sam haddad ,md,frcpc professor of medicine, university of ... · emphasis-hf investigators (29...

Heart Failure the present and the future!

Sam Haddad ,MD,FRCPCProfessor of Medicine, University of Ottawa

Ottawa Heart Institute

Heart Failure

• Heart failure is common, yet it is difficult to treat. It presents in many different circumstances in which therapy needs to be individualized.

• About 500.000 Canadian with Heart Failure “5 million Americans”

• HF remains one of the most common reasons for hospital admission, as well as one of the most costly cardiovascular disorders.

• Canada’s average annual in-hospital mortality rate is:– 9.5 deaths/100 hospitalized patients >65 years of age– 12.5 deaths/100 hospitalized patients >75 years of age

• HF patients have a poor prognosis, with an average 1-year mortality rate of 33%

Causes of Left Ventricular Dysfunction

Metabolic

Drugs

Heavy metals

Infections

Connectivetissue diseases Neurologic

diseases

Inheriteddiseases

Otherdiseases

Pressure overload

Volume overload

Restrictivedisease

Primarycardiomyopathy

Coronary artery disease

Presenter

Presentation Notes

Many conditions can lead to HF. More than 2/3 of patients with HF have underlying CAD (MI, silent ischemia, chronic ischemia). Identifying the underlying cause of HF can be difficult. Our strategy as clinicians should be to manage the risk factors and treat the conditions before HF becomes established. HF is progressive despite the cause.

Stage AHigh Risk for developing

Heart failure

Stage BAsymptomatic LV dysfunction

Stage CPast or current

Symptoms of HF

Stage DEnd-stage HF

Stages of HF: ACC/AHA

Class Isymptoms at activity levels thatwould limit normal individuals

Class IIsymptoms of HF with

ordinary exertionClass III

symptoms of HF with lessthan ordinary exertion

Class IVSymptoms of HF at rest

NYHA Functional Class

DiastolicDysfunction

SystolicDysfunction

HeartFailure

SyndromeDeath

LVH

MI

ObesityDiabetes

HypertensionAbn. Sleep

HypertensionSmoking

LipidsDiabetes

LV Remodels

Time Decades Time Months

A B C D

Evidence-Based Approach to Left Ventricular Dysfunction

ModerateCHF

SevereCHF

MildCHF

ALVD

ALVD=asymptomatic left ventricular dysfunction.

Pre-Heart

Failure

X X X X

Monitor Therapy / Disease Modification

Evidence-Based Approach to Left Ventricular Dysfunction

ModerateCHF

SevereCHF

MildCHF

ALVD

ALVD=asymptomatic left ventricular dysfunction.

Pre-Heart

Failure

Choose Therapy / Monitor Disease Regression

Heart Failure

The Present

Treatment of Heart Failure

Eplerenone in Patients with Systolic Heart Failure and Mild

Symptoms

EMPHASIS-HF

Presenter

Presentation Notes

The full title of the study is ” A Multi-center, Double-Blind, Randomized, Paralleled Group Study to Evaluate the Effects of Two Different Doses of Losartan on Morbidity and Mortality in patients with Symptomatic Heart Failure Intolerant to ACE Inhibitor Treatment”. [PN 948-05 Protocol p10A]

Inclusion Criteria• Inclusion

– > 55 years of age– NYHA functional class II– Ejection fraction < 30% (or, if between 31% and 35%, QRS >130 msec)– Treated with the recommended or maximally tolerated dose of ACE

inhibitor (or an ARB or both) and a beta-blocker (unless contraindicated).– Within 6 months of hospitalization for a cardiovascular reason [or, if no

such hospitalization, BNP > 250 pg/ml or NT-pro-BNP >500 pg/ml (males) or 750 pg/ml (females) ]

• Exclusion– Serum potassium > 5.0 mmol/L– eGFR < 30 ml/min/1.73 m2

– Need for a potassium-sparing diuretic– Any other significant comorbid condition

Disposition of Patients

1373 Randomizedto placebo

2737 Randomized

1364 Randomizedto eplerenone 25-50 mg/d

4 did not start study drug17 lost to follow up

4 did not start study drug15 lost to follow up

EMPHASIS-HF Investigators (29 countries, 278 sites)

Median follow-up time 21 months, 4783 patient-years of follow-up

Prepared by Pfizer in response to an unsolicited request – Not for further distribution

Presenter

Presentation Notes

Chuck please add data from Appendix 2 page 23

Primary Endpoint Cardiovascular Death or Hospitalization for HF

*Unadjusted HR 0.66; 0.56, 0.78; p<0.0001

0

10

20

30

40

50

0 1 2 3

Prim

ary

Endp

oint

: Cu

mul

ativ

e K-

M R

ate

(%)

Years from Randomization

Eplerenone

HR [95% CI] = 0.63 [0.54, 0.74] P < 0.0001

Placebo

No. at RiskPlacebo 1373 848 512 199 Eplerenone 1364 925 562 232

356 (25.9)

249 (18.3)


Presenter

Presentation Notes

Chuck please add fig 3 of ERM

Mortality From Any Cause

*Unadjusted HR, 0.78; 0.64, 0.95; p=0.01

0

10

20

30

40

0 1 2 3


All-

Cau

se M

orta

lity:

C

umul

ativ

e K

-M R

ate

(%)

Eplerenone

HR [95% CI] = 0.76 [0.62, 0.93] P = 0.0081

Placebo


213 (15.5)

171 (12.5)


Hospitalization From Any Cause

*Unadjusted HR, 0.78; 0.69, 0.89; p <0.0001

0

10

20

30

40

50

60

70

0 1 2 3

All-C

ause

Hos

pita

lizat

ion:

Cu

mul

ativ

e K-

M R

ate

(%)


Eplerenone

HR [95% CI] = 0.77[0.67, 0.88] P < 0.0001

Placebo


491(35.8)

408 (29.9)


Heart Failure Hospitalization

0

10

20

30

40

0 1 2 3

Hea

rt F

ailu

re H

ospi

taliz

atio

n:

Cum

ulat

ive

K-M

Rat

e (%

)


Eplerenone

HR [95% CI] = 0.58 [0.47, 0.70] P < 0.0001

Placebo


*Unadjusted HR, 0.61; 0.50, 0.75; p <0.0001

253 (18.4)

164 (12.0)


Conclusions

• The addition of eplerenone to recommended treatment resulted in a

– 37% reduction in the rate of the composite outcome of death from cardiovascular causes or hospitalization for heart failure.

– 24% reduction in the rate of death from any cause– 23% reduction in the rate of hospitalization from any cause– 42% reduction in the rate of hospitalization for heart failure

• The effect of eplerenone on the primary outcome was consistent across all prespecified subgroups.

• NNT – To prevent one patient experiencing the primary endpoint, per year of follow

up, is 19– To postpone one death, per year of follow up, is 51

Heart Rate

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 with beta-blockers

Systolic Heart failure treatment withthe If inhibitor ivabradine Trial

SHIFT Primary Objective

To evaluate whether the If inhibitor ivabradineimproves cardiovascular outcomes in patients with:

1. Moderate to severe chronic heart failure2. Left ventricular ejection fraction ≤35%3. Heart rate ≥70 bpm in sinus rhythm4. Best recommended therapy

• ≥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 hospitalization for worsening heart failure ≤ 12 months

Inclusion Criteria

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

Presenter

Presentation Notes

The study was undertaken in 677 centres in 37 countries. Patients needed to be on optimum and stable background treatment for at least 4 weeks. Treatments not allowed at inclusion and during the study included nondihydropyridine calcium-channel blockers, class I antiarrhythmics, and strong inhibitors of cytochrome P450 3A4.

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. Eur J Heart Fail 2010;12:75-81

Presenter

Presentation Notes

After a run-in of 14 days without study treatment to enable confirmation of inclusion and exclusion criteria, patients were randomly allocated to treatment groups by computer generated assignment through a telephone interactive voice response system. The starting dose of study drug on day 0 was 5 mg twice daily of ivabradine or matching placebo. After a 14-day titration period, the ivabradine dose was increased to 7·5 mg twice daily (or corresponding placebo), unless the resting heart rate was 60 bpm or lower. If heart rate was between 50 bpm and 60 bpm, the dose was maintained at 5 mg twice daily. If the resting heart rate was lower than 50 bpm or the patient had signs or symptoms related to bradycardia, the dose was reduced to 2·5 mg twice daily.

Chronic Heart Failure Background Treatment

89 9184

61

22

3

90 9183

59

22

40

10

20

30

40

50

60

70

80

90

100

Beta-blockers ACEIs and/orARBs

Diuretics Aldosterone antagonists

Digitalis ICD/CRT

Patients (%)IvabradinePlacebo

Swedberg K et al. Lancet 2010;376(9744):875-85

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

IvabradinePlacebo89

56

26

Patients (%)

Background Beta-blocker Treatment


Mean Heart Rate Reduction

(70% of patients on ivabradine 7.5 mg bid)

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


0 6 12 18 24 30

30

20

10

0

Hospitalization for HF

26%Placebo

Ivabradine

HR = 0.74 (0.66–0.83)P < 0.0001

Months

Cumulative frequency (%)


Death from Heart Failure

26%

0 6 12 18 24 30

10

5

0

HR = 0.74 (0.58–0.94) P = 0.014

Placebo

Ivabradine

Months

Cumulative frequency (%)


• Ivabradine significantly reduces major risks associated with heart failure:

–18% reduction in CV death or hospital admission for worsening HF

–26% reduction in death from heart failure

–26% reduction in hospital admission for worsening heart failure

• Benefits are apparent early, are consistent in predefined subgroups, and have been demonstrated on top of recommended therapy

• Treatment is well tolerated

Conclusion


Neprilysin

• a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin.

• Inhibition of neprilysin increases the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling.

The Rise and Fall of Omapatrilat

inhibits both neutral endopeptidase (NEP) and angiotensin converting enzyme.

Overture: Hear FailureOctave: Hypertension

The rates of angioedema were much higher in blacks, 5.54% forOmapatrilat and 1.62% for enalapril.

http://en.wikipedia.org/wiki/Neutral_endopeptidase

http://en.wikipedia.org/wiki/Angiotensin_converting_enzyme

Background

To compare the angiotensin receptor–neprilysin inhibitor LCZ696 with enalaprilin patients who had heart failure with a reduced ejection fraction.

In previous studies, enalapril improved survival in such patients.

Methods

In this double-blind trial, 8442 patients with class II, III, orIV heart failure and an ejection fraction of 40% or less randomly assigned to receive either LCZ696 (at a dose of 200 mg twice daily)or enalapril (at a dose of 10 mg twice daily), in addition torecommended therapy.

The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designedto detect a difference in the rates of death from cardiovascular causes.

Screening

Primary and Secondary Outcomes

In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril:LCZ696 was more effective than enalapril in . . .• Reducing the risk of CV death and HF hospitalization• Reducing the risk of CV death by incremental 20%• Reducing the risk of HF hospitalization by incremental 21%• Reducing all-cause mortality by incremental 16%• Incrementally improving symptoms and physical limitationsLCZ696 was better tolerated than enalapril . . .• Less likely to cause cough, hyperkalemia or renal impairment• Less likely to be discontinued due to an adverse event• More hypotension, but no increase in discontinuations• Not more likely to cause serious angioedema

PARADIGM-HF: Summary of Findings

10%

Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the

Renin-Angiotensin System

20%

30%

40%

ACEinhibitor

Angiotensinreceptorblocker

0%

% D

ecre

ase

in M

orta

lity

18%

20%

Effect of ARB vs placebo derived from CHARM-Alternative trialEffect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial

Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

Angiotensinneprilysininhibition

15%

Heart Failure

The Future!

Heart Failure, The Future!

• Devices and Transplantation• Stem cell treatment• Genetic, Personal medicine• Prevention

Devices in HF Care

Presenter

Presentation Notes

~5,400 in the US ~1,600 OUS

HMII vs REMATCH

Proposed LVAD Candidate “Triggers”

• Cardiogenic shock “temp device”• Refractory Ventricular Arrhythmia • Need for inotrope more than 24 hrs!• Refractory heart failure symptoms• Multiple admissions• Others

Future directions

• By 2050 there would be >1 million new cases per year in the United States.

• While the war to reduce the toll of CVD, broadly considered, must continue, the battle to control HF has now moved to the center stage of this war.

• This battle will be long and difficult, and because the “enemy has many faces” it will have to be fought simultaneously on multiple fronts and with many different weapons.

Braunwald, JACC, HF 2013

Prevention

• Childhood or adolescence• Target high risk group “Genomic profiles”• High risk per Markers “ex NT-proBNP and

cardiac-specific hs Tn• Multi-markers panel

sam haddad ,md,frcpc professor of medicine, university of ... · emphasis-hf investigators (29...

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