1. A study compared the angiotensin receptor–neprilysin inhibitor LCZ696 to enalapril in patients with heart failure and reduced ejection fraction. LCZ696 was superior to enalapril in reducing risks of death and hospitalization for heart failure. 2. A trial investigated spironolactone in patients with heart failure and preserved ejection fraction. Spironolactone did not significantly reduce the primary outcome but did lower the risk of hospitalization for heart failure. It increased hyperkalemia but with monitoring, serious adverse events were similar to placebo. 3. A study examined intravenous ferric carboxymaltose in patients with heart failure, reduced

1. Mixed results for heart failure
therapies
Dr. Virbhan Balai
National Heart Institute, N. Delhi

3. Background
• The angiotensin receptor–neprilysin inhibitor
LCZ696 was compared with enalapril in
patients who had heart failure with a reduced
ejection fraction.
• In previous studies, enalapril improved
survival in such patients.

4. Methods
• Double-blind trial
• 8442 patients with class II, III, or IV heart
failure and an EF≤ 40% were randomly
assigned to receive either LCZ696 (at a dose of
200 mg twice daily) or enalapril (at a dose of
10 mg twice daily), in addition to
recommended therapy.
• Lcz696 combines the neprilysin inhibitor
secubitril and ARB valsartan.

5. • The primary outcome was a composite of
death from cardiovascular causes or
hospitalization for heart failure, but the trial
was designed to detect a difference in the rates
of death from cardiovascular causes.

6. Results
• The trial was stopped early, according to prespecified rules, after a
median follow-up of 27 months, because the boundary for an
overwhelming benefit with LCZ696 had been crossed.
• At the time of study closure, the primary outcome had occurred in
914 patients (21.8%) in the LCZ696 group and 1117 patients
(26.5%) in the enalapril group (hazard ratio in the LCZ696 group,
0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001).
• A total of 711 patients (17.0%) receiving LCZ696 and 835 patients
(19.8%) receiving enalapril died (hazard ratio for death from any
cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558
(13.3%) and 693 (16.5%), respectively, died from cardiovascular
causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001).

7. • As compared with enalapril, LCZ696 also
reduced the risk of hospitalization for heart failure
by 21% (P<0.001) and decreased the symptoms
and physical limitations of heart failure
(P=0.001). T
• he LCZ696 group had higher proportions of
patients with hypotension and nonserious
angioedema but lower proportions with renal
impairment, hyperkalemia, and cough than the
enalapril group.

8. Conclusions
• LCZ696 was superior to enalapril in reducing
the risks of death and of hospitalization for
heart failure. (Funded by Novartis;
PARADIGM-HF

10. Background
• Mineralocorticoid-receptor antagonists
improve the prognosis for patients with heart
failure and a reduced left ventricular ejection
fraction.
• To the effects of spironolactone in patients
with HFpEF.

11. Methods
• Randomized, double-blind trial
• 3445 patients with symptomatic heart failure
and a left ventricular ejection fraction of 45%
or more were assigned to receive either
spironolactone (15 to 45 mg daily) or placebo.
• The primary outcome was a composite of
death from cardiovascular causes, aborted
cardiac arrest, or hospitalization for the
management of heart failure.

12. Results
• With a mean follow-up of 3.3 years, the primary outcome
occurred in 320 of 1722 patients in the spironolactone group
(18.6%) and 351 of 1723 patients in the placebo group
(20.4%) (hazard ratio, 0.89; 95% confidence interval [CI],
0.77 to 1.04; P=0.14).
• Of the components of the primary outcome, only
hospitalization for heart failure had a significantly lower
incidence in the spironolactone group than in the placebo
group (206 patients [12.0%] vs. 245 patients [14.2%];
hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P=0.04).
• Neither total deaths nor hospitalizations for any reason were
significantly reduced by spironolactone.

13. • Treatment with spironolactone was associated
with increased serum creatinine levels and a
doubling of the rate of hyperkalemia (18.7%, vs.
9.1% in the placebo group) but reduced
hypokalemia.
• With frequent monitoring, there were no
significant differences in the incidence of serious
adverse events, a serum creatinine level of 3.0 mg
per deciliter (265 μmol per liter) or higher, or
dialysis.

14. Conclusions
• In patients with heart failure and a preserved
ejection fraction, treatment with
spironolactone did not significantly reduce the
incidence of the primary composite outcome
of death from cardiovascular causes, aborted
cardiac arrest, or hospitalization for the
management of heart failure.

16. Background
• Iron deficiency may impair aerobic
performance.
• This study aimed to determine whether
treatment with intravenous iron (ferric
carboxymaltose) would improve symptoms in
patients who had heart failure, reduced left
ventricular ejection fraction, and iron
deficiency, either with or without anemia.

17. Methods
• 459 patients with chronic heart failure of New
York Heart Association (NYHA) functional class
II or III, a LVEF ≤40% (for pt`s with NYHA class
II) or ≤ 45% (for NYHA class III), iron deficiency
(ferritin level <100 μg per liter or between 100
and 299 μg per liter, if the transferrin saturation
was <20%), and a hemoglobin level of 95 to 135
g per liter.
• Patients were randomly assigned, in a 2:1 ratio, to
receive 200 mg of intravenous iron (ferric
carboxymaltose) or saline (placebo).

18. • The primary end points were the self-reported
Patient Global Assessment and NYHA
functional class, both at week 24.
• Secondary end points included the distance
walked in 6 minutes and the health-related
quality of life.

19. Results
• Among the patients receiving ferric
carboxymaltose, 50% reported being much or
moderately improved, as compared with 28% of
pt`s receiving placebo, according to the Patient
Global Assessment (odds ratio for improvement,
2.51; 95% confidence interval [CI], 1.75 to 3.61).
• Among the pt`s assigned to ferric carboxymaltose,
47% had an NYHA functional class I or II at
week 24, as compared with 30% of patients
assigned to placebo (odds ratio for improvement
by one class, 2.40; 95% CI, 1.55 to 3.71).

20. • Results were similar in patients with anemia
and those without anemia.
• Significant improvements were seen with
ferric carboxymaltose in the distance on the 6-
minute walk test and quality-of-life
assessments.
• The rates of death, adverse events, and serious
adverse events were similar in the two study
groups.

21. Conclusions
• Treatment with intravenous ferric
carboxymaltose in patients with chronic heart
failure and iron deficiency, with or without
anemia, improves symptoms, functional
capacity, and quality of life; the side-effect
profile is acceptable.

22. Thoracic Spinal Cord Stimulation for Heart
Failure as a Restorative Treatment (SCS
HEART study): first-in-man experience.

23. BACKGROUND
• Preclinical studies suggest that
neuromodulation with thoracic spinal cord
stimulation (SCS) improves left ventricular
(LV) function and remodeling in systolic heart
failure (HF).

24. • OBJECTIVE:
• The purpose of this study was to evaluate the
safety and efficacy of a SCS system for the
treatment of systolic HF.

25. METHODS:
• We performed a prospective, multicenter pilot
trial in patients with New York Heart Association
(NYHA) class III HF, left ventricular ejection
fraction (LVEF) 20%-35%, and implanted
defibrillator device who were prescribed stable
optimal medical therapy.
• Dual thoracic SCS leads were used at the T1-T3
level.
• The device was programmed to provide SCS for
24 hours per day (50 Hz at pulse width 200 μs).

26. RESULTS:
• Enrolled 22 patients from 5 centers:17 patients
underwent implantation of a SCS device and 4 patients
who did not fulfill the study criteria served as
nontreated controls.
• No deaths or device-device interactions were noted
during the 6-month period in the 17 SCS-treated
patients.
• Fifteen of 17 completed the efficacy endpoint
assessments: composite score improved by 4.2 ± 1.3,
• 11 patients (73%) showed improvement in ≥4 of 6
efficacy parameters.

27. • There was significant improvement in
– NYHA class (3.0 vs 2.1, P = .002; 13/17 improved);
– Minnesota Living with Heart Failure Questionnaire (42 ± 26 vs
27 ± 22, P = .026; 12/17 improved);
– Peak maximum oxygen consumption (14.6 ± 3.3 vs 16.5 ± 3.9
mL/kg/min, P = .013; 10/15 improved);
– LVEF (25% ± 6% vs 37% ± 8%, P<.001; 14/16 improved);
– LV end-systolic volume (174 ± 57 vs 137 ± 37 mL, P = .002;
11/16 improved)
• but not in N-terminal prohormone brain natriuretic peptide.
• No such improvements were observed in the 4 nontreated
patients.

28. CONCLUSION
• The results of this first-in-human trial suggest
that high thoracic SCS is safe and feasible and
potentially can improve symptoms, functional
status, and LV function and remodeling in
patients with severe, symptomatic systolic HF.

29. The vulnerable phase after
hospitalization for heart failure

30. • Despite available therapy, mortality and
readmission rates within 60–90 days of
discharge for patients hospitalized with heart
failure (HF) approach 15% and 30%,
respectively.
• This early post discharge period has been
termed the 'vulnerable phase' and accounts for
a disproportionate amount of the >US$30
billion spent annually on HF care in the USA.

31. • The pathophysiology underlying these early
adverse events is likely associated with
persistently elevated filling pressures at time of
discharge and subsequent acute or subacute
worsening of post discharge haemodynamics.
• Despite limited proven strategies to reduce early
adverse events, hospitals in the USA face
penalties for 30-day readmission rates that exceed
current expectations, and an urgent need exists for
novel approaches to improve early post discharge
outcomes.

32. • The objective of this Review is to describe the early post
discharge problem among patients hospitalized for HF, the
associated patient profile and pathophysiology, and the
limitations of current post discharge treatment strategies.
• To identify therapeutic targets and outline a progressive
management approach that should be considered by
clinicians for reducing early post discharge morbidity and
mortality.
• Although these strategies require prospective validation,
they are practical, affordable, and have the potential to
improve patient outcomes substantially after HF
hospitalization.

36. Pulmonary arterial capacitance in patients
with heart failure and reactive pulmonary
hypertension.

37. AIMS
• Reactive pulmonary hypertension (PH) is a severe
form of PH secondary to left-sided heart failure.
• Given the structural and functional abnormalities
in the pulmonary vasculature that occur in
reactive PH,
• It was hypothesized that pulmonary artery
capacitance (PAC) may be profoundly affected,
with implications for clinical outcome.

38. • Pulmonary arteriolar capacitance (PAC)
• Pulmonary arteriolar capacitance reflects the
ability of the pulmonary vessels to dilate
during systole and recoil during diastole.
• PAC is inversely proportional to PP and
directly proportional to SV.
• PAC = Stroke volume (SV)
Pulmonary artery pulse pressure (PP)

39. METHODS AND RESULTS
• 393 HF pt`s were studied of whom
– 124 (32%) were classified as having passive PH
– 140 (36%) as having reactive PH
– 91 patients with pulmonary arterial
hypertension(PAH).

40. • Definition:-
1. No PH (mean pulmonary artery pressure ≤25
mm Hg.
2. Passive PH (mean PAP>25, PCWP>15 mm Hg,
and PVR ≤3 Wood units).
3. Reactive PH (mean PAP>25, PCWP>15 mm Hg,
and PVR >3 Wood units).

41. • Mean PAC was highest in patients without PH
(4.5 ± 2.1 mL/mmHg),
• Followed by the passive PH group
(2.8 ± 1.4 mL/mmHg)
• Lowest in those with reactive PH
(1.8 ± 0.7 mL/mmHg) (P = 0.0001).

42. • PAC and PVR fitted well to a hyperbolic inverse
relationship (PAC = 0.25/PVR, R(2) = 0.70), with
reactive PH patients dispersed almost predominantly on
the flat part of the curve where a reduction in PVR is
associated with a small improvement in PAC.
• Elevated PCWP was associated with a significant
lowering of PAC for any PVR (P = 0.036).
• During a median follow-up of 31 months, both reactive
PH [hazard ratio (HR) 2.59, 95% confidence interval
(CI) 1.14-4.46, P = 0.02] and reduced PAC (HR 0.72
per 1 mL/mmHg increase, 95% CI 0.59-0.88,
P = 0.001) were independent predictors of mortality.

43. CONCLUSIONS
• The development of reactive PH is associated
with a marked reduction in PAC.
• PAC is a strong independent haemodynamic
marker of mortality in HF.
• PAC may contribute to the increased mortality
associated with reactive PH.

44. Acute heart failure in elderly patients: worse
outcomes and differential utility of standard
prognostic variables. Insights from the
PROTECT trial.

45. AIMS
• Previous heart failure (HF) trials suggested
that age influences patient characteristics and
outcome.
• However, under-representation of elderly pt`s
has limited characterization of this cohort.
• Whether standard prognostic variables have
differential utility in various age groups is
unclear.

46. METHODS AND RESULTS
• The PROTECT trial investigated 2033 patients
(median age 72 years) with acute HF randomized
to rolofylline or placebo.
• Patients were divided into five groups based on
the quintiles of age: ≤59, 60-68, 69-74, 75-79, and
≥80 years.
• Baseline characteristics, medications, and
outcomes (30-day death or cardiovascular/renal
hospitalization, and death at 30 and 180 days)
were explored.

47. • The prognostic utility of baseline characteristics
for outcomes was investigated in the different
groups and in those aged <80 years vs. ≥80 years.
• With increasing age, patients were more likely to
be women with hypertension, AF, and higher EF.
• Increased age was associated with increased risk
of 30- and 180-day outcomes, which persisted
after multivariable adjustment (hazard ratio for
180-day death = 1.17; 95% confidence interval
1.11-1.24 for each 5-year increase).

48. • The prognostic utility of baseline
characteristics such as previous HF
hospitalization and serum sodium, systolic
blood pressure, and NYHA class was
attenuated in the elderly for the endpoint of
180-day mortality.
• An increase in albumin was associated with a
greater reduction in risk in pt`s aged ≥80 years
vs. <80 years.

49. CONCLUSIONS
• In a large trial of acute HF, there were
differences in baseline characteristics and
outcomes amongst patients of different ages.
• Standard prognostic variables exhibit different
utility in elderly patients.

50. Dilemmas in end-stage heart
failure

51. • Heart failure (HF), a complex clinical syndrome
due to structural or functional disorder of the
heart.
• It is a major global health issue, with a prevalence
of over 5.8 million in the USA alone, and over 23
million worldwide.
• As a leading cause of hospitalizations among
patients aged 65 years or older.
• HF is a major consumer of healthcare resources,
creating a substantial strain on the healthcare
system.

52. • This paper discusses the epidemiology of HF,
financial impact, and multifaceted
predicaments in end-stage HF care.
• A search was conducted on the U.S. National
Library of Medicine website
(www.pubmed.gov) using keywords such as
end-stage heart failure, palliative care, ethical
dilemmas.

53. • Despite the poor prognosis of HF (worse than
that for many cancers), many HF patients,
caregivers, and clinicians are unaware of the
poor prognosis.
• In addition, the unpredictable clinical
trajectory of HF complicates the planning of
end-of-life care, such as palliative care and
hospice, leading to underutilization of such
resources.

54. Conclusion
• Ethical dilemmas in end-stage HF are
numerous, embroiling not only the patient, but
also the caregiver, healthcare team, and
society.

55. THANKYOU