Clinical Trials 210 The Selective Cardiac Myosin Activator, CK-1827452, Increases Systolic Function in Heart Failure J.G.F. Cleland 1 , F.I. Malik 2 , The CY 1121 Investigators; 1 University of Hull, United Kingdom; 2 Cytokinetics, Inc., South San Francisco, CA Background: CK-1827452 (CK-452) increases systolic function by the novel mech- anism of directly activating cardiac myosin. In healthy volunteers, the most sensitive indicator of its effect was a concentration-dependent increase in systolic ejection time (SET) accompanied by increases in stroke volume (SV), fractional shortening (FS), and ejection fraction (EF). We sought to confirm these findings in stable heart failure (HF) patients. Methods: This first Phase II trial of CK-452 is a multi-center, double- blind, randomized, placebo-controlled study in patients with EF ! 40% and treated with an ACE inhibitor or ARB, beta-blocker, 6 diuretics. The study has enrolled 2 cohorts of 8 patients who received 3 escalating doses of CK-452 and 1 placebo treat- ment randomized into the sequence to maintain blinding. Each of the four 2 hr infusions was at least 1 week apart. Infusions of 24 hrs are being studied in cohorts 3 and 4. Results: The pharmacokinetics of CK-452 in stable HF patients were similar to those in healthy volunteers. Echocardiographic data were paired with coincident measured plasma concentrations of CK-452 for analysis. Doppler-derived SET and SV measured during the 2 nd hour of infusion were the most sensitive indicators of drug effect. Placebo Corrected Changes from Baseline [CKe452] (ng/mL) 1e100 101e200 201e300 301e450 450e817 Baseline SET (ms) 320 e2.6 6 5.1 14 6 6.3# 59 6 7.6* 59 6 6.8* 92 6 8.8* SV (mL) 75 e1.4 6 2.7 e5.8 6 3.3 3.5 6 4.0 8.9 6 3.5# 27 6 4.6* FS (%) 18 0.7 6 0.9 0.0 6 1.2 2.8 6 1.4 0.7 6 1.3 5.0 6 1.6* EF (%) 35 e0.1 6 1.4 0.7 6 1.7 0.9 6 2.1 1.6 6 1.9 1.7 6 2.3 Least Squares Mean 6 SEM #p ! 0.05 *p ! 0.01 There was a statistically significant correlation between concentration and increases in SET, SV (each p ! 0.0001), and FS (p 5 0.008). Concentration-related increases in EF did not achieve statistical significance. Heart rate decreased at the higher con- centrations and blood pressure was unchanged. There were no significant treatment- related adverse events at these concentrations. Data from 24 hour infusions in cohorts 3 and 4 will be available at the time of presentation. Conclusions: CK-452 appears to be well tolerated and increases systolic function in stable HF patients over a broad range of plasma concentrations. Data from this first Phase II trial may support trans- lation of this novel and unique mechanism into populations with more severe heart failure. 211 Does Chronotropic Incompetence Limit the Functional Status of Heart Failure Patients? David O. Martin 1 , John D. Day 2 , Allan Murphy 3 , Sumit Verma 4 , Kenneth A. Ellenbogen 5 , Shelly Christman 6 , Stacia Kraus 7 , Kira Q. Stolen 6 ; 1 The Cleveland Clinic Foundation, Cleveland, OH; 2 LDS Hospital, Salt Lake City, UT; 3 Riverside Regional Medical Center, Newport News, VA; 4 Sacred Heart Hospital of Pensacola, Pensacola, FL; 5 Medical College of Virgina, Richmond, VA; 6 Clinical Affairs, Boston Scientific CRM, St. Paul, MN; 7 The Integra Group, Brooklyn Park, MN Introduction: Chronotropic response is not well studied in heart failure (HF) pa- tients, especially those receiving cardiac resynchronization therapy (CRT). Methods: Chronotropic response was determined by peak exercise testing in 241 patients in the exercise sub-study of the multi-center Pacing Evaluation -Atrial Support Study in Cardiac Resynchronization Therapy (PEGASUS - CRT). Patients in sinus rhythm who met standard indications for a CRT defibrillator underwent exercise testing six weeks post implant with the device programmed to DDD-40. Chronotropic in- competence (CI) was defined as the inability to achieve 70% of age predicted max- imal heart rate (HR). Device diagnostics including HR variability and activity log were evaluated for six weeks prior to exercise testing using mixed linear models ac- counting for repeated measures within a patient. Results: Of the 241 patients, 78 (32.4%) were classified as CI. At baseline, no differences were detected between CI and non-CI patients in the following: ejection fraction, age, weight, gender, New York Heart Association class or medication usage (ACE inhibitors, beta blockers, angiotensin receptor blockers). Patients that were non-CI at six weeks dem- onstrated significantly higher exercise capacities (see Table). Self reported quality of life did not differ between the two groups at 6-weeks (p 5 0.87) nor did HRV as- sessed over time (p 5 0.202). However, activity log was significantly higher in non-CI compared to CI patients (p 5 0.016). Conclusion: These data indicate that many CRT patients may not have an adequate HR response to accommodate the de- mands of daily activities. Device based measures of activity level may provide a clin- ical perspective to help differentiate patients that may benefit from additional HR support. Further evaluation of device diagnostics in determining CI is warranted. CI (n 5 78) Non-CI (n 5 163) Resting HR (bpm) 68.3 6 12.7 77.7 6 14.3* Peak HR (bpm) 95.3 6 14.7 130.1 6 16.5* HR Reserve (bpm) 27.0 6 13.7 52.4 6 19.1* Peak VO2 (ml/kg/min) 13.0 6 4.2 15.6 6 4.5* Exercise Duration (min) 7.1 6 3.6 10.1 6 3.7* *All p-values !0.0001 212 Extracorporeal Ultrafiltration (UF) vs. Usual and Customary Care for Patients with Severe Heart Failure (HF) Mazen Hanna 1 , ONeill Jim 2 , W.H. Wilson Tang 1 , David Weinstein 1 , Jimmy Teo 1 , Sey Lau 1 , Randall Starling 1 , Emil Paganini 1 , David Taylor 1 ; 1 Cardiology, Cleveland Clinic, Cleveland, OH; 2 Cardiology, Blanchardstown Hospital, Dublin, Ireland Background: In patients with heart failure, ultrafiltration (UF) may lead to greater weight loss and less hospitalization for heart failure than usual diuretic therapy. These benefits have yet to be translated to more ill patients who are invasively monitored in an intensive care unit. Methods: We conducted a single-center, prospective, random- ized controlled trial in patients with advanced heart failure admitted to a heart failure intensive care unit (ICU) for intensive hemodynamic guided therapy, comparing early UF (NxStage, n 5 17) versus usual customary care (UC, n 5 19). The primary end- point was the time required for the PCWP to be maintained at a value of #18 mm Hg for at least 4 consecutive hours. Secondary endpoints included changes in body weight, volume removal, renal function (cystatin C), neurohormones (NT-proBNP), and quality of life. Hospital readmission rates and survival were followed over a pe- riod of 90 days. Results: Both groups showed similar baseline variables (mean age 60 6 5 years, mean PCWP 28.5 6 4 mmHg, mean LVEF 17.6 6 7%) There was a trend towards less time required for the PCWP to be maintained at a value of less than or equal to 18 mm Hg (UF 22.0 6 4.3 hrs vs UC 34.8 6 6.8 hrs, p 5 0.081). UF group demonstrated greater weight reduction, higher average total volume removed, and shorter hospital length of stay (Table). There were no signifi- cant differences in changes in renal function, neurohormones, and hemodynamics. There were also no significant differences in adverse events (12 vs 10, p 5 0.79) or 90-day mortality (4 vs 4, p 5 0.86). Conclusions: In our cohort of advanced heart failure patients with volume overload, early ultrafiltration as compared to usual care with diuretics appeared safe and effective in providing greater reduction in weight and average volume removed leading to a shorter length of stay without adverse car- dio-renal consequences. Secondary Endpoints Ultrafiltration Usual Care P Value Change in weight (Kg) e4.68 6 3.5 e1.99 6 2.5 0.017 Average toal volume removed (ml/kg/hr) 3.338 6 2.551 0.733 6 1.011 0.0001 Hospitalization length of stay (days) 6.98 6 4.8 (median 4.5 days) 18.9 6 18.9 (median 9.6 days) 0.0008 213 Effects of Single IV Doses of BG9928, an Adenosine A1 Antagonist, in Patients with Heart Failure Stephen Gottlieb 1 , David DeNofrio 2 , Stuart Russell 3 , Ying Zuh 4 , Scott Stecher 4 , Barry Ticho 4 , William Abraham 5 ; 1 University of Maryland Medical Center, Baltimore, MD; 2 Tufts-New England Medical Center, Boston, MA; 3 Johns Hopkins Hospital, Baltimore, MD; 4 Biogen Idec, Inc., Cambridge, MA; 5 Ohio State University Medical Center, Columbus, OH Background: There is a need for therapies that maintain renal function while facil- itating diuresis in patients with heart failure (HF). BG9928 is a potent inhibitor of the adenosine A 1 receptor under investigation as a therapy for HF. The objectives of this study were to assess safety, tolerability, and effects of single IV doses of BG9928 in patients with HF receiving standard therapy. Methods: This was a multicenter, ran- domized, double-blind, placebo-controlled, dose-escalation study. Patients received IV BG9928 (0.03 mg/kg [n 5 8], 0.3 mg/kg [n 5 8], 1.0 mg/kg [n 5 8], or 3.0 mg/ kg [n 5 3]) or placebo (n 5 8). Safety assessments, pharmacokinetic parameters, and sodium excretion, urine volume, adjusted creatinine clearance, weight loss, and hemodynamic changes were recorded. Results: Change from baseline in urinary sodium excretion for the 0e8 hour postdose interval was numerically greater for all dosing groups compared with placebo and maximal in the 0.3 mg/kg group (0.3 mg/ kg vs. placebo, P 5 0.023). Adjusted creatinine clearance was not different among The 12 th Annual Scientific Meeting  HFSA S67