Ionotropic Therapy in Acute Heart Failure

Dr Sajeer K TSenior Resident

Dept of cardiology, MCH ,Calicut

Acute heart failure syndromes (AHFS) are defined as gradual or rapid changes in signs and symptoms of heart failure (HF) that require urgent therapy

AHFS Definition

1. New-onset or de novo HF ( 20%): (HF stage A & B) - present first time with symptoms of HF

- have risk factors for HF/structural heart disease

2. Worsening chronic HF (80%): - history of chronic HF & present with an episode of decompensation (stage C) - 10% to 15% has advanced or end-stage HF (stage D)

A practical approach to differentiating AHFS: - relies on systolic BP at the time of presentation

1.Hypertensive group : - female - normal LVEF - in hospital mortality rate - 2% (with 5% mortality and 30% readmission rates with in 60–90 days of discharge)

2.Normotensive group: - low LVEF - signs and symptoms of pulmonary/systemic congestion (oedema) before and at the time of admission - in-hospital mortality rate - 3% (with 7% mortality and 30% readmission rates within 60–90 days of discharge)

3. Hypotensive group: - low SBP levels (≤120 mm Hg) at the time of presentation - low LVEF - history of HF ( mortality rate 7% during hospitalization & with 14%mortaliy and 30% readmission rates within 60–90 days of discharge)

Current and investigational pharmacologic agents for the treatment of AHFS

Clinical stratification and treatmentStevenson and colleagues developed an approach for the evaluation and treatment of

decompensated advanced chronic systolic heart failure

- Based on assumption that hemodynamic abnormalities are the immediate cause of the symptoms and signs of AHF- by addressing these derangements5→ pts improve symptomatically

-Patient is assigned to one quadrant of a 2 × 2 table, defined by the presence or absence of congestion (wet or dry) and low perfusion (cold or warm)

Mechanisms of Action and Effects of Inodilators

Common pathway

- increased intracellular (cAMP) and calcium concentrations

-Dobutamine ( beta agonist) -Dopamine ( catecholamine)-Milrinone (PDE inhibitor)

Intracellular cAMP causes release of ca2+ from the SR.

Calcium →used by contractile proteins

Increased stroke volume.

Levosimendan: - Calcium sensitizer - ATP-dependent K+ channel opener

Mechanisms of Action and Effects of Inodilator contd..

Dobutamine ↑ cAMP production: - by beta-adrenergic-mediated stimulation of adenylate cyclase - stimulates cAMP production

Dobutamine is a racemic mixture that stimulates beta1- and beta 2-receptors

Dobutamine:

Simplified schematic of postulated intracellular actionsof beta -adrenergic agonists

Beta 1-receptors stimulation

Activates guanine nucleotide regulatory cascade (via G proteins)

Increased adenylate cyclase activityATP → increased cAMP

Release of calcium from the sarcoplasmic reticulum

- Calcium is used by contractile proteins - increased stroke volume

- Rate of infusion doses of Dobutamine needed to increase cardiac output usually ranges from 2.5 to 15 µg/kg/min.

-Onset of action is within 1 to 2 minutes-plasma half-life of Dobutamine - 2 minutes.

- Infusion for 24 to 72 hours- - cardiac output return toward baseline values (raising the concern of pharmacologic tolerance with prolonged infusion)

- Overall effect of dobutamine on BP is variable - depends on the relative effects on the vascular tone and cardiac output achieved

-Heart rate is often decreased because of reflex withdrawal of sympathetic tone in response to improved cardiovascular function

- Major side effects of Dobutamine: - tachycardia( in patients with AF and atrial and ventricular arrhythmia

- Patients taking a beta blocker may have an attenuated initial response to Dobutamine until the -blocker has been metabolized

- Increased energy demands of the failing myocardium lead to a state of relative energy depletion (through an initial compensatory phase of increased oxygen extraction)

↓ inodilator stimulation would impose further energy demands and ultimately accelerate myocardial cell death

Dopamine—endogenous catecholamines

Dose-dependent effects <2µ g/kg per min: (vasodilation) - by direct stimulation of dopamine postsynaptic type 1 and presynaptic type 2 receptors in the splanchnic and renal arterial beds - direct effects on renal tubular epithelial cells → natriuresis 2 to 5µ g/kg per min – (increased HR and cardiac output) - direct stimulation of beta-adrenergic receptors in the heart induce NE release from vascular sympathetic neurons 5 - 15µ g/kg per min- (↑ed HR and peripheral vasoconstriction) - stimulate beta and alpha-adrenergic receptors

Schematic representation of postulated mechanismsof intracellular action of alpha 1-adrenergic agonists

Major side effect of dopamine – tachycardia(More pronounced with dopamine than Dobutamine)

A new or unexplained tachycardia or arrhythmia in a patient receiving “low-dose” dopamine - suspect inappropriately high dopamine infusion rate

Milrinone: - Selectively inhibits phosphodiesterase (PDE) III ( enzyme that catalyzes the breakdown of cAMP) - increased cAMP

Milrinone—phosphodiesterase inhibitors

Increased intracellular calcium concentration and myocardial contractility as well as acceleration of myocardial relaxation

Increased cAMP peripherally produces vasodilation (both the arterial and venous circulation)

- decreased SVR and PVR - decreased left and right ventricular filling pressures

- increased cardiac output

Milrinone Dosage: - ± loading dose of 50µg/kg per min - continuous infusion of between 0.25 and 1.0µ g/kg per min

Improvement in hemodynamic function occurs in 5 to 15 minutes after initiation of therapy

Side effect of Milrinone: - hypotension ( avoid loading dose) - Non sustained VT

Intravenous inotropes (Dobutamine or Milrinone) may be considered to relieve symptoms and improve end-organ function in patients with advanced HF characterized by

- L V dilation- reduced LVEF- diminished peripheral perfusion or end-organ dysfunction

(low output syndrome)- systolic blood pressure < 90 mm Hg- have symptomatic hypotension despite adequate filling pressure- unresponsive to, or intolerant of, intravenous vasodilators

The HFSA 2006 Comprehensive HF Practice Guideline (Dobutamine and Milrinone)

Levosimendan

Levosimendan increases calcium myofilament responsiveness by directly affecting contractile proteins to increase contractility without increasing intracellular calcium concentrations

(2) it opens KATP channels in myocytes & SM cells

act as a vasodilator ( anti-ischemic and antistunning effects)

(1) Enhances calcium myofilament responsiveness by binding to cardiac troponin C increases contraction (functions as a calcium sensitizer)

Dual mechanism of action:

key differentiating property of levosimendan

- does not increase intracellular levels of cAMP or calcium

- does not cause increased myocardial oxygen consumption

- Opens KATP channels in myocytes and vascular SM cells - results in vasodilatation and cardio protection - reduces preload and after load - increased blood flow to organs (including increased coronary blood flow) - anti-ischemic and antistunning effects

Loading dose - 12µ g/kg applied over 10 minutes Continuous infusion- 0 .1 to 0.2 µg/kg per min over 24 hours

- a subject of controversy

- lack of prospective, placebo controlled trials

- lack of alternative therapies

Role of intravenous inotropes therapy in AHF

Clinical characteristics of patients with acute heart failure syndromes in clinical registries

Acute Decompensated Heart Failure National Registry (ADHERE)Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE- HF)Euro Heart Failure Survey (EHFS)EFICA French study

Use of Inodilator Therapy in Acute Heart Failure Syndromes- Registries

ADHERE database (Oct 2001-2003) :- Designed to study prospectively the outcomes, characteristics, and management of AHFS.

>150,000 patients- 50% presented with PSF <3% presented with a systolic BP of 90 mm Hg

14% of the patients in ADHERE - treated with ≥1 acute infusions of inodilator agent (Dobutamine 6%, Dopamine 6%, and Milrinone 3%)

Patients with PSF who were treated with Inodilators had a higher mortality rate than patients with PSF who were not treated with Inodilators (19% v/s 2% respectively).

European Heart Journal Supplements (2005) 7 (Supplement B), B13–B19

Analysis of ADHERE data provides evidence that patients with PSF may respond differently to treatment with positive inotropes compared with those with impaired LVEF

Subgroup analysis in patients with PSF who received ionotropic agent showed - longer length of hospital stay (mean: 12.9 v/s. 9.6 days P =0.0001) - higher mortality rate (19 v/s. 14% P = 0.002)

Key issues highlighted by ADHERE - Many patients with no apparent clinical indication received positive inotropes, even though these drugs are associated with increased mortality

European Heart Journal Supplements (2005) 7 (Supplement B), B13–B19

Trials: Intravenous Inodilator Therapy

Regimens of intravenous inodilator therapy:

- Short-term therapy: - infused over several hours to a few days in

combination with diuretics- discontinued when patients are clinically stable -

- Intermittent intravenous therapy:- 4- to 6-hour pulse infusion for several days per /wk

or as a single 24- to 72-hour infusion once weekly

- Continuous intravenous infusions:

Short-Term Use of Inodilator Treatment-Dobutamine v/s Levosimendan

Levosimendan V/s Dobutamine: - LIDO trial - CASINO trial

- SURVIVE –W trial

Levosimendan Infusion versus Dobutamine (LIDO) study Levosimendan Infusion versus Dobutamine (LIDO) study

Kaplan–Meier survival analysis in the LIDO The prospective benefit observed at 31 days for Levosimendan-treated

patients was maintained through the 180-day follow-up period.

Calcium Sensitizer or Inotrope or None in Low-Output Heart Failure Study (CASINO)

Dobutamine was associated with lower 6-month survival compared with Levosimendan or placebo in patients with decompensated low output HF

- enrolled 600 patients hospitalized with NYHA class IV HF- randomized to Levosimendan, Dobutamine, or placebo 48 hrs after presentation- primary end point of the study was mortality at one month, 6 months, or 1 yr

Heart Failure Update 2004 and Eur J Heart Fail

Survival curves for the three treatment arms of the CASINO studybefore complete follow-up of patients

Survival of Patients with Acute Heart Failurein Need of Intravenous Ionotropic Support (SURVIVE)trial

JAMA. 2007;297:1883-1891.

Trials: Intravenous Inodilator Therapy

Intermittent intravenous therapy : Dobutamine v/s placebo trials

LEVOSIMENDAN

Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy Versus Placebo in the Short-Term Treatment of

Decompensated Heart Failure (REVIVE)

- large-scale, placebo-controlled, double-blind study- in 600patients hospitalized for AHFS with LVEF <0.35 & dyspnea at rest who required intravenous diuretics

- Randomized to receive either Levosimendan or placebo in addition to standard therapy

REVIVE-1 data ( n=100) - Levosimendan treatment A/W- improvement in the composite end point at 24 hrs and 5 days- a significant reduction in BNP levels at 24 hours and 5 days- shorter lengths of initial hospitalization

Randomized Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure Due to an Acute Myocardial Infarction (RUSSLAN)

LEVOSIMENDAN

Randomized Study on Safety and Effectiveness of Levosimendan in Patients with Left Ventricular Failure Due to an Acute Myocardial Infarction (RUSSLAN)

Kaplan–Meier survival analysis in the RUSSLAN trial The prospective survival benefit of Levosimendan compared to placebo at 14 days were maintained through 180 days of follow-up

- indicated in patients with symptomatic low COP HF secondary to cardiac systolic dysfunction without severe hypotension

ESC 2005 guideline on acute HF: Levosimendan

class IIa/ Level of evidence B

Milrinone

Short-Term Use of Inodilator Treatment- Milrinone

OPTIME-CHF investigators:- randomized 949 patients (mean age- 65 years) - patients with an exacerbation of systolic HF with NYHA

class III to IV HF and an LVEF <0.40 (mean LVEF, 0.23)

- studied the effect of short-term Milrinone infusion (48 to 72hrs) - primary outcome:

- cumulative days of hospitalization within 60 days of randomization

- secondary outcomes:-adverse events and mortality

Kaplan-Meier survival curves for in-hospital survival to 60 days by heart failure etiology and treatment assignment in a post hoc analysis of the OPTIME-CHF trial. (Adapted from J Am Coll Cardiol)

Dopamine:

Dopamine:

No randomized controlled trials studying the effects of short-term, intermittent, or long-term continuous infusion of dopamine

According to the ESC guideline on acute HF:

Dopamine may be used as an Inotrope (2µ g/kg per min ) - acute HF with hypotension.

Infusion of low doses of dopamine (2–3 µg/kg per min) - used to improve renal blood flow and diuresis in

decompensated HF with hypotension and low urine output ( if no response is seen→ the therapy should be terminated

-(class IIb)

Digoxin in Acute Heart failure

Digoxin in Acute Heart failure

- Digoxin has been used in patients with Chronic HF for >200yrs - it remains an important agent in the modern era

- its role in the treatment of acute HF is unclear

In a study involving 6 patients with acute MI with HF →IV Digoxin v/s Dobutamine

Digoxin - no effect on LV filling pressure

- slight effect on cardiac index & stroke work index (in contrast to marked favorable hemodynamic effects produced by IV dobutamine)

- NEJM 1980;303:846–850.

Comparative Hemodynamic and Neurohormonal Effects of IV Captopril and Digoxin and Their Combinations in Patients With

Severe Heart Failure

In 16 patients with severe HF and sinus rhythm, the effects of acute administration IV Digoxin and IV Captopril on rest and exercise hemodynamics were studied

- JAAC1989;13:134-42)

Digoxin and Captopril were given separately and in combination both at rest and during maximal exercise

Digoxin - decreased PCWP - increased stroke work index.

Digoxin in combination with Captopril resulted in - further decrease in PCWP - further increase in stroke work index

Comparative Hemodynamic and Neurohormonal Effects of IV Captopril and Digoxin and Their Combinations in Patients With Severe Heart Failure - JAAC1989;13:134-42)

When given separately

↓in PCWP – by captopril – 24% by digoxin - 34% (p = 0.004)

↓SVR - by captopril 23% (p = 0.09)

- by dogoxin 20% (p = 0.03)

Only Digoxin increased - cardiac index by 23% (p = 0.03)

- stroke work index by 52% (p = 0.01)

Despite the beneficial hemodynamic and neurohormonal effects and long-term safety data

- the effects of Digoxin on clinical outcomes in patients with AHFS is not well studied

ACC/AHA 2005 guideline on chronic HF : “Digoxin is not indicated as primary therapy for the stabilization of patients with an acute exacerbation of HF symptoms, including fluid retention or hypotension.”

HFSA 2006 Comprehensive HF Practice GuidelineESC 2005 guideline on acute HF - do not address Digoxin

Istaroxime in acute heart failure

Istaroxime in acute heart failure

- Positive inotropic + positive lusitropic properties

- Inhibit sarcolemmal Na-K ATPase → cytosolic Ca accumulation→ +ve inotropism

-Stimulate SR calcium ATPase → rapid sequestration of cytosolic calcium into the SR during diastole → Promotes myocardial relaxation (lusio)

- improves myocardial contractility, hemodynamics, LVEF- Improves diastolic relaxation in the absence of pro arrhythmic or ischemic effects

Series1

-4

-2

0

Series1

-0.8

-0.4

0

0.4

0.8

HORIZON-HF

• Change in E’ velocity: 0.5 cm/sec for istaroxime vs. -0.7 cm/sec for placebo (p = 0.048)

• Change in pulmonary capillary wedge pressure: -3.7 mm Hg vs. -0.2 mm Hg (p = 0.001), respectively

• Cardiac index: 0.12 L/min/m2 vs. 0.03 L/min/m2 (p = 0.57), respectively

Trial design: Patients admitted with acute decompensated HF were randomized to istaroxime, an inotropic and lusitropic agent (n = 89), versus placebo (n = 31).

Results

Conclusions• Istaroxime may be beneficial in improving

hemodynamics and diastolic function in patients with acute decompensated HF.

• Future studies are needed to address the impact on clinical outcomes from this agent.

Shah SJ, et al. Am Heart J 2009;Apr24:[Epub]

(p = 0.048) (p = 0.001)

Istaroxime Placebo

cm/s

ec

0.5

-0.7-3.7

-0.2

Change in E’ velocity

Change in pulmonary capillary wedge

pressure

mm

Hg

ESC HF Guidelines-2012 - inotropes dosage recommended

Recommendations for inotropes in AHF

ESC HF Guidelines-2012

- Conventional inotropes (Dobutamine, dopamine, Milrinone) can rapidly improve hemodynamic parameters in patients with AHFS/LO

- Benefits may be offset by risks of adverse effects including increased myocardial oxygen demand and excessive intracellular accumulation of calcium → arrhythmogenic & promote cell death

- role of IV Digoxin remains to be determined

- Development of drugs that improve contractility without producing calcium overload represents an important but unaccomplished goal in the management of patients with AHFS/LO.

summary

Use of current intravenous inotropes has been a/w risk for - hypotension

- atrial and ventricular arrhythmias- increased post discharge mortality

There is an unmet need for new agents to safely improve cardiac performance (contractility and/or active relaxation) in this patient population.

CONCLUSION

Thank you