heart failure therapies 88

8/4/2019 Heart Failure Therapies 88

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Newer pharmacotherapeuic

agents in treatment of CHF


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Drugs with (some) definitebenefits


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N-3 polyunsaturated fatty acids

GISSI-HF study on 6975 patients with

1gram/day N-3 PUFA

All cause mortality reduction 29 to 27 % CV mortality reduction 59 to 57 %


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Recombinant human

BNP:NESIRITDE

IV bolus 2 mcg/kg, F/B INF @ 0.01

mcg/kg

Dose adjusted thereafter as needed Arterial and venous vasodilation

Increased mortality @ 30 days; renal

dysfunction Use: Symptom relief

Other BNPs: CAPERITIDE (Japan; in

use), ULARITIDE, CD-NP (trial stage)


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Vasopressin antagonists

V1a blocker- SVR, afterload (Relcovaptan )

V2 blocker- water diuresis, Na+ (Tolvaptan)

Both- CONIVAPTAN

Relcovaptan - data not available

Tolvaptan (30-90 mg/day)- EVEREST trial (long

term benefits absent, short term symptom relief)

CONIVAPTAN (oral and IV)- only limited data.

Used for short term effects.


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Phosphodiesterase (PDE-5)

Inhibitors :SILDENAFIL

Acts by lowering pulmonary vascular

resistance.

effort tolerance . (even with no PAH)

Long term data on efficacy and safety is

needed: RELAX trial- ongoing.

(Use with caution in borderline BP)


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Calcium sensitizers

IV INF for acute stages: no long term benefits

Pimobendan: Approved in Japan, limited data on

long term effects

Levosimendan (0.05 to 0.6g/kg/min): effectsnot attenuated by -blockers; effects similar to

Dobutamine. Used in some European countries.

Benefit LIDO, RUSSLAN No benefit- SURVIVE.


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Partial Fatty Acid Oxidation (pFOX)

inhibitors They are metabolic modulators.

They oxidation (fatty acid oxidation) andthereby favour glucose metabolism

Prototype-etomoxir, oxfenicin, perhexiline Trimetazidine inhibit 3-ketoacyl Coenzyme A

thiolase. No vasodilator eff. (small scale trials)

Ranolazine: activity of PYR decarboxilase. No

clinical trials for use in HF Antianginal effect :Na+ entry in cells (by

inhibiting delayed rectifier K+ current)


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Immunomodulators

Basis of immunomodulation: inflammation

plays a role in the pathogenesis of HF

Cytokine targeting therapy:

1. TNF inhibitors: Etanercept (RECOVER &RENAISSANCE trials), Infliximab

(ATTACH)-trial failed.

2. MMP inhibitors (eg: batimastat): Reversesremodeling, improve cardiac function (only

pre-clinical data)


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Immunomodulators-contd.

Statins in HF: The GISSI-HF and

CORONA trials showed no benefit .

No indication for initiation if LVEF


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Beta Interferons

To be used in idiopathic dilated

cardiomyopathy with PCR positivity for

viral genomes (enterovirus or adenovirus)

in EMB samples.

Eradicates viral genomes and LVEF.


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Circulation 2001; 103:220

Immunomodulators-contd3.

IVIG: An initial trial by Gullestad et al* had

shown an in LVEF by 5% @ 6 months.

But its use is limited by cost concerns.

Immunosuppressive therapy

(prednisolone, AZA) role in HF due to an

inflammatory origin (eg: progression of

acute myocarditis)


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Drugs with possible

benefits; but no

supportive data.


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Relaxin

Relaxin is a naturally occurring human

peptide vasodilator

IV infusion @ 30 mcg/kg/day dyspnea

and improve survival rates @ 60 days.

(Only preliminary data is available)


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Adrenomodulin

Peptide originally isolated from human

phaeochromocytoma cells.

Effects- vasodilatation, myocardial

contractility.

(Only preliminary data available)


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Neutral endopeptidase Inhibitors

Candoxatril, Ecadotril

NEP breaks down ANP and BNP

NEP Inhibitors- ANP and BNP, diuresisand natriuresis. Raised ANP and BNPprevent RAAS activation (in response todiuresis)

Vasopeptidase inhibitors : Omapratilat combined NEP and ACE inhibition.[IMPRESS, OVERTURE]


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Cardiac myosin activators

omecamtiv mecarbil .

myocardial contractility

Do not myocardial oxygen demand Phase II trial


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Drugs with lack of efficacy proven:

not used currently for Heart

Failure


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Endothelin antagonism

ET receptors: ET-A and ET-B

ET receptor antagonists-

1. Selective ET-A antagonist: Darusentan

(EARTH trial).

2. Dual receptor anatagonist: Tesozentan (IV),

enrasentan (oral) and Bosentan (oral)

[ENABLE, ECORE, EARTH] Studies shown-no benefit, side effects+


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Endothelin converting enzyme

inhibitors (ECE)

Blocks conversion of pro-ET-1 to ET-1

DB07171 : Used alone or with NEPinhibitors improve hemodynamics. But no

data in humans.

Triple inhibitors (ACE, ECE and NEP) areunder development.
http://www.drugbank.ca/drugs/DB07171http://www.drugbank.ca/drugs/DB07171


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Cenrally acting

sympatholytics:Moxonidine

MOXCON- showed harmful effects:

terminated.


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Adenosine A1 receptor antagonist

Rolofylline

PROTECT trial-showed no benefit, side

effects+

Abandoned


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VESNARINONE

Multiple mechanisms

Main effects-

1. inhibition of the outward delayed rectifying

potassium current

2. an increase in the fast sodium inward

current

3. phosphodiesterase inhibition

VEST trial: mortality; abandoned!!!


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GENE THERAPY

The target gene is combined with a viralvector (usually an adenovirus) and isdelivered into the myocardium via the

coronary circulation. Most common gene is sarcoplasmic

reticulum calcium ATPase pump(SERCA2a) gene.

Other targets-2 adrenoreceptor, adenylcyclase, V2 vasopressin receptor.

heart failure therapies 88

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