Chronic Vagus Nerve Stimulation (CVNS) - A New Target for Treatment of Congestive Heart Failure

The 12th Annual Scientific Meeting



HFSA

S71

223 Correlation of Ejection Fraction to Early Post-Discharge Sudden Death and AllCause Mortality in The EVEREST Trial Norman C. Wang1, Marvin A. Konstam2, Aldo P. Maggioni3, Brian Traver4, John C. Burnett5, Liliana Grinfeld6, Karl Swedberg7, James E. Udelson2, Faiez Zannad8, Thomas Cook4, Christopher Zimmer9, O’Connor Christopher10, Alan B. Miller11, Mihai Gheorghiade12, The EVEREST Investigators; 1University of Pittsburgh Medical Center, Pittsburgh, PA; 2Tufts-New England Medical Center, Boston, MA; 3 ANMCO Research Center, Florence, Italy; 4University of Wisconsin, Madison, WI; 5Mayo Clinic, Rochester, MN; 6Hospital Italiano, Buenos Aires, Argentina; 7 Sahlgenska University Hospital/Ostra, Gothenburg, Sweden; 8INSERM, Centre d’Investigations Cliniques, Nancy, France; 9Otsuka Maryland Research Center, Rockville, MD; 10Duke University, Durham, NC; 11University of Florida, Jacksonville, FL; 12Northwestern University Medical School, Chicago, IL Background: The post-discharge period after a hospitalization for heart failure (HF) is associated with a significant risk of sudden death. Implantable cardioverter-defibrillators (ICDs) are typically deferred to obtain optimal medical therapy, leaving an unprotected period for arrhythmic death. Methods: In EVEREST, we evaluated 4,133 patients with an LVEF #40% for sudden death and all-cause mortality at 91 days after discharge from a HF admission. We excluded patients with an ICD at enrollment, leaving 3,440 patients. Patients were stratified by LVEF. Events were adjudicated by an independent committee. Results: See table for Kaplan-Meier Estimates. At 91 days after discharge, 277 (8.1%) patients had died. Of these, 90 (32%) of those were classified as sudden.

Figure 1. : Kaplan-Meier Estimates of the Time to SCD in CRT-D and CRT-P Patients

225 Effects of Lixivaptan, a Novel Vasopressin V2 Receptor Antagonist, in Chronic Heart Failure: Results from a Double-Blind, Placebo-Controlled, Multiple-Dose Study William Abraham1, Steven Goldsmith2, Stephen Gottlieb3; 1Ohio State University Medical Center, Columbus, OH; 2Hennepin County Medical Center, Minneapolis, MN; 3University of Maryland Medical Center, Baltimore, MD

Conclusions: Sudden death is not uncommon 3 months after a HF admission. Decreasing LVEF is associated with increasing rates of sudden death and all-cause mortality. Anti-arrhythmic therapies may have a role in bridging patients to ICD implantation.

Objective: Hyponatremia (serum sodium !135 mmol/L) is an electrolyte abnormality that occurs frequently in chronic heart failure (HF). It is associated with worse outcomes and often complicates patient management. Few treatments exist beyond fluid restriction and hypertonic saline. Lixivaptan is a selective, orally active antagonist of the vasopressin v2 receptor under development for the treatment of hyponatremia and heart failure. We assessed the effect of multiple ascending doses of lixivaptan in patients with chronic heart failure. Methods: A total of 42 patients with NYHA Class II-IV heart failure on stable loop diuretic treatment were enrolled in the study. Four cohorts of patients received twice-daily doses of 30, 75, 150, or 250 mg lixivaptan or placebo for 6 days. Each dose level was studied in ascending order. Fluid intake and urine output were monitored, as well as vital signs, ECG, laboratory evaluations, body weight, signs and symptoms of heart failure, and degree of thirst. Results: Lixivaptan administration was well tolerated. Changes from baseline in body weight after 6 days of treatment are reported in the table. Change in Body Weight With Lixivaptan

224 Comparison of Sudden Cardiac Death in Heart Failure Patients with Cardiac Resynchronization and Defibrillator Therapy (CRT-D) Versus CRT Alone (CRT-P) William T. Abraham1, James B. Young2, Kevin Wheelan3, W. Ben Johnson4, Andrew L. Smith5, Paula Brinkman6, Yanping Chang6; 1Ohio State University; 2Cleveland Clinic Foundation; 3Baylor University; 4Iowa Heart Institute; 5Emory University; 6 Medtronic Inc. Introduction: Multiple large, randomized controlled trials have demonstrated the benefit of cardiac resynchronization therapy on functional status, ventricular remodeling, morbidity, and mortality in heart failure patients. Sudden cardiac death (SCD) in patients receiving CRT-D versus CRT-P in the general population has not been adequately evaluated. Methods: Analyses were based on 1485 patients enrolled in the InSync ICD Registry of CRT-D (N 5 373) and InSync Registry of CRT-P (N 5 1112). Twenty-four month cumulative survival curves were constructed using the Kaplan-Meier method. The difference between the curves was tested for significance by the adjusted p-value from the Proportional Hazards Model (PHM) stratified using the propensity score to adjust for differences in baseline demographics. Results: Compared to CRT-P, CRT-D patients were more likely to be male (p ! 0.0001), younger (67.7 vs. 70.7; p ! 0.0001), and had a lower mean LVEF (22.8 vs. 25.6; p ! 0.0001). CRT-D patients were more likely to have a history of an ischemic heart condition (p ! 0.0001), myocardial infarction (p ! 0.0001), coronary artery disease (p ! 0.0001), non-sustained ventricular tachycardia (p ! 0.0001) and receive beta-blockers (p ! 0.0001). Twenty-four month survival rates from death attributed to SCD were 97.3% for CRT-D and 94.2% for CRT-P (adjusted p 5 0.008). The results of the stratified PHM demonstrated a relative risk reduction in SCD of 72% (odds ratio 5 0.28, 95% CI 5 (0.11, 0.71)) with CRT-D compared to CRT-P. Conclusion: This data shows that fewer CRT-P patients survived compared to CRT-D patients for deaths attributed to sudden cardiac death. This observation suggests that lives may be saved from SCD by CRT-D compared to CRT-P.

Placebo Lixivaptan Lixivaptan Lixivaptan Lixivaptan Dose n/a Change in Body weight (kg) 1.4

30 mg 3.2

75 mg 3.2

150 mg 1.8

250 mg 2.0

Statistically significant and dose-dependent increases in urine volume and serum sodium concentrations were also observed. No clinically significant changes in other laboratory tests, vital signs, or ECG values were reported. Conclusions: Lixivaptan appears to be safe and well tolerated in patients with chronic heart failure. Increased urine volume was associated with non-dose-dependent weight loss and dose-dependent increases in serum sodium concentrations. Lixivaptan is a promising new agent for the treatment of hyponatremia and volume management in chronic heart failure.

226 Chronic Vagus Nerve Stimulation (CVNS) - A New Target for Treatment of Congestive Heart Failure Gaetano M. De Ferrari1, Antonio Sanzo1, Harry J.G.M. Crijns2, R. Dennert2, Goran Milasinovic3, S. Raspopovic3, Martin Borggrefe4, C. Wolpert4, J. Kuschyk4, A. Schoene4, Helmut Klein5, J. Smid5, Antonello Gavazzi6, A. Iacovoni6, Markus Zabel7, Peter J. Schwartz1; 1Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 2University Hospital Maastricht, Maastricht, Netherlands; 3Clinical Center of Serbia, Belgrade, Serbia; 4University of Heidelberg Hospital Mannheim, Mannheim, Germany; 5Otto von Guericke University Hospital, Magdeburg, Germany; 6Ospedali Riuniti, Bergamo, Italy; 7University Hospital Goettingen, Goettingen, Germany Background: Congestive Heart Failure (CHF) is a progressive disease characterized by autonomic imbalance with increased sympathetic and decreased parasympathetic activity. Therefore, patients with CHF may benefit from enhancement of efferent

S72 Journal of Cardiac Failure Vol. 14 No. 6S Suppl. 2008 vagal nerve activity. Materials and Methods: The CardioFit System (BioControl Medical, Ltd., Israel) is an implantable nerve stimulation system consisting of a fully implantable nerve stimulator, a multipolar stimulation lead placed around the right cervical vagus and a right ventricular sensing lead. Optimization of CVNS occurs during a four week run-in period, two-to-four weeks post-implantation. Results: Twenty-eight patients with moderate-to-severe CHF (NYHA class II-IV) have been enrolled and successfully implanted in a multi center (7-site) open-label international pilot study of 6-month safety and efficacy; 3-month clinical outcome data are available for the first 23 subjects. Baseline data include: mean age 56 years (range 30e75); ischemic etiology in 74%; prior ICD in 57%; concomitant beta blocker and ACE inhibitor or angiotensin receptor blocker in 100%. No complication occurred during the device implantation. Adverse events, including cough, pain in jaw and voice alteration in 5, 3 and 4 subjects respectively, are expected in vagus nerve stimulation and had resolved with modification of stimulation protocol and over time in affected patients without sequelae. At 3-months, average NYHA class was reduced from 2.8 to 2.0; improvements (p ! 0.01) in quality of life (Minnesota Living with HF questionnaire) from 47.1 6 3.0 to 30.0 6 2.9) and 6-minute walk (396 6 17 to 467 6 22 meters) were also observed. LV ejection fraction increased (p ! 0.05) from 22 6 2% to 27 6 2%. Conclusion: Chronic Vagus Nerve Stimulation in patients with advanced heart failure is feasible and appears to be well tolerated and safe. Initial data suggest a favourable trend of clinical outcomes. Further study appears to be warranted.

table1: Comparison between echocardiographic parameters in responders (D EF $ 10%) and non-responders (D EF !10%) to long-term carvedilol in heart failure

Parameters EF (%) LVESV index LVIDd (cm) LA area (cm2) E velocity DT (ms) Tei-index ET (ms) MR (Grade 1e4)

Responders (n 5 19)

Non-responders (n 5 13)

Non-ischemic CM: n 5 15

Non-ischemic CM: n 5 5

Before Carvedilol

After Carvedilol

Before Carvedilol

After Carvedilol

28.4 6 10.8 57.4 6 30.3 6.0 6 0.9 23.8 6 7.5 0.92 6 0.3 168.9 6 53.7 0.76 6 0.23 235 6 47 1.9 6 1.2

48.2 6 10.1* 36.5 6 19.0* 5.5 6 0.7* 20.6 6 1.3* 0.67 6 0.3* 214.5 6 54.1* 0.68 6 0.25* 284 6 31* 1.0 6 0.5*

38.9 6 7.7 38.9 6 19.4 5.6 6 0.9 20.9 6 8.6 0.86 6 0.4 192.1 6 57.3 0.67 6 0.22 269 6 31 1.3 6 0.9

44.4 6 9.1* 35.7 6 10.9 5.4 6 0.4 20.7 6 7.5 0.72 6 0.2 200.9 6 49.3 0.60 6 0.16 291 6 33 1.1 6 1.2

(t-test: *p ! 0.05, CM-Cardiomyopathy, ESV-end-systolic volume, LVIDd-LV internal dimension in diastole, LA-Left atrium, DT-Deceleration time, ET-Ejection time, MR-Mitral regurgitation) Conclusion: Tei-index is a simple and quick assessement of systolic and diastolic functions obtained by TDI that significantly improves in responders to carvedilol. Larger studies are needed to further evaluate the utility of Tei index and identify other parameters to assess response to medical therapy in HF patients.

227 Predictors and Significance of Decrease in Serum Creatinine in Heart Failure Patients Treated for Volume Overload with Diuretics or Ultrafiltration Maya E. Guglin1, Bradley Bart2, James Fang3, Karl Hibler, Mike Schollmeyer4, Maria Rosa Costanzo5; 1University of South Florida, Tampa, FL; 2Hennepin County Medical Center, Minneapolis, MN; 3Case Western Reserve University, Cleveland, OH; 4CHF Solutions, Inc, Brooklyn Park, MN; 5Midwest Heart Foundation, Lombard, IL Background: In the UNLOAD trial, patients admitted for heart failure with volume overload received either ultrafiltration (UF) or standard care (SC) with diuretics. UF resulted in greater fluid removal and weight loss and was associated with fewer rehospitalizations at 90 days. In most of the patients serum creatinine (Cr) increased during hospitalization, however, in some it decreased. Predictors and clinical significance of decrease in Cr are unknown. Methods: Cr was assessed on admission and at discharge. Patients were divided into those who had decreased Cr at discharge and those with unchanged or increased Cr. Differences between groups were evaluated using Fisher’s exact test. The relationships between continuous independent variables and decreased Cr were examined with Spearman’s rho correlation coefficient. Results: The proportion of patients having a decrease in Cr did not differ between UF and SC (24/86 or 27.9% vs 28/90 or 31.1%, p 5 NS). For all patients combined, systolic blood pressure #115 mmHG, baseline Cr O1.2 mg/dL, and glomerular filtration rate ! 60 mL/min were associated with decreased Cr at discharge (p ! 0.05 for all). For both UF and SC patients, elevated baseline Cr was associated with decreased Cr at discharge (p ! 0.05). In UF patients, glomerular filtration rate ! 60 mL/min was associated with decreased Cr at discharge (p ! 0.02). SC patients with a history of coronary artery disease and atrial arrhythmia were less likely to have decreased Cr at discharge (p ! 0.05). Patients with decreased Cr were more likely to be re-hospitalized during the 90-day follow-up than those with increased or unchanged Cr (37.5% vs 20.4%, p 5 0.03). More re-hospitalizations occurred in SC arm (51.9% v s 24.1%, p 5 0.023), but not in UF (19.0% vs 16.9%, p 5 NS). Conclusions: Patients with lower blood pressure and compromised kidney function on admission were more likely to have decreased Cr at discharge. Decreases in Cr were associated with increased re-hospitalization in SC but not UF patients.

229 Post-Discharge Adjudicated Outcomes in Patients with Implantable Cardioverter-Defibrillators in the EVEREST Trial Norman C. Wang1, Marvin A. Konstam2, Aldo P. Maggioni3, Brian Traver4, John C. Burnett5, Liliana Grinfeld6, Karl Swedberg7, James E. Udelson2, Faiez Zannad8, Thomas Cook4, Christopher Zimmer9, O’Connor Christopher10, Alan B. Miller11, Mihai Gheorghiade12, The EVEREST Investigators; 1University of Pittsburgh, Pittsburgh, PA; 2Tufts-New England Medical Center, Boston, MA; 3ANMCO Research Center, Florence, Italy; 4University of Wisconsin, Madison, WI; 5Mayo Clinic, Rochester, MN; 6Hospital Italiano, Buenos Aires, Argentina; 7Sahlgrenska 8 University Hospital/Ostra, Gothenburg, Sweden; INSERM, Centre d’Investigations Cliniques, Nancy, France; 9Otsuka Maryland Research Institute, Rockville, MD; 10Duke University, Durham, NC; 11University of Florida, Jacksonville, FL; 12Northwestern University Medical School, Chicago, IL Background: The implantable cardioverter-defibrillator (ICD) has been shown to reduce mortality in outpatients with reduced left ventricular ejection fraction (LVEF). The impact of the ICD status on mortality after an admission for worsening heart failure (HF) is not well established. Methods: In EVEREST, we evaluated 4,133 patients with LVEF #40% for all-cause mortality and cause of death, adjudicated by an independent committee; and divided by the presence or absence of an ICD at admission. Results: Patients with ICDs were more likely to be male (83.7 vs 72.8%; p ! 0.001), older (67.2 6 11.2 vs 65.5 6 11.9 years; p ! 0.001), have lower LVEF (24.2 6 8.3 vs 28.1 6 7.9%; p 5 0.004), receive beta-blockers (79.0 vs 68.8%; p ! 0.001), have higher BUN (36.5 6 20.6 vs 29.1 6 15.3 mg/dL; p ! 0.001), have higher creatinine (1.6 6 0.6 vs 1.3 6 0.5 mg/dL; p ! 0.001), and have higher BNP (1915.2 6 5731.3 vs 1203.7 6 3129.6 pg/dL; p ! 0.001). They were less likely to receive ACE inhibitors or ARB (72.8 vs 86.2%; p ! 0.001). Results for the overall study follow-up period (median 9.9 months) are presented in the table.

228 Assessment of Response to Carvedilol in Heart Failure Patients Utilizing Echocardiographic Measurements of Systolic and Diastolic Parameters Suman S. Kuppahally1, Ibrahim S. Abu Romeh1, Edward M. Gilbert1, Feras Bader1; 1 Cardiology, University of Utah, Salt Lake City, UT Background: Carvedilol improves both systolic and diastolic functions in heart failure (HF) patients. Left Ventricular Ejection Fraction (LVEF) is used to assess response to carvedilol therapy, but is generally subjective in nature. Myocardial performance index (MPI, Tei-index) assesses both LV systolic and diastolic functions using tissue Doppler imaging (TDI). We conducted this study to evaluate changes in systolic and diastolic echocardiographic parameters after long-term carvedilol therapy. Methods: In 32 patients with chronic HF, LVEF !45%, (59% males, age 56 6 13.7 years), we evaluated 2D Doppler echocardiograms and Tei-index by TDI. Comparisons were made between parameters before and 6 months after maximum carvedilol (median-8.5 months). Responders were defined by improvement in EF of $10%. Results: There were 19 responders and 13 non-responders. Tei index significantly improved in responders compared to nonresponders. Other parameters compared between the two groups are shown in the table.

Conclusions: Post-discharge mortality is high independent of the presence of an ICD after a patient has been hospitalized for HF and did not appear to reduce mortality. Given these findings, other therapies should be considered.

230 Ejection Fraction and Cardiac Resychronisation: Does Method Matter? Ian P. Clements1, Stuart D. Christenson1, Brian P. Mullan2, David L. Hayes1; 1 Cardiology, Mayo Clinic, Rochester, MN; 2Nuclear Medicine, Mayo Clinic, Rochester, MN Background: A left ventricular (EF) ejection fraction (EF) of 0.35 or less is an important criterion when considering the need for cardiac resychronization therapy (CRT). Current guidelines do not distinguish between methods of LVEF measurement. This study was undertaken to determine if differences existed between echocardiographic (ECHO) and equilibrium radionuclide angiocardiographic (ERNA) estimates of