2. • Serelaxin :
• Recombinant form of human relaxin – 2, a hormone that is
released during pregnancy.
• Human-relaxin-2 mediates vasodilation by increasing the
production of NO.
• Relaxin also causes vasodilation by an indirect mechanism,
where it inhibits the potent vasoconstrictors angiotensin II and
endothelin.
3.
4. • The phase III RELAX-AHF trial enrolled 1161 patients within 16
hrs of presentation who had dyspnoea, congestion, mild to
moderate renal insufficiency and SBP >125 mm Hg.
• 48 hour infusion of either Serelaxin 30mcg/kg/day or placebo.
9. VMAC Trial (Vasodilation in the management of
AHF) (2002)
• A study comparing blood flow and clinical and safety effects
of the addition of nesiritide, placebo or IV NTG to standard
care for the treatment of worsening congestive heart failure.
10. Outcome of VMAC trial:
• Nesiritide reduced PCWP and all PA pressures compared to
NTG and placebo.
• At 3 hrs, dyspnoea was improved by BNP compared to
placebo; the change with NTG was not statistically significant.
11. VMAC outcomes (contd)…
• By 24 hrs, symptomatic hypotension occurred in only 4% of
BNP patients and 5% of NTG patients.
• Fewer adverse events in patients treated with BNP than with
NTG.
Limitations :
-Increases risk of worsening renal function in patients with ADHF.
-Maybe associated with an increased risk of death after
treatment for ADHF.
12. ASCEND – HF (Acute study of clinical effectiveness of
nesiritide in decompensated HF) (2011)
13. • Reduced dyspnoea to a modest degree but did not meet pre-
specified criteria for statistical significance at 6 and 24 hours.
14. Nesiritide did not affect 30 day all cause mortality nor did it worsen renal
function as had been suggested by prior meta-analyses of smaller studies.
15.
16. Inotropic agents
Cardiac myosin activators:
• Increases myocardial contractility.
• They increase the systolic ejection time without increasing the
rate of LV pressure development, resulting in increased stroke
volume and cardiac output.
• No increase in myocyte calcium.
• No change in myocardial O2 consumption.
• Acute Treatment with Omecamtiv Mecarbil to Increase
Contractility in Heart Failure trial (ATOMIC – HF) Phase II-b trial
underway.
17. Intravenous Omecamtiv mecarbil did not meet the primary
endpoint of dyspnoea improvement, but it was generally well
tolerated, it increased systolic ejection time, and it may have
improved dyspnea in the high-dose group.
18. Istaroxime :
• Stimulates membrane-bound Na+,K+ - ATPase
• Enhances the activity of Sarcoendoplasmic reticulum
Ca2+ATPase type 2a (SERCA-2a)
• Resulting in increased cytosolic calcium accumulation
during systole, with positive inotropic effects and rapid
sequestration of cytosolic calcium into the sarcoplasmic
reticulum during diastole, leading to an enhanced
lucitropic effect.
• HORIZON-HF study : Addition of Istaroxime to standard
therapy lowered PCWP and HR and increased SBP.
• No change in neurohormones, renal function or Trop-I
levels.
19. Renoprotective agents
• Adenosine A1 receptor antagonists (Rolofylline)
increase renal blood flow and enhance diuresis
without activating the tubuloglomerular feedback.
• PROTECT trial (2010) showed no clinical
improvement including renal protection , and use of
the drug was associated with more seizures and
stroke events.
20. Neurohormonal antagonists
• Endothelin receptor antagonists block the action of
endothelin-1, a potent vasoconstrictor.
• Tezosentan , a non-selective ETA-B antagonist improves
hemodynamics in HF.
• The Value of Endothelin Receptor Inhibition with Tezosentan in
Acute heart failure Study (VERITAS - 2007).
• Tezosentan did not improve symptoms or clinical outcomes in
patients with acute heart failure.
22. Levosimendan contd…
SURVIVE (2007) :
• To demonstrate a 25% reduction in mortality for levosimendan
compared with dobutamine.
• All-cause mortality was similar in both groups.
• There were greater decreases in BNP level in the
levosimendan group compared with the dobutamine group.
• There was a higher incidence of cardiac failure in the
dobutamine group whereas a higher incidences of atrial
fibrillation, hypokalemia, and headache in the levosimendan
group.
23. REVIVE – 2 (2013) :
• 82 patients in the placebo arm and 58 patients in the
levosimendan arm had symptom worsening at day five.
• Levosimendan-treated patients experienced fewer episodes of
and required fewer pharmacological interventions for
worsening heart failure and had fewer prolonged hospital
stays.
• Excess of adverse events reported in the treatment arm.
Increased number of deaths with levosimendan compared with
placebo (five vs four deaths in the REVIVE-1 pilot study and 45
vs 35 deaths in REVIVE-2). In addition, hypotension, headache,
ventricular tachycardia, atrial fibrillation, and ventricular
extrasystoles were significantly more common among the
levosimendan-treated patients.
24. Milrinone
• Phosphodiesterase 3 inhibitor
• Increases heart’s contractility and decreases pulmonary
vascular resistance.
• Outcomes of a Prospective Trial of Intravenous Milrinone for
Exacerbations of Chronic Heart Failure (OPTIME-CHF) study :
• Milrinone-treated patients with ischemic etiology tended to
have worse outcomes than those treated with placebo in terms
of the primary end point (days hospitalized from cardiovascular
causes within 60 days-13.6 days for milrinone vs. 12.4 days for
placebo) and the composite of death or rehospitalization (42%
vs. 36% for placebo).
25. • In contrast, outcomes in nonischemic patients treated with
milrinone tended to be improved in terms of the primary end
point (10.9 vs. 12.6 days placebo) and the composite of death
or rehospitalization (28% vs. 35% placebo).
• Milrinone may have a bidirectional effect based on etiology in
decompensated HF. Milrinone may be deleterious in ischemic
HF, but neutral to beneficial in nonischemic cardiomyopathy.
26. • Cinaciguat :
- Soluble guanylate cyclase activator
-Vasodilation
-Improved hemodynamics at high doses
-Significant hypotension, recent studies terminated.
