Key learning from SHIFT and

the meaning of “early”

treatment
Erwinanto MD
Department of Cardiology and Vascular Medicine
Division of Cardiovascular, Department of Internal Medicine
Faculty of Medicine Universitas Padjadjaran
Dr. Hasan Sadikin General Hospital
Bandung
PATIENTS NEED NEW

TREATMENT
 Symptomatic NYHA II-IV !!!

Ponikowski P, et al. Eur Heart J 2016 doi:10.1093/eurheartj/ehw128

 DOCTORS OFTEN SAY:

No need to change heart failure medications because

• My patient is on “OPTIMAL MEDICATIONS”

• My patient has “MILD” symptom

• My patient is “STABLE”
Patients with the same level of functional

capacity can report different daily

functioning, symptoms, and quality of life.

Am Heart J 2012;163:88-94
ACE-I 100%
Beta-blocker 93%
MRA 57%

69% NYHA II
25% NYHA III

Packer M, et al. Circulation 2015;131:54-61

 Death from cardiovascular causes

1.0
ACE-I 100%
Cumulative probability

0.6 Beta-blocker 93%

0.5 MRA 57%
0.4 69% NYHA II
0.3
25% NYHA III
0.2

0.1

0.0
0 180 360 540 720 900 1080 1260

Days from randomization

McMurray JJV, et al. N Engl J Med 2014;371:993-1004.

 HEART RATE AS A

THERAPEUTIC TARGET
Association between high heart rate and cardiovascular risk

Tavazzi L. Eur Heart J suppl 2003;5(suppl G):G15-G18

Heart rate at discharge and 6-month mortality

Zuanetti G, et al. Eur Heart J Suppl 1999;1(suppl H): 52—6.

CIBIS II: Survival benefit of betablocker in stable
heart failure

CIBIS-II Investigators and Committees. Lancet 1999; 353: 9–13

 Inclusion
criteria

• 6558 patients
•  18 years
• Symptomatic Chronic Heart Failure, class II to IV
NYHA
• Ischemic / non ischemic etiology

• Documented hospital admission for worsening

Heart Failure  12 months
• LV systolic dysfunction (EF  35%)
• HR  70 bpm
• Sinus rhythm

Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

 Primary composite endpoint

Primary Composite Endpoint:

Cumulative
- Cardiovascular death
frequency (%)
- Hospitalization for worsening HF
40
Ivabradine
Placebo
30 - 18%

p<0.0001
20

10

0 Months
0 6 12 18 24 30

Swedberg K, et al. Lancet. 2010, doi:10.1016/S0140-6736(10)61198-1

 Effect of ivabradine on major outcomes

Swedberg K, et al. Lancet. 2010;376:875-885.

 Selective lowering heart rate with

ivabradine in the SHIFT trial improves

MORTALITY outcome
Clinical outcomes in the ivabradine group according to HR reduction at day 28

Bohm M, et al. Clin Res Cardiol 2013;102:11–22

Bohm M, et al. Clin Res Cardiol 2013;102:11–22
 SPEED is vital
Hospitalization for Heart Failure

Hazard ratio=0.70 Placebo

30

P<0.0001
Vascular death (%)

20
Ivabradine

10

0
0 6 12 18 24 30
Time (months)

Böhm M, et al. Clin Res Cardiol. 2013;102:1-12.

Safety of ivabradine

Bohm M, et al. Clin Res Cardiol 2013;102:11–22

UNDERSTANDING RECOMMENDATION

OF IVABRADINE IN CLINICAL

PRACTICE GUIDELINES
 2016 ESC Guidelines
Recommendation Class LOE

Ivabradine should be considered to reduce the risk of HF

hospitalization and cardiovascular death in symptomatic
patients with LVEF ≤35%, in sinus rhythm and a resting heart
rate ≥70 bpm despite treatment with an evidence-based dose of IIa B
betablocker (or maximum tolerated dose below that), ACE-I (or
ARB), and an MRA (or ARB).

Ivabradine should be considered to reduce the risk of HF

hospitalization and cardiovascular death in symptomatic
patients with LVEF ≤35%, in sinus rhythm and a resting heart
rate ≥70 bpm who are unable to tolerate or have contra- IIa C
indications for a beta-blocker. Patients should also receive an
ACE-I (or ARB) and an MRA (or ARB).

Ponikowski P, et al. Eur Heart J 2016 doi:10.1093/eurheartj/ehw128

Ponikowski P, et al. Eur Heart J 2016 doi:10.1093/eurheartj/ehw128
PROBLEM SOLVING
Treatment must be REDUCED or STOPPED if the

1. Resting heart rate decreases persistently below 50 bpm or if

symptoms of bradycardia occur:

o Review need for other heart rate-slowing drugs or drugs

interfering with ivabradine liver metabolism.

o Arrange electrocardiogram to exclude other than sinus

bradycardia rhythm disturbances.

o Consider screening for secondary causes of bradyarrhythmias

(e.g. thyroid dysfunction).

Ponikowski P, et al. Eur Heart J 2016 doi:10.1093/eurheartj/ehw128

2. Stop the drug if develops persistent/continuous AF

3. Visual phenomena are usually transient, and disappear during the

first few months and not associated with serious retinal

dysfunction. However, if they result in the patient’s discomfort,

the discontinuation of ivabradine should be considered.

4. In case of lactose or galactose intolerance (component of the

ivabradine tablet), if symptoms occur, there may be a need to

stop the drug.

Ponikowski P, et al. Eur Heart J 2016 doi:10.1093/eurheartj/ehw128

TAKE-HOME MESSAGE
• Ivabradine should be considered to reduce

hospitalization and cardiovascular mortality in HF patients with

sinus rhythm, EF <35% and HR ≥70 bpm who remain symptomatic

despite treatment with evidence-based medical therapy.

• The effect of ivabradine is particularly pronounced in patients with

baseline heart rate ≥75 bpm.

• Patients achieving 50-60 bpm and displaying ˃10 bpm reduction at

day 28 have the best prognosis.