A Phase I, Placebo Controlled Cross-Over Study of Subcutaneous Cenderitide with LVAD Support a Phase I, Placebo Controlled Cross-Over Study of Subcutaneous Cenderitide with LVAD Support

S38 Journal of Cardiac Failure Vol. 23 No. 8S August 2017 AAs in the CT to determine key AA requirements and if key deletions, substitutions or replacements would modify MANP which is now entering clinical trials. Hypothesis: MANP represents the best-in-class novel potent pGC-A activator resulting in robust cGMP, cardiorenal and aldosterone suppressing actions. Methods: In vitro screening of 6 MANP variants were tested (10-8M dose) in HEK293 cells overexpressing GC-A while in vivo actions were determined in normal canines (33 pmol/kg/min). Physiologic parameters were determined before, during and 2 hours following a 45-minute infusion. Results: In vitro, only two variants (MANP1 and MANP4) demonstrated enhanced pGC-A/cGMP activity supporting their potential role as next generation MANPs. Unexpectedly, MANP1 was a potent hemodynamic peptide but with markedly reduced natriuretic and cGMP activity. MANP4 paralleled the actions of MANP but with less urinary cGMP activity and less sustained biological actions than MANP. MANP had the most prolonged aldosterone suppressing activity of all three designer peptides. Conclusion: MANP therefore represents the best-in-class GC-A/cGMP activating designer peptide now entering clinical trials. Importantly, the novel 12 AA CT of MANP is a mandatory structural requirement for MANP’s potent action. Continuing studies of MANP are clearly warranted in heart failure and hypertension to explore efficacy as a novel new therapeutic agent.

while plasma NT-proBNP followed a similar trend. There was no increase of Troponin-T levels after Cenderitide injection. Cenderitide was well tolerated with no adverse events in the current study. Conclusions: SQ Cenderitide was successfully absorbed, activated cGMP and well tolerated in patients with LVAD support without myocardial toxicity. Cenderitide may have minor blood pressure lowering effects together with decreases in NT-proBNP consistent with myocardial unloading. Further clinical trials for efficacy are warranted to clarify cardiorenal protective effects of chronic Cenderitide administration as a co-therapy in the LVAD population to improve outcomes.

096 Vasopressin Antagonism for Severe Decompensated Right-Sided Heart Failure: Time for Critical Study? Andrija Vidic1, Zackary D. Goff1, Anuradha Godishala2, Jerrica E. Shuster2, Susan M. Joseph3, John T. Chibnall1, Paul J. Hauptman1; 1Saint Louis University School of Medicine, Saint Louis, Missouri; 2Barnes Jewish Hospital, Saint Louis, Missouri; 3Baylor University, Dallas, Texas

094 What Doses of β-Blockers are Being Used for Systolic Heart Failure in Patients Without Chronic Obstructive Pulmonary Disease? Tyler Trump1, John Robinson2, Qaisar Syed1, Phillip Kostelic1, Kimberly Kerr2, Suzanne Kemper1, William Carter1; 1West Virginia University School of Medicine, Charleston, West Virginia; 2University of Charleston School of Pharmacy, Charleston, West Virginia Introduction: Current guidelines recommend β-blockers (BBs) should be used for patients with systolic heart failure (SHF) to improve survival. In addition to BBs, ACE inhibitors, aldosterone receptor antagonists, and recently sacubitril/valsartan are Class I indications for most patients with SHF. The results of the SHIFT Trial led to ivabradine, which is a specific sinus node rate depressant, to be added as a Class IIa recommendation for patients with SHF and a sinus rate (SR) ≥ 70 bpm. Despite recommendations, the dosages of BBs prescribed for SHF are frequently less than 50% of target dose. Chronic obstructive pulmonary disease (COPD) is the most common reason for omitting and under-dosing BB therapy. Thus, the inappropriate under-dosing of BBs will likely increase the use of ivabradine. Hypothesis: SHF patients, even those without COPD, will have 1) under-dosing of BBs and 2) a SR over 70 bpm, hence a Class IIa indication for ivabradine. Methodology: Retrospective chart review of SHF patients without COPD admitted to Charleston Area Medical Center from January 1, 2010 through September 30, 2016. Dosages of BBs, heart rate (HR) and SR on admission and discharge, other cardiac medications, echocardiogram ejection fraction, and EKG data were recorded. Sinus rhythm was determined after careful review of EKG and rhythm strips. Results: Of the 115 SHF patients without COPD, 99 (86.1%) were taking BBs, 53 (53.5%) carvedilol; 33 (33.3%) metoprolol succinate; 11 (11.1%) metoprolol tartrate; 2 (2.0%) other and 13(11.3%) no BBs. Mean dose of carvedilol at admission was 18.8 ± 14.8 mg (target dose 50 mg); mean dose of metoprolol succinate was 54.2 ± 46.8 mg (target dose 200 mg). Mean SR (not atrial paced or Afib) at admission and discharge were 80.1 ± 15.3 bpm and 73.3 ± 12.3 bpm, respectively. Conclusions: While almost all patients with SHF are appropriately being prescribed BBs, a large percentage was not titrated up to even 50% of the target doses established in the guidelines and 64/115 (55.6%) patients had a resting HR ≥70 bpm at discharge. Inappropriate dosing of BBs could potentially be responsible for worsening outcomes and potential over-utilization of ivabradine to adequately suppress HR.

Introduction: Although decompensated right heart failure (RHF) with or without left heart failure is associated with poor outcomes, targeted treatment is lacking. Loop diuretic therapy is often complicated by renal failure; conversely, vasopressin antagonism (vaptans) may offer an option by increasing urine output and fluid mobilization without impacting blood pressure or renal function. Methods: Electronic medical records (2 institutions over 4 years) were searched for patients with HF (per ICD-9 codes) treated with vaptans. Patients with ≥2 criteria were classified as RHF: moderate or severe RV dysfunction/enlargement, TAPSE <1.6 cm, IVC collapse <50% with sniff, CVP/ PCWP >0.63, RA pressure >15 mmHg, bilirubin >2.0 mg/dl, ascites/JVD/pitting edema, RHF risk score > 4 or inotrope/nitric oxide use for ≥2 weeks post left ventricular assist device (LVAD) implant. Echocardiographic, hemodynamic and laboratory data were obtained; urine output, creatinine, BUN and sodium were compared 1 day pre- versus 1 day post-vaptan initiation. Data are presented as mean ±SD or median. Sign Test compared values over time. Results: A total of 112 patients (age 57.8 ± 14.6y, 72% male, LV ejection fraction 25.6 ± 17.9%) met inclusion criteria for RHF. Baseline prevaptan values were RAP 18.3 ± 7.6 mmHg, cardiac index 1.8 ± 0.4 L/min/m2, BNP 1313 ± 1105 pg/ml, CrCl 56 ± 24 cc, BUN 42.7 ± 23.8 mg/dl, [Na+] 130.7 ± 6.5 mEq/L and AST 142 ± 425 u/L. Most patients (n = 103/112) received intravenous inotrope (prior to vaptan n = 91); LVADs were implanted in 47 (greater than 1 week prior to vaptan n = 18). Overall length of stay was 33.6 ± 26.9 days with 291 ± 271 ICU hours. Vaptan treatment (90% tolvaptan, 10% conivaptan; median dose 15 mg and 20 mg respectively; median duration 3 days) was associated with increased 24h urine output (1775 ± 1169 vs 2774 ± 2154 ml, P = .005) and [Na+] (125.0 ± 4.4 vs 131.0 ± 6.0 mEq/ L, P < .001) without change in Cr or BUN (Fig. 1). [Na+] change was greater for pretreatment values <129 mEq/L. Furosemide IV daily dose equivalent of diuretics decreased significantly pre vs post vaptan initiation (72.5 ± 53.7 vs 66.6 ± 77.5 mg/d, P = .018). Conclusions: Vaptans were associated with significant urine output and loop diuretic dose reduction in patients with decompensated RHF including those already on inotrope or post LVAD without causing renal injury. A pilot RCT of vaptans in this cohort appears warranted.

095 A Phase I, Placebo Controlled Cross-Over Study of Subcutaneous Cenderitide with LVAD Support a Phase I, Placebo Controlled Cross-Over Study of Subcutaneous Cenderitide with LVAD Support Tomoko Ichiki, John A. Schirger, LuAnne J. Koenig, Jacqueline R. Wanek, Denise M. Heublien, Christopher G. Scott, Lyle D. Joyce, Horng H. Chen, John C. Burnett; Mayo Clinic, Rochester, Minnesota Introduction: Left ventricular assist device (LVAD) support significantly improves the short-term prognosis of end-stage heart failure (HF) patients, but improvement of renal function may be limited and progressive cardiac fibrosis may occur. Improved outcomes may require co-therapies which mediate organ protection including of the heart and kidney. Cenderitide (CDNP) is a Mayo engineered designer natriuretic peptide (NP) that co-activates particulate guanylyl cyclase A and B receptors and functions via the second messenger cGMP. We previously reported that Cenderitide has cardiorenal protective and anti-apoptosis/fibrosis properties in preclinical studies. We sought to determine if Cenderitide co-therapy with LVAD support would be safe and biologically active. Hypothesis: Single dose of subcutaneous (SQ) Cenderitide will be safe and well tolerative together with activation of plasma cGMP in patients with LVAD support. Methods: Sixteen stable HF patients with LVAD support (Heartmate II, all males) were enrolled in a cross-over design of SQ low (Low-C, 5 ug/kg, n = 8) or high dose (High-C, 10 ug/kg, n = 7) Cenderitide administration compared to placebo. Vital signs, plasma CDNP, cGMP, and NT-proBNP levels were measured before or after drug administration over 24 hours. For toxicity, Troponin-T levels were also determined. Results: Both Low-C and High-C group significantly and similarly increased plasma CDNP and cGMP levels dose-dependently for 2 hours after drug injection. Mean arterial pressure (MAP) in both group trended to be lower, but not significantly compared to placebo

Fig. 1. Treatment response (means) to vaptans. Left axis: Cr, BUN, and [Na+]; right axis: urine output in ml.