Inder Anand, MD, FRCP, D Phil (Oxon.)Professor of Medicine, University of Minnesota,

VA Medical Centers, Minneapolis and San Diego, USA

Heart Rate Reduction as a Target of Therapy with Beta Blockers and

Ivabradine: What is the Goal and How to Achieve it?

22nd Annual Heart Failure 2018An Update on Therapy

Disclosure Information

• I have received honorarium from Amgen, ARCA, AstraZeneca, Boehringer Ingelheim, LivaNova, Novartis, and Zensun

• I will not discuss the use of any off-Label / Investigational, unapproved drugs or devices during this presentations

Levine HJ, et al. J Am Coll Cardiol. 1997;30:1104-1106.

1000

500

300

100

50

20

5 10 15 20 25 30

Man

WhaleWhale

Horse

ElephantLion

DogCat

Ass

Giraffe

Monkey

Tiger

Marmot

Rat

Mouse

Hamster

Hear

t rat

e (b

pm)

Life expectancy (years)

35 40 80 100

Resting Heart Rate and Life Expectancy in Mammals

Levine, HJ. JACC. 1997;30:1104–6.

Number of Heart Beats/Lifetime for Each Species is Remarkably Constant and Predetermined

• “You’re probably born with a certain number of heartbeats.

Don’t use them up too fast”

• “God has given each of us just so many heartbeats. The slower we play them out, the longer we live.’

• “Can human life be extended by cardiac slowing?”

Levine, HJ. JACC 1997;30:1104–6

Resting Heart Rate and Life Expectancy

Background

• In humans elevated heart rate is associated with poor long-term outcomes in the normal population and in a variety of CV conditions including heart failure

• Is heart rate a good clinical biomarker?

The first evidence of the prognostic importanceof heart rate: 1945 Population Study

Levy RL, et al. JAMA. 1945;129:585-588.Age (years)

Tachycardia

0

10

20

30

40

50

25 30 35 40 45 50 55 60

Mortality Rate per 1000 person-years

No Tachycardia

The Paris Prospective Study (n=5713 normal men)

Risk of Sudden Death Increases WithResting Heart Rate in the General Population

Jouven X, et al., N Engl J Med. 2005;352:1951-1958.

0.00.51.01.52.02.53.03.54.0

Resting heart rate (bpm)<60 60-64 65-69 70-75 >75

P<0.001

Adjusted Relative risk of sudden death from MI increased with resting HR

Adjusted for age, tobacco use, physical activity, diabetes, BMI, BP, Cholesterol, h/o sudden death or MI, and exercise duration.

Adj

uste

d R

R o

f Sud

den

Dea

th

AhighrestingheartrateasanindependentpredictorofmortalityinCADpatientsThe Coronary Artery Surgery Study (CASS) registry;

24,913 CAD patients; 14.1-year follow-up

Diaz A, et al. Eur Heart J. 2005;26:967-974.

Years after enrolment

Adjusted survival curves foroverall mortality

Adjusted survival curvesfor cardiovascular mortality

Cum

ulat

ive

surv

ival

P<0.0001 P<0.0001

0 5 10 15 20

0.5

0.6

0.7

0.8

0.9

1.0

≤62 63-70 71-76 77-82 ≥83 bpm

0 5 10 15 20

0.5

0.6

0.7

0.8

0.9

1.0

≤62

63-70

71-76

77-82

≥83 bpm

≤62

63-70

71-76

77-82

≥83 bpm

Fosbol et al. Int J Cardiol, 2010;140:279-286.

DIAMOND study(Danish Investigations and Arrhythmia ON Dofetilide)

1518 patients with HF and 1510 patients post MI, 10 years follow up

Resting Heart Rate and All-cause Mortality in HF and Post MI Patients

P<0.0001

0 2 4 6 8 10Years

1.0

0.8

0.4

0.0

0.6

0.2

> 91 bpm81-91 bpm71-80 bpm40-70 bpm

Mortality

10 bpm é in HR was associated with • 14% é increase in mortality in MI-patients (HR 1.14; 95%-CI: 1.09-1.19) • 10% é in mortality in HF-patients (HR, 1.10; CI: 1.06-1.15).

Is Change in Heart rate Related to Change in Mortality and Morbidity?

To qualify as a good biomarker

Changes in heart rate (bpm)

Kjekshus J, et al. Eur Heart J. 1999;1(suppl.H):H64-H69.

Changes in mortality (%)

-18 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10-100

-80

-60

-40

-20

0

20

40

60

XAMOTEROLPROFILE

PROMISE

VHeFT(HDZ/ISDN)SOLVD

CONSENSUS

ANZ

USCARVEDILOL

BHATCIBIS

NORTIMOLOL

MOCHA

GESICA

VHeFT(prazosin)

Reduction of Heart Rate and Outcomes in Cardiovascular Trials

Meta-regression of 23 beta-blocker HF trials involving 19,209 patients

Mortality benefit was related to magnitude of HR reduction and not to the dose of

BB. Pooled Mortality Hazard Ratio was 0.76 for an average HR Reduction 12 bpm

McAlister et al Ann Intern Med 2009;150:784-794

O

O

O

O

-20 -10-15 -5

1

0

-1

-2

-3

Dea

th L

og R

isk

Rat

io

Heart Rate Reduction (beats/min)

Relation Between Magnitude of Heart Rate Reduction and Outcomes in Heart Failure

What is the optimal HR in patients with HFrEF ?

All-cause Mortality Hazard inGISSI-HF (n = 6975)

FC all'Ecg (incrementi di 10)

0

0,5

1

1,5

2

2,5

3

<50 50-60 60-70 70-80 80-90 90-100 100-110 110-120 120-130 >=130

HR

Heart rate by ECG in increments of 10 bpm

Heart Rate (bpm)

Mor

talit

y Ha

zard

Rat

io

How to define an optimal HR for CHF patients ?

Primary and secondary endpoints in the ivabradine group according to groups defined by HR achieved at 28 days

Böhm M, et al. Lancet 2010; 376: 886-894.

HR at D28

5

10

<60 bpm 60 - <65 bpm 65 to <70 bpm

15

20

2530

35

70 to <75 bpm ≥75 bpm

CV death & HF hospitalization

HF hospitalization

In Practice Heart Rate Remains High in Most Patients with HFrEF Receiving Standard of

Care

Jankowska EA & Ponikowski P. 2011

Rate of use%

Dosage mg/day

HR achieved(bpm)

Carvedilol 33 21 75

Bisoprolol 49 5 75

Metoprolol 13 64 75

40 48 56 64 72 80 88 96 104112120128136

Heart rate (bpm)

0

200

400

600

800

1000

1200

1400

1600

1800

X±SD: 77±15Median: 75bpmIQR: 68-84

Poland 2010: 5563 pts with systolic CHF (LVEF ≤ 45%); NYHA II-III; managed by cardiologists and internists; 100% on ACEI or ARB; 96% on β-blockers

Pts treated with ≥ 50% recommended β-BL dosemedian HR: 75 bpm; IQR: 68-84Pts treated with < 50% recommended β-BL dosemedian HR: 75 bpm; IQR: 66-85

No correlation between resting HR and % recommended β-blocker dose at baseline

Heart Rate in Patients with CHF Managed in the Community

Heart Rate In Most Recent HF Trials

Fox et al Lancet 2008;372:817-21.

34% ↑53 % ↑

ProspectivedatafromtheBEAUTIFULTrialon5438patientswithstableCADandLVSD

In placeboarmofBeautiful Trial, patients with HR >70 bpm compared with HR <70 bpm:

Heart Rate as a Predictor of Cardiovascular Outcomes

Can a Pure Heart Reducing Agent Added to Standard of Care Therapy Including Beta-

blockers Improve Outcomes by Decreasing Heart Rate in Patients with HFrEF?

Systolic Heart failure treatment withthe If inhibitor ivabradine Trial

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

SHIFT tested the effects of heart rate reduction with ivabradine on outcomes in patients with HFrEF

• Pure heart rate reducing agent by blocking the hyperpolarization-activated cyclic nucleotide-gated HCN channel reduces the pacemaker if current reduces the diastolic depolarization slope and slows the heart rate.

• No effect on myocardial contractility.

• At recommended doses, ivabradine heart rate by approximately 10 bpm.

Ivabradine is a First-in-Class, HCN Channel Blocker that Lowers Heart Rate

RR

Pureheart ratereduction0 mV

-40 mV

-70 mV

closedopen

closed

Ivabradine

Inclusion and Exclusion Criteria

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

Study design

HR and tolerabilityIvabradine 5 mg bid

Matching placebo, bid

Every 4 monthsD0 D14 D28 M4

Ivabradine 7.5/5/2.5 mg bid according to

3.5 years

Screening7 to 30 days

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

Mortality-Morbidity Event-Driven trial of 6,505 patients with Chronic HF. Patients received ivabradine or Placebo in addition to SOC meds that included maximally tolerated doses of beta-blockers and in most cases, ACE inhibitors and/or ARBs, spironolactone, and diuretics

Mean Heart Rate Reduction

0 2 weeks 1 4 8 12 16 20 24 28 32Months

90

80

70

60

50

67

7575

80

64

Heart rate (bpm)

Placebo

Ivabradine

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

Ivabradine Improved Outcomes

0 6 12 18 24 30Months

40

30

20

10

0

- 18%

Primary outcomeCV death or hospitalization for HF

Placebo

Ivabradine

HR = 0.82p<0.0001

ARR 4.2NNT for 1 year = 24

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

0 6 12 18 24 30Months

30

20

10

0

- 26%

Hospitalization for HF

Placebo

Ivabradine

HR = 0.74p<0.0001

ARR 4.7NNT for 1 year = 21

Heart Rate Achieved on Treatment Predicted of Outcomes with Ivabradine

Patients with CV death and hosp. for worsening HF (%)

Primary composite end point according to heart rate achieved at day 28

Böhm M, et al. Lancet. 2010;376:886-894.

≥75 bpm70-<75 bpm60-<65 bpm65-<70 bpm

<60 bpm

Months0 6 12 18 24 30D28

50

40

30

20

10

0

P<0.0001

Yancy, C et al JACC 2016;68:1476–88

2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Stage C HFrEF

Redefining Standard of Care

• There is an inverse semi-logarithmic relation between heart rate and life expectancy in mammals.

• The faster the heart rate, the shorter the lifespan; the slower the heart rate, the longer animals live.

• In humans elevated heart rate is associated with poor long-term outcomes in the normal population and in a variety of CV conditions including heart failure, suggesting a significant role of heart rate as a cardiovascular Biomarker.

• Heart rate remains elevated in many HF patients despite treatment with beta-blockers.

• SHIFT Trial confirms the importance of HR in the pathophysiology of HF and supports the concept that reduction in HR contributes significantly to beneficial outcomes in patients with HF.

• HR is not only a risk factor but may well be a modifiable mediator of CV disease, particularly of HF

Conclusions