Mixed results for heart failure therapies

Dr. Virbhan BalaiNational Heart Institute, N. Delhi

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.

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.

• 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.

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).

• 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.

Conclusions

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

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.

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.

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.

• 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.

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.

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.

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).

• 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.

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).

• 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.

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.

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

BACKGROUND

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

• OBJECTIVE:• The purpose of this study was to evaluate the

safety and efficacy of a SCS system for the treatment of systolic HF.

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).

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.

• 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.

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.

The vulnerable phase after hospitalization for heart failure

• 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.

• 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.

• 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.

Pulmonary arterial capacitance in patients with heart failure and reactive pulmonary

hypertension.

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.

• 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)

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).

• 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).

• 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).

• 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.

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.

Acute heart failure in elderly patients: worse outcomes and differential utility of standard

prognostic variables. Insights from the PROTECT trial.

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.

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.

• 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).

• 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.

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.

Dilemmas in end-stage heart failure

• 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.

• 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.

• 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.

Conclusion

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

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