Inorganic Nitrate Does Not Worsen Physical Activity

The 20th Annual Scientific Meeting patients were, after a further 36h wash-out, randomized to blinded twice-daily treatment with LCZ696 200 mg or enalapril 10 mg. Suspected angioedema or angioedemalike events were reported by the investigators or identified by the sponsor and were adjudicated by an independent angioedema adjudication committee (AAC). Results: Prior to run-in 77.3% of patients used ACE-inhibitors and 22.9% ARBs. Investigators reported 25 angioedema events during the enalapril run-in period (18.6 ± 6.3 days) and 29 events during the LCZ696 run-in period (30.3 ± 9.2 days). During the doubleblind period (27 ± 11 months), 45 events were reported for enalapril and 48 for LCZ696. Of all 147 reported events, 54 were confirmed by the AAC as angioedema (run-in period 25/54, double-blind period 29/93), with 25 confirmed events for enalapril and 29 for LCZ696. The incidence of confirmed angioedema was higher in black patients than in non-black patients (Table). The majority of events were of mild severity, requiring no treatment or antihistamines only. In 5 patients (enalapril: 2, LCZ696: 3) angioedema required hospitalization, including 1 black patient, but no patient required mechanical airway support. Conclusion: In PARADIGM-HF, the incidence of confirmed angioedema was low, with no severe cases. Black patients were at higher risk of angioedema events with both treatments. A wash-out period when switching treatment is considered important to avoid the risk of overlapping ACE- and neprilysin inhibition.

Table. Run-in Enalapril N = 10513 Adjudicated angioedema: n (%) patients Black patients: n (%) Hospitalized but no mechanical airway support Study drug permanently discontinued due to event

Double-blind

LCZ696 N = 9419

Enalapril N = 4229

LCZ696 N = 4203

15 (0.14)

10 (0.11)

10 (0.24)

19 (0.45)

2/559 (0.36) 1

2/493 (0.41) 0

1/214 (0.47) 1

5/213 (2.35) 3

15

8

4

7

•

HFSA

S67

186 Inorganic Nitrate Does Not Worsen Physical Activity Lien Trieu1, Payman Zamani2, Victor Tran2, Haideliza Soto-Calderon2, Melissa Beraun2, Jeffrey A. Brandimarto2, Swapna Varakantam2, Paschalis-Thomas Doulias3, Raymond R. Townsend2, Jesse Chittams2, Kenneth B. Margulies2, Thomas P. Cappola2, David C. Poole4, Harry Ischiropoulos3, Julio A. Chirinos2; 1Rowan School of Osteopathic Medicine, Stratford, NJ; 2University of Pennsylvania, Philadelphia, PA; 3Children’s Hospital of Philadelphia, Philadelphia, PA; 4Kansas State University, Manhattan, KS Introduction: Data suggests impaired nitric oxide (NO) bioavailability in HFpEF. However, a recent trial demonstrated that organic nitrate led to decreased physical activity. Important biochemical differences exist between organic and inorganic nitrate. Hypothesis: In contrast to organic nitrate, inorganic nitrate does not impair physical activity in HFpEF subjects. Methods: In this pilot study, we randomized 12 HFpEF subjects to 2 weeks of potassium nitrate (KNO3, n = 9) or placebo (potassium chloride, PB, n = 3). Subjects were given 6 mmol twice daily for the first week (Wk 1), increasing to 6 mmol thrice daily for the second week (Wk 2). Subjects were given actigraphy monitors (wActiSleepBT Monitor, Actigraph, LLC., Pensacola, FL), and data was downloaded at the end of each week. Steps taken and an estimate of kilocalories expended per day were recorded. Because follow-up visits were scheduled during the last 1–2 days of each week, data was abstracted for days 1–5 in all subjects. Values for days 3–5 were averaged to obtain estimates corresponding to steady state drug effects (SS). Values from Day 1 vs. SS were compared using paired t-tests for each week in each treatment group. Daily values from Wk 1 and Wk 2 were also analyzed as a panel dataset, incorporating the correlations between repeated measures in the same subject. Results: Inorganic nitrate did not reduce activity over either week of therapy when comparing steady state values for steps and kCals from Wk 1 vs. Wk 2 (P > .20 for both), or Day 1 vs. SS values for each week. There was a trend for increased steps taken during Wk 1 (Day1: 8019.7 vs. SS: 9244.1 steps; Δ1224.4; P = .066). Similarly, there was trend towards increased kcal expended during Wk 1 (Day1: 1239.3 vs. SS: 1683.3 kCal, Δ443.9, P = .06) and Wk 2 (Day1: 1318.5 vs. SS: 1678.7 kCal, Δ360.2, P = .086). Further, inorganic nitrate did not reduce activity when comparing daily values during Wk 1 and Wk 2 as a panel dataset (Fig. 1). No changes with activity were seen in the 3 PB subjects. Conclusions: Our study suggests that, unlike organic nitrate, inorganic nitrate does not reduce either step count or kCal expended over 2 weeks of therapy. We found trends towards increased activity during each week with inorganic nitrate. The effects of potassium nitrate in HFpEF are currently being investigated in a larger trial.

185 Effect of Stem Cell Therapy on All-Cause Mortality in Patient with Heart Failure: A Comprehensive Updated Meta-Analysis of Randomized Controlled Trials Adam M. Mizeracki, Rahman Shah; UTHSC, Memphis, TN Background: Heart failure (HF) remains a major public health burden, so development of new therapeutic strategies is necessary. Recently cell therapy has emerged a potential therapeutic option. Several small randomized controlled trials (RCTs) suggest that stem cell therapy improve clinical, functional, and quality-of-life outcomes in patients with HF. However those RCTs were underpowered to evaluate the effect of cell therapy on mortality. Therefore we conducted a comprehensive updated metaanalysis of RCTs to assess the effect of cell therapy on all-cause mortality in patient with HF. Methods: Scientific databases and websites were searched for RCTs to April 1, 2016. RCTs comparing cell therapy with placebo in patients with heart failure (either ischemic or non-ischemic cardiomyopathy) were eligible. The pooled risk ratios were calculated using random-effects models. The primary outcome was long term (defined at 12 months or longer follow-up) all-cause mortality. Results: Data from 12 trials were included. In patient with HF, stem cells therapy reduces the risk for all-cause mortality by 54 % (RR, 0.46; 95% CI, 0.33–0.66; P < .001). There was no significant heterogeneity between the trials (Q = 5.02, df = 11, P = .930; I2 = 0.0). Conclusions: In patients with HF, stem cell therapy improves long term survival. Further larger randomized clinical trial are needed to confirm this finding.

187 Initial Safety and Efficacy Experience with Extended Release Milrinone in No-Option Stage D Heart Failure Patients Shane Nanayakkara1, Viv Mak2, Karina Crannitch2, Peter Bergin2, David Kaye1; 1 BakerIDI Heart and Diabetes Institute, Melbourne, Australia; 2Alfred Hospital, Melbourne, Australia Introduction: The management of patients with Stage D heart failure (HF) presents a major clinical challenge. For many patients, heart transplantation and mechanical circulatory support are not management options due to advanced age or co-morbidities, thus leaving few therapeutic options available. Recently, there has been a growing interest in the use of home intravenous inotropes for use with palliative intent, however broader use is limited by cost, complexity, and line-related sepsis. Methods: On this basis we developed an extended release formulation of milrinone (CRD-102), designed to achieve a stable plasma profile similar to that with intravenous therapy. Preclinical studies showed zero order in-vivo release kinetics and prolonged plasma appearance. We conducted a pilot study of CRD-102 in 20 no-option Stage D HF patients. Baseline features included (mean ± SD): age 66 ± 12 years; LVEF 22 ± 7%;