Magdy El-Masry,MDProf. of Cardiology

Tanta Faculty of MedicineTanta,Egypt

Acute Heart Failure:Therapeutic Update

CardioEgypt 2014

Algorithm for management of acute heart failure

Current therapeutic strategies

Novel therapeutic strategies

Newer inotropic drugs

New Recommendations for the Hospitalized Patient

Presentation Focus

(i) Acute Decompensated HF :Worsening chronic HF or De novo HF

(ii) Pulmonary edema

(iii) Hypertensive AHF

(iv) Cardiogenic shock

(v) Isolated right HF

(vi) ACS and HF

Acute heart failure is a heterogeneous syndrome with multiple presentations

Suggested initial triage in patients with suspected AHF syndromes

3%

50% 47%

Suggested treatment algorithm for patients with hypertensive AHF syndromes.

Suggested treatment algorithm for patients with normotensive AHF syndromes .

Suggested treatment algorithm for patients with hypotensive AHF syndromes.

What Should be the Goals of Therapy of AHF?

• Make the patient feel better: reduce dyspnea and improve QOL• Reduce Mortality• Reduce Rehospitalization• Do it safely

Various targets for therapies used in the management of acute heart failure.

Current Treatment of Acute Heart Failure

Diuretics

ReduceFluid

Volume(Na+&H20)

Vasodilators

DecreasePreloadand/or

Afterload

Inotropes

AugmentContract-

ility

88% 21% 15%

Use in ADHERE Registry

Loop diuretics Vasodilators

Inotropics

MOST COMMON IV MEDICATIONS USED IN AHF

Used in 88% of cases 10% 1% 10%

6%6% 3%

?

Novel therapeutic targets for thetreatment of acute heart failure

Sites of action of drugs producing diuresis and natriuresis.

Rolofylline

Tolvaptan

Sites of action of vasodilators.

NesiritideUlaritide

Relaxin

Sites of action of inotropic agents.

Istaroxime

Levosimendan

Omecamtiv mecarbil

Why do new agents fail in Phase III trials?

In recent years a repeated finding, particularly in clinical trials of patients with AHF, is that the positive results that are observed in preclinical and Phase II studies are not confirmed in large Phase III RCTs.

A Word About Inotropes.

In the setting of AHF, inotropic agents are only recommended in patients with SBP > 90 mmHg and evidence of inadequate organ perfusion despite other therapeutic interventions.

Intravenous Inotropic Agents Used in AHF

Issues with Current Inotropes

Initial choice of therapy

Weaning

Patient related variables

Differences in efficacy

Adverse effect profile

Survival data

“Long-term” infusions

There is an urgent clinical need for agents that improve cardiac performancewith a favourable safety profile.

Drugs Inotropic mechanism

Digoxin Sodium-potassium-ATPase inhibition

Dobutamine, dopamine b-Adrenoceptor stimulation

Enoximone, milrinone Phosphodiesterase inhibition

Levosimendan Calcium sensitization

Istaroxime Sodium-potassium-ATPase inhibitionplus SERCA activation

Omecamtiv mecarbil Acto-myosin cross-bridge activation

Gene transfer SERCA activation

Nitroxyl donor;CXL-1020

SERCA activation plus vasodilation

Ryanodine receptorstabilizer; S44121

Ryanodine receptor stabilization

Etomoxir, pyruvate Energetic modulation

Inotropic mechanisms and drugs

Results of the recent AHF trials (disappointing)

Primary End Point Patients Study

Calcium Sensitizer (Levosimendan)Change CI 24 h and PCWP 24 h 203 LIDOMortality 30 d and Mortality 180 d

299 CASINO

Composite global assess. at 6 h, 24 h 5 d

600 REVIVE II

Mortality 180 d 800 SURVIVE

SERCA agonist & Na/K ATPase inhibitor (Istaroxime)PCWP Changes from baseline 120 HORIZON-HF

Phase 2 testing offered disappointing data

This clinical trial was designed to evaluate an intravenous formulation of omecamtiv mecarbil in 613 patients hospitalized with acute heart failure.

The Phase 2 study did not meet its primary endpoint of dyspnea (shortness of breath) response but did show favorable dose- and concentration-related trends on dyspnea response

ATOMIC-AHF (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure) ESC Congress 2013 in Amsterdam

Calcium sensitizersLevosimendan (Simdax®) increasessensitivity of troponin in the heartto calcium. This results in increased myocardial contractility. It is infusedi.v. for short treatment of AHF.

Levosimendan : ESC Guidelines 2012

Patients with hypotension, hypoperfusion or shock

An i.v. infusion of levosimendan (or a phosphodiesterase inhibitor) may be considered to reverse the effect of ẞ-blockade if ẞ-blockade is thought to be contributing to hypoperfusion. • The ECG should be monitored continuously because inotropic

agents can cause arrhythmias and myocardial ischaemia, • and, as these agents are also vasodilators, blood pressure should be

monitored carefully.Class of recommendation IIb . Level of evidence C

2013 ACCF/AHA Guideline for the Management of Heart FailureA Report of the American College of Cardiology Foundation/American Heart Association Task

Force on Practice Guidelines

Updated GuidelinesNew Recommendations for the Hospitalized Patient

Worsening chronicheart failure (75%)

De novo heartfailure (23%)

Advanced/ end-stageheart failure (2%)

Fonarow GC. Rev Cardiovasc Med. 2003; 4 (Suppl. 7): 21Cleland JG et al. Eur Heart J. 2003; 24: 442

The Major Reason for Heart Failure Hospitalizations

Therapies in the Hospitalized HF Patient

Recommendation COR LOE

HF patients hospitalized with fluid overload should be treated with intravenous diuretics

I B

HF patients receiving loop diuretic therapy, should receive an initial parenteral dose greater than or equal to their chronic oral daily dose, then should be serially adjusted

I B

New

Therapies in the Hospitalized HF Patient

Recommendation COR LOE

When diuresis is inadequate, it is reasonable toa) Give higher doses of intravenous loop diuretics; or b) add a second diuretic (e.g., thiazide)

IIa B

New

Therapies in the Hospitalized HF Patient

Recommendation COR LOE

Low-dose dopamine infusion may be considered with loop diuretics to improve diuresis

IIb B

Ultrafiltration may be considered for patients with refractory congestion

IIb C

Intravenous nitroglycerin, nitroprusside or nesiritide may be considered an adjuvant to diuretic therapy for stable patients with HF

IIb A

New

New

New

Therapies in the Hospitalized HF Patient

Recommendation COR LOE

HFrEF patients requiring HF hospitalization on GDMT should continue GDMT unless hemodynamic instability or contraindications

I B

Initiation of beta-blocker therapy at a low dose is recommended after optimization of volume status and discontinuation of intravenous agents

I B

New

New

Recommendations for Inotropic Support

Recommendations COR LOECardiogenic shock pending definitive therapy or resolution I C

Short-term support for threatened end-organ dysfunction in hospitalized patients withstage D and severe HFrEF

IIb B

Short-term intravenous use in hospitalized patients without evidence of shock orthreatened end-organ performance is potentially harmful

III:Harm B

New

New

New