s ystolic h eart failure treatment with the if inhibitor ivabradine t rial

SSystolic ystolic HHeart failure treatment witheart failure treatment with

the the IfIf inhibitor ivabradine inhibitor ivabradine TTrialrial

SSystolic ystolic HHeart failure treatment witheart failure treatment with

the the IfIf inhibitor ivabradine inhibitor ivabradine TTrialrial

Michel Komajda and Karl Swedberg

on behalf of the Investigators

Michel Komajda and Karl Swedberg

on behalf of the Investigators

Disclosures

SHIFT Executive Committee members received fees, research grants, or both from Servier, as well as fees for speaking or consulting from other major cardiovascular pharmaceutical companies

Background

Elevated heart rate is associated with poor outcome in a number of cardiovascular conditions including heart failure

Heart rate remains elevated in many heart failure patients despite treatment by beta-blockers

Ivabradine is a novel heart rate-lowering agent acting by inhibiting the If current in the sino-atrial node

We hypothesized that the addition of ivabradine to recommended therapy would be beneficial in heart failure patients with elevated heart rate

Fosbol 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 bpm81-91 bpm71-80 bpm40-70 bpm

Resting heart rate and mortalityResting heart rate and mortality in HF post MI patients in HF post MI patients

Mortality

Ivabradine: pure heart rate reductionIvabradine: pure heart rate reduction

If inhibition reduces the diastolic depolarization slope, thereby lowering heart rate

RR

Pureheart ratereduction

0 mV

-40 mV

-70 mV

closedopen

closed

Ivabradine

Thollon et al. Br J Pharmacol. 1994;112:37-42.

Primary objectivePrimary objective

To evaluate whether the To evaluate whether the IIff inhibitor ivabradine inhibitor ivabradine

improves cardiovascular outcomes improves cardiovascular outcomes

in patients within patients with

1. Moderate to severe chronic heart failure1. Moderate to severe chronic heart failure

2. Left ventricular ejection fraction 2. Left ventricular ejection fraction 35%35%

3. Heart rate 3. Heart rate 70 bpm and70 bpm and

4. Recommended therapy4. Recommended therapy

To evaluate whether the To evaluate whether the IIff inhibitor ivabradine inhibitor ivabradine

improves cardiovascular outcomes improves cardiovascular outcomes

in patients within patients with

1. Moderate to severe chronic heart failure1. Moderate to severe chronic heart failure

2. Left ventricular ejection fraction 2. Left ventricular ejection fraction 35%35%

3. Heart rate 3. Heart rate 70 bpm and70 bpm and

4. Recommended therapy4. Recommended therapy

EuropeGermany Portugal

Belgium Greece SpainDenmark Ireland SwedenFinland Italy TurkeyFrance The Netherlands UK

BulgariaCzech RepublicEstoniaHungary

South AmericaArgentinaBrazilChili

North AmericaCanada

AsiaChinaHong KongIndiaSouth KoreaMalaysia

AustraliaAustralia

LatviaLithuaniaNorwayPolandRomania

RussiaSlovakiaSloveniaUkraine

Multinational studyMultinational studyMultinational studyMultinational study

6505 patients, 37 6505 patients, 37 countriescountries, 677 , 677 centrescentres

18 years

Class II to IV NYHA heart failure

Ischaemic/non-ischaemic aetiology

LV systolic dysfunction (EF 35%)

Heart rate 70 bpm

Sinus rhythm

Documented hospital admission for worsening heart failure 12 months

Inclusion criteriaInclusion criteria

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

Study designStudy 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

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

3.5 years

Screening 7 to 30 days

Study endpointsStudy endpoints

Cardiovascular death

Hospitalisation for worsening heart failure

Primary composite endpointPrimary composite endpoint

Other endpointsOther endpoints

All-cause / CV / HF death

All-cause / CV / HF hospitalisation

Composite of CV death, hospitalisation for HF or non-fatal MI

NYHA class / Patient & Physician Global Assessment

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

In total population and in patients with at least 50% target dose of beta-blockers In total population and in patients with at least 50% target dose of beta-blockers In total population and in patients with at least 50% target dose of beta-blockers In total population and in patients with at least 50% target dose of beta-blockers

Patients and follow-up

Median study duration: 22.9 months; maximum: 41.7 monthsMedian study duration: 22.9 months; maximum: 41.7 monthsMedian study duration: 22.9 months; maximum: 41.7 monthsMedian study duration: 22.9 months; maximum: 41.7 months

6558 randomized

3268 to ivabradine 3290 to placebo

3264 analysed1 lost to follow-up

3241 analysed2 lost to follow-up

7411 screened

Excluded: 27Excluded: 27 Excluded: 26Excluded: 26

Swedberg K, et al. Lancet. 2010;online August 29.

Baseline characteristics

IvabradineIvabradine

32413241

PlaceboPlacebo

32643264

Mean age, yMean age, y 60.760.7 60.160.1

Male, %Male, % 7676 7777

Ischaemic aetiology, %Ischaemic aetiology, % 6868 6767

NYHA II, %NYHA II, % 4949 4949

NYHA III/IV, %NYHA III/IV, % 5151 5151

Previous MI, %Previous MI, % 5656 5656

Diabetes, %Diabetes, % 3030 3131

Hypertension, %Hypertension, % 6767 6666

Swedberg K, et al. Lancet. 2010;online August 29.

Baseline characteristics

IvabradineIvabradine

32413241

PlaceboPlacebo

32643264

Mean heart rate, bpmMean heart rate, bpm 8080 8080

Mean LVEF, %Mean LVEF, % 2929 2929

Mean SBP, mm HgMean SBP, mm Hg 122122 121121

Mean DBP, mm HgMean DBP, mm Hg 7676 7676

eGFR, mL/min/1.73 meGFR, mL/min/1.73 m22 7575 7575

Swedberg K, et al. Lancet. 2010;online August 29.

Chronic HF background treatment

89 9184

61

22

3

90 91

83

59

22

40

10

20

30

40

50

60

70

80

90

100

Beta-blockers ACEIs and/orARBs

Diuretics Aldosterone antagonists

Digitalis ICD/CRT

Ivabradine

Placebo

Patients (%)Patients (%)Patients (%)Patients (%)

Swedberg K, et al. Lancet. 2010;online August 29.

Background beta-blocker treatment

0

10

20

30

40

50

60

70

80

90

100

BB at

randomization

At least 50%

target daily dose

Target daily dose

89

56

26

89

56

26

Patients (%)Patients (%)Patients (%)Patients (%)

Ivabradine

Placebo

Swedberg K, et al. Lancet. 2010;online August 29.

Main reasons for not achieving Main reasons for not achieving

Beta-blocker target dose, %Beta-blocker target dose, %

IvabradineIvabradine

n=2099n=2099

PlaceboPlacebo

n=2126n=2126

HypotensionHypotension 4444 4545

FatigueFatigue 3232 3232

DyspneaDyspnea 1414 1414

DizzinessDizziness 1313 1212

BradycardiaBradycardia 66 66

Main reasons for not Main reasons for not

prescribing beta-blocker, %prescribing beta-blocker, %

IvabradineIvabradine

n=344n=344

PlaceboPlacebo

n=341n=341

COPDCOPD 3737 3232

HypotensionHypotension 1717 2020

AsthmaAsthma 1010 1111

Cardiac decomp.Cardiac decomp. 77 99

FatigueFatigue 55 66

Background beta-blocker treatment

Swedberg K, et al. Lancet. 2010;online August 29.

Mean heart rate reduction Mean heart rate reduction

70% of patients on ivabradine 7.5 mg bid70% of patients on ivabradine 7.5 mg bid

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

Months

90

80

70

60

50

67

7575

80

64

Heart rate (bpm)Heart rate (bpm)Heart rate (bpm)Heart rate (bpm)

Placebo

Ivabradine

Swedberg K, et al. Lancet. 2010;online August 29.

0 6 12 18 24 30

Months

40

30

20

10

0

Primary composite endpointPrimary composite endpoint (CV death or hospital admission for worsening HF)(CV death or hospital admission for worsening HF)

- 18%

Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)

Placebo

Ivabradine

HR (95% CI), 0.82 (0.75–0.90),

p<0.0001

Swedberg K, et al. Lancet. 2010;online August 29.

0 6 12 18 24 30

Months

30

20

10

0

Hospitalization for HF

- 26%

Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)

Placebo

Ivabradine

HR (95% CI), 0.74 (0.66–0.83),

p<0.0001

Swedberg K, et al. Lancet. 2010;online August 29.

0 6 12 18 24 30

Months

30

20

10

0

Cardiovascular deathCardiovascular death

Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)

Placebo

Ivabradine

HR (95% CI), 0.91 (0.80–1.03),

p=0.128

Swedberg K, et al. Lancet. 2010;online August 29.

Death from heart failure

- 26%

0 6 12 18 24 30Months

10

5

0

HR (95% CI), 0.74 (0.58–0.94),

p=0.014

Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)

Placebo

Ivabradine

Swedberg K, et al. Lancet. 2010;online August 29.

Effect of ivabradine Effect of ivabradine on outcomes on outcomes

EndpointsEndpoints Hazard ratioHazard ratio 95% CI95% CI pp value value

Primary composite endpoint 0.820.82 [0.75;0.90][0.75;0.90] pp<0.0001<0.0001

All-cause death 0.900.90 [0.80;1.02][0.80;1.02] pp=0.092=0.092

Death from heart failure 0.740.74 [0.58;0.94][0.58;0.94] pp=0.014=0.014

Hospitalisation for any cause 0.890.89 [0.82;0.96][0.82;0.96] pp=0.003=0.003

Hospitalisation for cardiovascular reason

0.850.85 [0.78;0.92][0.78;0.92] pp=0.0002=0.0002

Cardiovascular death / hosp. for HF or non-fatal MI

0.820.82 [0.74;0.89][0.74;0.89] pp<0.0001<0.0001

Swedberg K, et al. Lancet. 2010;online August 29.

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

1.51.00.5Hazard ratio

Favours ivabradine Favours placebo

Effect of ivabradine in Effect of ivabradine in prespecified subgroupsprespecified subgroups

Swedberg K, et al. Lancet. 2010;online August 29.

NYHA class changesNYHA class changes

28

68

5

24

70

6

0

10

20

30

40

50

60

70

Improvement Stability Worsening

pp=0.0003=0.0003pp=0.0003=0.0003PatientsPatients (%) (%)PatientsPatients (%) (%)

Ivabradine

Placebo

Swedberg K, et al. Lancet. 2010;online August 29.

Patient Global Assessment Patient Global Assessment

8

25

68

7

21

72

0 10 20 30 40 50 60 70 80

Worsening

Stability

Improvement

Patients (%)

pp< 0.05< 0.05pp< 0.05< 0.05

last post randomisation valuelast post randomisation valuelast post randomisation valuelast post randomisation value

Ivabradine

Placebo

Swedberg K, et al. Lancet. 2010;online August 29.

Physician Global Assessment Physician Global Assessment

pp= 0.001= 0.001pp= 0.001= 0.0019

34

57

8

31

61

0 10 20 30 40 50 60 70

Worsening

Stability

Improvement

Patients (%)

Ivabradine

Placebo

Swedberg K, et al. Lancet. 2010;online August 29.

last post randomisation valuelast post randomisation valuelast post randomisation valuelast post randomisation value

Mean heart rate reduction Mean heart rate reduction Patients with >50 % beta-blocker dose Patients with >50 % beta-blocker dose (n= 3181)(n= 3181)

40

50

60

70

80

90

100

Basel

ine

D14 D28M

04M

08M

12M

16M

20M

24M

28M

32M

36

Mean HR in sinus rhythm (bpm)Mean HR in sinus rhythm (bpm)Mean HR in sinus rhythm (bpm)Mean HR in sinus rhythm (bpm)

79

63

67

Patients receiving at least half the target dose of beta-blockersPatients receiving at least half the target dose of beta-blockersPatients receiving at least half the target dose of beta-blockersPatients receiving at least half the target dose of beta-blockers

7475

Placebo

Ivabradine

Swedberg K, et al. Lancet. 2010;online August 29.

1.51.00.5Hazard ratio

Favours ivabradine Favours placebo

Ivabradine Hazard ratio

Primary compositeendpoint 330

(11.9 PY)0.90362

(13.3 PY)

Cardiovascular death 176 (5.9 PY)

1.00175 (5.9 PY)

Hospital admission forworsening HF

213 (7.7 PY)

0.81260 (9.6 PY)

Placebo

Patients with at least 50% BB Patients with at least 50% BB target dose (n=3181) target dose (n=3181)

pp value value

nsns

nsns

pp=0.021=0.021

Swedberg K, et al. Lancet. 2010;online August 29.

Incidence of selected adverse Incidence of selected adverse events events (N = 6492)(N = 6492)

Patients with an eventPatients with an event

Ivabradine Ivabradine

N=3232, % N=3232, % (n)

Placebo Placebo

N=3260, N=3260, %% (n)

pp value value

All serious adverse events 45% 45% (1450) 48% 48% (1553) 0.0250.025

All adverse events 75% 75% (2439) 74% 74% (2423) 0.3030.303

Heart failure 25% 25% (804) 29% 29% (937) 0.00050.0005

Symptomatic bradycardia 5% 5% (150) 1% 1% (32) <0.0001<0.0001

Asymptomatic bradycardia 6% 6% (184) 1% 1% (48) <0.0001<0.0001

Atrial fibrillation 9% 9% (306) 8% 8% (251) 0.0120.012

Phosphenes 3% 3% (89) 1% 1% (17) <0.0001<0.0001

Blurred vision 1% 1% (17) < 1% < 1% (7) 0.0420.042Swedberg K, et al. Lancet. 2010;online August 29.

Incidence of serious adverse Incidence of serious adverse eventsevents

Patients with an eventPatients with an event

Ivabradine Ivabradine

N=3232, % N=3232, % (n)(n)

Placebo Placebo

N=3260, % N=3260, % (n)(n)

pp value value

All serious adverse events All serious adverse events

Cardiac disorders Cardiac disorders

General disorders, administration conditionsGeneral disorders, administration conditions

Infection and infestations Infection and infestations

Respiratory, thoracic, mediastinal disordersRespiratory, thoracic, mediastinal disorders

Surgical and medical proceduresSurgical and medical procedures

Gastrointestinal disordersGastrointestinal disorders

Neoplasm benign, malignant and unspecified Neoplasm benign, malignant and unspecified

Renal and urinary disordersRenal and urinary disorders

Hepatobiliary disordersHepatobiliary disorders

Eyes disordersEyes disorders

45% (1450)

28% (920)

7% (240)

7% (216)

3% (107)

3% (102)

3% (89)

2% (68)

2% (51)

1% (29)

1% (18)

49% (1553)

30% (991)

8% (254)

7% (236)

4% (122)

4% (122)

3% (103)

2% (61)

1% (47)

1% (39)

<1% (13)

0.025

0.091

0.617

0.381

0.347

0.197

0.342

0.534

0.685

0.273

0.374

Swedberg K, et al. Lancet. 2010;online August 29.

Patients with an Patients with an adverse event, adverse event,

leading to withdrawalleading to withdrawal

Ivabradine Ivabradine

N=3232, % N=3232, % (n)

Placebo Placebo

N=3260, N=3260, %% (n)

pp value value

All adverse events 14% 14% (467) 13% 13% (416) 0.0510.051

Heart failure 2% 2% (70) 3% 3% (82) 0.3670.367

Symptomatic bradycardia 1% 1% (20) <1% <1% (5) 0.0020.002

Asymptomatic bradycardia 1% 1% (28) <1% <1% (5) <0.0001<0.0001

Atrial fibrillation 4% 4% (135) 3% 3% (113) 0.1370.137

Phosphenes <1% <1% (7) <1% <1% (3) 0.2240.224

Blurred vision <1% <1% (1) <1% <1% (1) 1.0001.000

Treatment discontinuationTreatment discontinuation

Swedberg K, et al. Lancet. 2010;online August 29.

ConclusionConclusion

Heart failure with systolic dysfunctionwith systolic dysfunction and elevated heart rate

is associated with poor outcomes (primary composite endpoint

in the placebo group is 18%/year)

Ivabradine reduced cardiovascular mortality or heart failure

hospitalisation by 18% (p<0.0001). The absolute risk reduction

was 4.2%

This beneficial effect was mainly driven by a favourable effect

on HF death (26%) and hospitalisation for HF (26%)

Overall, treatment with ivabradine was safe and well tolerated

Clinical implicationsClinical implications

The addition of ivabradine to recommended

therapy significantly reduces death and

hospitalisations related to heart failure in patients

with heart rate 70 bpm

The NNT for 1 year to prevent …

One primary endpoint is 26

One hospitalisation for heart failure is 27

Available now online from Available now online from Lancet Lancet

http://www.lancet.com published online August 29, 2010 DOI:10.1016/S0140-6736(10)61198-1