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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/DB071718/4/2019 Heart Failure Therapies 88
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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.
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