M. Böhm Innere Medizin III (Kardiologie / Angiologie / Internistische Intensivmedizin)

Universitätsklinikum des Saarlandes

Homburg/Saar

michael.boehm@uks.eu

Is Heart Rate a Treatment Target?

per day: 80 x 60 min x 24 h = 115.200 beats

per year: 42.048.000 beats

80 years: 3.363.840.000 beats

~300 mg ATP per beat

~ 30 kg ATP per day

Heart Rate Reduction by 10 beats

saves ~ 5 kg ATP per day

Ferrari et al., EHJ 2008, 10(Suppl) F7-10

Heart Rate – New Paradigm

Life Expectancy and Heart Rate

Levine et al., J Am Coll Cardiol 1997; 30:1104-06 CMR5-3

1000

500

300

100

50

20

5 10 15 20 25 30

Man

Whale Whale

Horse

Elephant Lion

Dog

Cat

Ass

Giraffe

Monkey

Tiger

Marmot

Rat

Mouse Hamster

Heart

Rate

(B

eats

/m

in)

Life Expectancy (Years)

35 40 80 100

Life Expectancy and Total Number of Heart Beats

Levine et al., J Am Coll Cardiol 1997; 30:1104-06 CMR5-2

100

50

30

10

5

2

102 104 106 108 1010 1012

Man

Whale Whale

Horse Elephant Lion

Dog Cat Ass Giraffe Monkey

Tiger

Marmot

Rat Mouse

Hamster

Life Expectancy

(Years)

Beats / Lifetime

Can We Increase Life Span

by Heart Rate Reduction?

Coburn et al., Hopkins Med J 1970;128:169-193

Digoxin treatment and life span in mice

SU

RV

IVO

RS

(%

)

100

90

80

70

60

50

40

30

20

10

0

0 100 200 300 400 500 600 700 800 900 1000 1100 1200

Days after experiment began

Untreated (74)

50% = 700 Days

Treated (136)

50% = 850 Days

Ischemia

+

+ +

+

+

Microalbuminuria ↑

oxidative stress ↑

plaque stability ↓

arterial stiffness ↑

oxygen consumption ↑

diastole length ↓

coronary perfusion ↓

tachycardiomyopathy ↑

oxygen demand ↑

ventricular efficiency ↓

ventricular relaxation ↓

cardiac hypertophy ↑

Heart Rate

Atherosclerosis

Remodeling Comorbidities

Chronic heart failure

Epidemiology

or Observational

Cardioprotective Effects of Heart Rate Reduction

Risk Marker

Reil and Böhm Lancet 372: 779-780, 2008

Ischemia

+

+ +

+

+

Microalbuminuria ↑

oxidative stress ↑

plaque stability ↓

arterial stiffness ↑

oxygen consumption ↑

diastole length ↓

coronary perfusion ↓

tachycardiomyopathy ↑

oxygen demand ↑

ventricular efficiency ↓

ventricular relaxation ↓

cardiac hypertophy ↑

Heart Rate

Atherosclerosis

Remodeling Comorbidities

Chronic heart failure

Ivabradine

If- Channel

Events ↓? Inhibition Heart rate ↓

Epidemiology

Treatment

Cardioprotective Effects of Heart Rate Reduction

Risk Marker

Risk Factor

Reil and Böhm Lancet 372: 779-780, 2008

HPMS.ppt

Human Papillary Muscle Strips

-2

-1

0

1

2

Frequency (Hz)

0.5 1.0 1.5 2.0 2.5 3.0

NF

NYHA IV

Change in d

iasto

lic t

ensio

n (

mN

)/

develo

ped t

ensio

n (

mN

) 0 1 2 3

0.0

0.2

0.4

0.6

0.8 NYHA IV

NF

Frequency (Hz)

Contraction Relaxation

Böhm et al., Clin Invest, 1992

Pacing-Modulated Heart Rate and O2-Uptake with (1) and without (2) Heart Failure

Kindermann et al., Eur Heart J (2002)

0

50

100

150

200

70

85 90

100 105 110

120 130

140 150

1

1

2

2

3

3

4

4 5 6 7 8 9 10 11 12 13 14 15

End 2

[l/min]

Exercise

0 0

HF [bpm]

HR

160

normal (2)

VO2

.

VO2

.

End 1

normal (2)

Pacing-Modulated Heart Rate and O2-Uptake with (1) and without (2) Heart Failure

Kindermann et al., Eur Heart J (2002)

0

50

100

150

200

70

85 90

100 105 110

120 130

140 150

1

1

2

2

3

3

4

4 5 6 7 8 9 10 11 12 13 14 15

End 2

[l/min]

Exercise

0 0

HF [bpm]

HR

160

HF(1)

normal (2)

HF (#1)

VO2

.

VO2

.

End 1

HF normal (2)

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

DIAMOND study; 1518 patients with HF post MI, 10

years follow up

P<0.0001

0 2 4 6 8 10 Years

1.0

0.8

0.4

0.0

0.6

0.2

> 91 bpm 81-91 bpm 71-80 bpm 40-70 bpm

Mortality

Resting heart rate and mortality

in heart failure post MI patients

AS-be12-1010

NYHA I NYHA II NYHA III NYHA IV

Exercise

Digitalis (bei VF)

HTx, LVAD

Chronic Heart Failure - Therapy

Diuretika

CRT / ICD

Aldosteron-Antag

ACE-hemmer / ARB

key:

neurohormonal

blockade

Beta-Blocker

AS-br3-1109

Correlation of change in HR with relative

risk reduction (RRR) in all-cause mortality

Meta-regression of beta-blocker trials n=19 537

Correlation of final achieved HR with

annualized mortality in 9 beta-blocker trials in

19 537 patients

Effect of change in heart rate and achieved heart rate on clinical outcomes in HF

Flannery G, et al. Am J Cardiol. 2008;101:865-869.

-12 -10 -8 -6 0

-4 -2

0.2

0.4

0.6

r²=0.41

Change in heart rate (bpm)

RRR mortality

60 70 80 90

0.05

0.15

0.20

0

0.10

r²=0.53

Heart rate achieved (bpm)

Annualized mortality

AS-be15-1010

23 trials in 19 209 HF patients with beta-blocker (mean EF=17%-36%)

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

Beta-blocker dose and heart rate reduction in chronic HF patients

Results of 13 univariable meta-regressions evaluating the effect of individual covariates on mortality benefits

of beta-blockers in heart failure

AS-as44-0810

Ischemia

+

+ +

+

+

Microalbuminuria ↑

oxidative stress ↑

plaque stability ↓

arterial stiffness ↑

oxygen consumption ↑

diastole length ↓

coronary perfusion ↓

tachycardiomyopathy ↑

oxygen demand ↑

ventricular efficiency ↓

ventricular relaxation ↓

cardiac hypertophy ↑

Heart Rate

Atherosclerosis

Remodeling Comorbidities

Chronic heart failure

Ivabradine

If- Channel

Events ↓? Inhibition Heart rate ↓

Epidemiology

Treatment

Cardioprotective Effects of Heart Rate Reduction

Risk Marker

Risk Factor

Reil and Böhm Lancet 372: 779-780, 2008

Study design

HR and tolerability Ivabradine 5 mg bid

Matching placebo, bid

Every 4 months D0 D14 D28 M4

Ivabradine 7.5/5/2.5 mg bid according to

3.5 years

Screening

7 to 30 days

Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81. AS-be35-1010

Mean ivabradine dose: 6.4 mg bid at 1 month

6.5 mg bid at 1 year

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

Months

90

80

70

60

50

67

75 75

80

64

Ivabradine

Placebo

Heart rate (bpm)

Mean heart rate reduction

Swedberg et al, Lancet 376 (2010): 875-885

Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY)

HR = 0.82 p<0.0001

0 6 12 18 24 30

Months

40

30

20

10

0

Ivabradine

Placebo

- 18%

Cumulative frequency (%)

Primary composite endpoint

Lancet. Online 29-08-2010 AS-ab18-0710 Swedberg et al, Lancet 376 (2010): 875-885

Ivabradine n=449 (7.5%PY) Placebo n=491 (8.3%PY)

HR = 0.91 p=0.128

0 6 12 18 24 30

Months

30

20

10

0

Ivabradine

Placebo

Cumulative frequency (%)

Cardiovascular death

Lancet. Online 29-08-2010 Swedberg et al, Lancet 376 (2010): 875-885

Ivabradine n=514 (9.4%PY) Placebo n=672 (12.7%PY)

HR = 0.74 p<0.0001

0 6 12 18 24 30

Months

30

20

10

0

Ivabradine

Placebo

Hospitalization for heart failure

- 26%

Cumulative frequency (%)

Swedberg et al, Lancet 376 (2010): 875-885

NNT=27 (annualized)

Death from heart failure

0 6 12 18 24 30

Time from randomisation (months)

0

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

- 26%

Endpoints Hazard ratio 95% CI p value

Primary composite endpoint 0.82 [0.75;0.90] p<0.0001

CV death 0.91 [0.80;1.03] p=0.128

Hospitalization for HF 0.74 [0.66;0.83] p<0.0001

All-cause death 0.90 [0.80;1.02] p=0.092

Death from HF 0.74 [0.58;0.94] p=0.014

Hospitalization for any cause 0.89 [0.82;0.96] p=0.003

Hospitalization for CV reason 0.85 [0.78;0.92] p=0.0002

Effect of ivabradine on outcomes

Swedberg et al, Lancet 376 (2010): 875-885

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 ≥77 bpm

Test for interaction

p=0.029

1.5 1.0 0.5 Hazard ratio

Favours ivabradine Favours placebo

Effect of ivabradine in prespecified subgroups

Lancet. Online 29-08-2010 Swedberg et al, Lancet 376 (2010): 875-885

Baseline heart rate is a predictor of endpoints on placebo

Primary composite endpoint: risk increases by 2.9% per 1-bpm increase, and by 15.6% per 5-bpm increase

50

40

30

20

10

0 0 6 12 18 24 30

Months

≥87 bpm

80 to <87 bpm

75 to <80 bpm

72 to <75 bpm

70 to <72 bpm

P<0.001

Patients with primary composite endpoint (%)

50

40

30

20

10

0 0 6 12 18 24 30

Months

≥87 bpm

80 to <87 bpm

75 to <80 bpm

72 to <75 bpm

70 to <72 bpm

P<0.001

Patients with first hospital admission for

heart failure (%)

≥87 bpm

80 to <87 bpm

75 to <80 bpm 72 to <75 bpm 70 to <72 bpm

50

40

30

20

10

0 0 6 12 18 24 30

Months

Patients with cardiovascular death (%)

P<0.001

Böhm et al, Lancet 376 (2010): 886-894

The Slower the Better?

Distribution of patients by classes of heart rate achieved at D28*

Placebo Ivabradine

Heart rate achieved at day 28 (bpm)

50

40

30

20

10

0 70 to <75 65 to <70 60 to <65 <60 ≥75

50

40

30

20

10

0 70 to <75 65 to <70 60 to <65 <60 ≥75

Patients in heart rate group (%) Patients in heart rate group (%)

Heart rate achieved at day 28 (bpm)

AS-aq13-0810 Böhm et al, Lancet 376 (2010): 886-894

The Slower the Better?

Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group

≥75 bpm

70-<75 bpm

60-<65 bpm

65-<70 bpm

<60 bpm

Patients with primary composite endpoint (%)

Months 0 6 12 18 24 30 Day 28

50

40

30

20

10

0

Böhm et al, Lancet 376 (2010): 886-894

The Slower the Better?

Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group

≥75 bpm 70-<75 bpm 60-<65 bpm 65-<70 bpm

<60 bpm

Patients with primary composite endpoint (%)

Months 0 6 12 18 24 30 Day 28

50

40

30

20

10

0

Böhm et al, Lancet 376 (2010): 886-894

Before Adjustment for Change in Heart Rate at 28 Days:

HR 0.82, 0.75 – 0.87, p = 0.0001

Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group

≥75 bpm 70-<75 bpm 60-<65 bpm 65-<70 bpm

<60 bpm

Patients with primary composite endpoint (%)

Months 0 6 12 18 24 30 Day 28

50

40

30

20

10

0

After Adjustment for Change in Heart Rate at 28 Days:

HR 0.95, 0.85 – 1.06, p = 0.352

Böhm et al, Lancet 376 (2010): 886-894

Before Adjustment for Change in Heart Rate at 28 Days:

HR 0.82, 0.75 – 0.87, p = 0.0001

Do HF patients frequently have heart rate 70 bpm?

AS-ar38-0810

IMPACT RECO III

1407 patients

HF OUTCOME*

3480 patients

ESC PILOT HF**

2450 patients

54.6

31

22.5

53.4

29.7

17.2

55.6

33.7

20.7

HF registries: more than 50% of patients have heart rate 70 bpm

*Courtesy of Prof Tavazzi

**Courtesy of Prof Maggioni

Pa

tie

nts

(%

)

HR 70 bpm HR >75 bpm HR >80 bpm

AS-ar39-0810

Heart rate in European surveys: beta-blocker therapy

HR 70 bpm HR >75 bpm HR >80 bpm

HF OUTCOME*

Beta-blocker (%) Beta-blocker (%)

ESC HF PILOT**

0

10

20

30

40

50

60

70

80

90

0

20

40

60

80

100

*Courtesy of Prof Tavazzi

**Courtesy of Prof Maggioni AS-ar40-0810

89 91

84

61

22

3

90 91

83

60

22

4

0

10

20

30

40

50

60

70

80

90

100

Beta-blockers ACEIs and/or ARBs

Diuretics Aldosterone antagonists

Digitalis ICD/CRT

Patients (%)

Chronic HF background treatment

Lancet. Online 29-08-2010

Ivabradine

Placebo

Swedberg et al, Lancet 376 (2010): 875-885

Ischemia

+

+ +

+

+

Microalbuminuria ↑

oxidative stress ↑

plaque stability ↓

arterial stiffness ↑

oxygen consumption ↑

diastole length ↓

coronary perfusion ↓

tachycardiomyopathy ↑

oxygen demand ↑

ventricular efficiency ↓

ventricular relaxation ↓

cardiac hypertophy ↑

Heart Rate

Atherosclerosis

Remodeling Comorbidities

Chronic heart failure

Trial Programme:

Is Heart Rate a Treatment Target? Yes!

But: Renal Disease, Stroke, HFPEF,

Vascular Comorbidities

M. Böhm Innere Medizin III (Kardiologie / Angiologie / Internistische Intensivmedizin)

Universitätsklinikum des Saarlandes

Homburg/Saar

Thank You!