 PY)

Cardiovascular death 176

(5.9 PY)
175
(5.9 PY) 1.00 ns

Hospitalization for 213 260

0.81
worsening HF (7.7 PY) (9.6 PY) p=0.021

0.5 1.0 1.5

Hazard ratio
Swedberg K, et al. Lancet. 2010
 Pre-randomization
background treatment
Number of hospitalizations for HF during trial
None One Two Three or > p-value
(n=5319) (n=714) (n=254) (n=218)

90 89 80 86 <0.0001
Beta-blockers (%)

91 89 90 93 0.13
ACEI and/or ARB (%)

58 69 67 73 <0.0001
MRA (%)

82 90 90 95 <0.0001
Diuretics (%)

20 30 33 35 <0.0001
Digitalis (%)
 HR reduction according to
β-blocker and HR category
HR reduction (bpm) from
baseline to 28 days with
Ivabradine*

16

12 Baseline
HR category (bpm)
8 ≥87
80 to <87
4 75 to <80
72 to <75
0
<72 Impact of baseline
No BB BB<25% BB 25-50% BB 50-100% BB ≥100% HR on HR reduction
β-blocker category with Ivabradine
No impact of BB dose
on HR reduction with Ivabradine

Swedberg K et al. J Am Coll Cardiol. 2012;59(22): 1938-45.

 Effect of ivabradine on readmissions in
the vulnerable phase after hospitalisation
for worsening systolic HF:
a post hoc analysis of
 Effect of ivabradine on all-cause hospitalizations over the 3
months after a first hospital admission for HF

0.5
Cumulative incidence of all-cause hospitalisations

IRR=0.79
following first hospitalisation for heart failure

0.4 P=0.04
IRR=0.75 Placebo
P=0.03
0.3
Ivabradine
IRR=0.70
0.2 p<0.05

0.1

0 1 2 3
Time (months) after hospital admission for heart failure
Komajda M et al. Eur J Heart Fail. 2016; doi: 10.1002/ejhf.582
 Effect of ivabradine on all-cause hospitalizations over the 3
months after a first hospital admission for HF

0.5
Cumulative incidence of all-cause hospitalisations

IRR=0.79
following first hospitalisation for heart failure

0.4 P=0.04
IRR=0.75 Placebo
P=0.03
0.3
Ivabradine
IRR=0.70
0.2 p<0.05

0.1

0 1 2 3
Time (months) after hospital admission for heart failure
Vulnerable phase
HF hospitalisation
Prospective randomized study to compare the
treatment strategies of uptitration of beta-blockers
alone versus early addition of ivabradine to beta-
blockers in stabilized patients hospitalized for HF

Hidalgo FJ et al. Int J Cardiol. 2016;217:7-11

During hospitalization
• Beta-Blockers
on BBs: not stop after admission, with reduction in doses if necessary (based
on clinical and hemodynamic condition of patients). BBs were uptitrated every
48 h in both groups
No BBs before admission: BBs were started at low doses (carv: 3125 mg/12 h
or 6.25 mg/12 h, bisop: 1.25 to 2.5mg/day) once the patient was stabilized, in
both groups.
• Ivabradine: added to BBs at initial dose of 5 mg bid after and uptitrated every
48 h until a dose of 7.5 mg bid based on HR
After discharge
• BBs: up-titration continued at the 14 and 28 days visits in both groups
• Ivabradine: up-titration to target dose of 7, 5 mg bid at 14 days
Hidalgo FJ et al. Int J Cardiol. 2016;217:7-11
Effect of early treatment of ivabradine with BBs vs BB alone in patients hospitalized
for Worsening Heart Failure: randomized ETHIC study

n=71 patients hospitalized for WHF

Greater improvement in LVEF
P=0.039

P=0.039
LVEF, %

Hidalgo FJ et al. Int J Cardiol. 2016;217:7-11

Effect of early treatment of ivabradine with BBs vs BB alone in patients hospitalized
for Worsening Heart Failure: randomized ETHIC study

n=71 patients hospitalized for WHF Better reduction in BNP

P=0.02
BNP, pg/ml

Hidalgo FJ et al. Int J Cardiol. 2016;217:7-11

Effect of early treatment of ivabradine with BBs vs BB alone in patients hospitalized
for WHF: randomized ETHIC study

n=71 patients hospitalized for WHF

Better HR control
HR, bpm

Hidalgo FJ et al. Int J Cardiol. 2016;217:7-11

Conclusions
1. Over the last decade HF management has substantially improved
and guideline-recommended therapies are now widely used in
the every-day clinical practice.

2. In order to optimize HF management, appropriate dosing and

timing of each intervention need to be carefully addressed

3. The registries show difficulties in reaching target (maximal) doses

of HF therapies. Thus, new approach to optimize dosing may soon
be needed (i.e. heart rate reduction seems to be an attractive
target for up-titrating beta-blockers and ivabradine)
Conclusion (cont’d)

4.For patients hospitalized due to HF decompensation, life-

saving therapies should be initiated before discharge and
carefully optimized during early post-discharge period.

5. In all HF patients, guidelines should be followed in order to

initiate timely and step-by-step all recommended, disease-
modifying therapies.
 Don’t wait until it’s too late …

Borer JS et al. Eur Heart J Online,2012