victoria trial

1. JOURNAl CLUB

2. VICTORIA (Vericiguat Global Study in
Subjects With Heart Failure With Reduced
Ejection Fraction)

3. Vericiguat
• A novel oral soluble guanylate cyclase stimulator
Mechanism of action
enhances the cyclic GMP pathway by directly
stimulating soluble guanylate cyclase ( sGC)
through a binding site independent of nitric
oxide
sensitizes sGC to endogenous NO by stabilizing
NO binding to sGC

4. Vericiguat in heart failure
Cyclic GMP pathway
The sGC is an intracellular receptor for endogenous
NO
NO is generated in endothelial cells (upon
physiological stimuli such as laminar blood flow
shear forces) and within endocardium.
NO diffuses to neighboring tissues such as vacular
endothelium and cardiac muscle, and stimulates
sGC to generate cGMP.
sGC mediated cGMP is essential for normal cardiac
and and vascular function

5. • In heart failure endothelial dysfunction and ROS
have been shown to reduce NO bioavailability,
resulting in relative sGC deficiency and
reduction in cGMP synthesis.

6. • Reduced sGC can lead to
Coronary microvascular dysfunction
Cardiomyocyte stiffness
Interstitial fibrosis
• Which ultimately lead to myocardial dysfunction
and progression of heart failure.

8. • Based on these mechanism vericiguat improve
HF by
Direct vasodilatory properties
Improving diastolic function
Improving endothelial function(vasomotoar
tone regulation
Improving cardiac reserve
• It is used in once daily oral dose.

10. • These hemodynamic improvements were
independent of change in heart rate, BP, primary
end point of pulmonary artery pressure.
• This showed that sGC stimulator were
beneficaila in HF beyond simply improving the
PAH.

11. SOCRATES -REDUCED [SOluble
guanylate Cyclase stimulatoR in heArT
failurE])
• In this study vericiguat was added to standard of
care in patients with worsening chronic HF
requiring hospitalization or IV diuretic treatment
and increased BNP or NT-proBNP
• did not reach statistical significant changes in NT
and NT-pro BNP levels
• BUT an exploratory analysis showed a clinically
significant reduction of NT-proBNP at the highest
dose group (10 mg).

12. • Exploratory analysis also revealed numerical trends
in both cardiovascular (CV) death and HF
hospitalization, as well as improved New York Heart
Association (NYHA) functional class in the 2 highest
dose groups along with concurrent improvement in
left ventricular EF with the highest target vericiguat
dose
• Vericiguat was safe and well tolerated relative to
placebo, except for treatment-emergent syncope and
hypotension that was more common in the 10-mg
group.

13. VICTORIA (Vericiguat Global Study in
Subjects With Heart Failure With Reduced
Ejection Fraction)

14. STUDY OBJECTIVES
The primary objective
to determine whether vericiguat is superior to
placebo on a background of standard of care in
increasing the time to the first occurrence of the
composite endpoint of CV death or HF
hospitalization in patients with HFrEF

15. Secondary objectives
to determine whether vericiguat is superior to
placebo in increasing
time to CV death
time to first and subsequent HF hospitalizations,
time to first occurrence of the composite of all-
cause mortality or HF hospitalization
time to all-cause mortality
to assess the safety and tolerability of vericiguat

16. Trial Design and Oversight
• Multinational,randomized, double-blind,
placebo-controlled trial

17. Patient Enrollment

18. Inclusion criteria:
1. At least 18 years of age
2. Chronic heart failure (NYHA class II, III, or IV) with a reduced
left ventricular ejection fraction of less than 45% within 12
months before randomization and an elevated natriuretic peptide
level within 30 days before randomization.
• For patients in sinus rhythm, the criteria included
 plasma BNP level of at least 300 pg per milliliter
 NT-proBNP level of at least 1000 pg per milliliter
• For patients in atrial fibrillation, the criteria included
 BNP level of at least 500 pg per milliliter
 NT-proBNP level of at least 1600 pg per milliliter.

19. 3. Prior HF hospitalization within 6 months (those
>3 months limited to 20%) or outpatient IV
diuretic therapy for HF within 3 months prior to
randomization

20. Exclusion Criteria
1. Systolic blood pressure <100 mm Hg
2. Concurrent or anticipated use of long-acting
nitrates of sGC stimulator, PDE5 inhibitors
3. Receiving IV inotropes, an implantable LV assist
device or awaiting heart transplantation
4. Correctable, complex, or clinically active cardiac
comorbidity
5. Prior cardiac valve intervention <3 months or
coronary revascularization <60 days
6. Unable to provide informed consent
7. Females of reproductive age not using an
acceptable form of contraception

21. Trial Conduct
• All the patients provided informed consent.
• Patients were then randomly assigned, in a 1:1 ratio, to 2.5 mg
of vericiguat or matching placebo, within six strata based on
geographic region and, within North America, race.
• Doses were increased to 5 mg and ultimately to the target
dose of 10 mg once daily in a blinded manner, as guided by
evaluation of blood pressure and clinical symptoms
• Patients were evaluated at weeks 2 and 4, and every 4 months
thereafter until the end of the trial.

22. Trial Outcomes
• The primary outcome was a composite of death from
cardiovascular causes or first hospitalization for heart
failure.
• The secondary outcomes were the
• components of the primary outcome
• first and subsequent hospitalizations for heart failure
• a composite of death from any cause or first
hospitalization for heart failure, and death from any
cause.
• Prespecified safety outcomes of clinical interest included
symptomatic hypotension and syncope.

23. Results
• Between September 25, 2016, and December 21,
2018, a total of 6857 patients were screened in
42 countries, and 5050 were enrolled at 616 sites

25. • The baseline characteristics were well matched in the two
groups
• The mean age of the enrolled patients was 67 years, and 24%
were women.
• At randomization, two thirds of the patients had been enrolled
within 3 months of their index hospitalization for heart
failure, 40% were classified as having NYHA class III heart
failure, and the mean ejection fraction was 29%.
• The median NT-proBNP level was 2816 pg per milliliter, as
determined in a central laboratory.

28. • The use of concomitant guideline-based medical
therapy was well balanced in the two groups:
60% of the patients received triple therapy (a beta
blocker and a MRA combined with either an ACE-
inhibitor, or an ARB, or sacubitril–valsartan)
15% received an angiotensin–neprilysin inhibitor
32% of the patients had an implantable
cardioverter– defibrillator, a biventricular
pacemaker, or both devices.

29. Follow up
• Adherence to the trial drug was greater than 80% in
93.8% of the patients in the vericiguat group and in
93.4% of the patients in the placebo group.
• The median dose of trial medication was 9.2 mg in
the vericiguat group and 9.2 mg in the placebo
group.
• After approximately 12 months, 90.3% of the
patients were receiving the 10-mg target dose
(89.2% in the vericiguat group and 91.4% in the
placebo group).

30. Follow-up

31. Trial outcome

32. Primary outcome

37. Secondary outcomes

39. Safety
• Serious adverse events occurred in 32.8% of the
patients in the vericiguat group and in 34.8% of
the patients in the placebo group.
• Adverse events (serious and nonserious)
occurred in 80.5% of the patients receiving
vericiguat and in 81.0% of the patients receiving
placebo

40. • The prespecified adverse events of clinical
interest were symptomatic hypotension and
syncope.

42. • Baseline systolic blood pressure was 121.2 mm
Hg in the vericiguat group and 121.5 mm Hg in
the placebo group.
• Systolic blood pressure declined slightly in both
groups over the first 16 weeks (more so in the
vericiguat group than in the placebo group) and
returned to baseline thereafter

43. Subgroup Analysis
• The effect of vericiguat on the primary outcome
was consistent across most prespecified
subgroups (including patients receiving
sacubitril–valsartan), except in the subgroups
defined according to age and NT-proBNP level

46. Discussion
• In this trial involving patients with chronic heart
failure and a reduced ejection fraction who had
worsening symptoms for which hospitalization or
urgent treatment was warranted, the incidence of
the composite of death from cardiovascular causes
or hospitalization for heart failure was lower with
vericiguat than with placebo.
• The difference favoring vericiguat appeared after
approximately 3 months of treatment and persisted
throughout the trial

47. • The 10% relative difference between the groups in the primary
composite outcome in this high-risk population at a median
follow-up of 10.8 months translated into an absolute event-
rate reduction of 4.2 events per 100 patient-years.
• Based on this absolute risk reduction, the number needed to
treat with vericiguat for 1 year to prevent a primary-outcome
event is approximately 24 patients (or 28 patients according
to the difference in 12-month Kaplan–Meier estimates)
• This outcome occurred in patients who were receiving
guideline-based medical therapy

48. • There was no significant between-group
difference in the incidence of death from any
cause.

49. Comparision with other novel drugs for
treating heart failure
VICTORIA PARADIGM-
HF
DAPA-HF
NYHA class III
or IV heart
failure
41% 25% 32%
median NT-
proBNP
1608 1437 2816
annualized rate
of the primary
composite
outcome
33.6% Two times Two times

50. • Although both of these trials showed more
substantial relative reductions in the primary
composite outcome of VICTORIA (a composite
of death from cardiovascular causes or first
hospitalization for heart failure), the annualized
reductions in absolute risk are similar.

51. • As expected, symptomatic hypotension and
syncope were more common in the patients
receiving vericiguat than in those receiving
placebo.
• The overall frequency of adverse events was
similar in the two groups, as were adverse events
related to renal function or electrolyte balance

52. Conclusion
• Among patients with CHF with recent decompensation, a novel strategy of
increasing soluble guanylate cyclase activity with vericiguat was effective.
• Vericiguat compared with placebo was effective at reducing cardiovascular
death or hospitalization for heart failure.
• There was a possible enhanced benefit among patients <75 years of age.
• There was no apparent reduction in all-cause mortality with vericiguat
compared with placebo.
• Vericiguat was safe and well tolerated and did not require monitoring of
renal function or electrolytes.
• Vericiguat may represent a novel treatment among patients with recent
heart failure decompensation