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The Effect of Neurohormonal Blockade in Patients Supported with LVAD
The 21st Annual Scientific Meeting Table 2. Cox regression analysis, primary outcome: composite of death, LVAD implant, or second inotrope
089 Implications of Renin-Angiotensin-System Blocker Discontinuation in Advanced Decompensated Heart Failure Douglas Darden1, Mark H. Drazner1, Wilfried Mullens2, Matthias Dupont2, W.H. Wilson Tang3, Justin L. Grodin1; 1University of Texas Southwestern, Dallas, Texas; 2Ziekenhuis Oost Limburg, Genk, Belgium; 3Cleveland Clinic, Cleveland, Ohio Introduction: The impact of renin-angiotensin-system blocker (RASB) use, or lack of, on renal function, blood pressure, and clinical outcomes during treatment for acute decompensated heart failure (ADHF) needs further clarification. Hypothesis: In comparison to patients with RASB use, discontinuing or non-use of a RASB will associate with worsening renal function, hypotension, and adverse long-term outcomes. Methods: Participants with an LVEF ≤ 40% in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization (ESCAPE) trial were included. Mixed effects models compared RASB use on serial serum creatinine and systolic blood pressure (SBP) measurements. Cox-proportional hazard models tested the association between RASB use and outcomes adjusted for age, male sex, potassium, SBP < 140 mmHg and baseline creatinine. Outcomes were validated in an independent ADHF cohort admitted to the Cleveland Clinic (n = 253). Results: Patients in the ESCAPE cohort (N = 402, age 56 ± 14 y, 74% male, 49% ischemic, LVEF 19 ± 6 %, and creatinine 1.5 ± 0.6 mg/ dL) were separated into 4 groups based on RASB use at baseline and discharge: continued (n = 316), discontinued (n = 21), initiated (n = 42), and non-use (n = 23). RASB discontinuation or non-use was associated with higher serial serum creatinine levels than RASB continuation or initiation (P < .001 for both) but not with SBP measurements (P > .3 for both). In comparison to RASB continuation, RASB discontinuation and nonuse was associated with ~75% increased risk of a 180-day composite of death, transplant, or re-hospitalization (HR 1.87, 95% CI 1.09–3.20, P = .02 and HR 1.72 1.04–2.82, P = .03, respectively, Figure A). Similarly in the validation cohort, RASB discontinuation and non-use versus RASB continuation were associated with ~65% and ~75% risk for 180-day death, transplant, LVAD, or re-hospitalization (HR 1.85, 95% CI 1.02– 3.34, P = .04 and HR 95% CI 1.64, 95% CI 1.03–2.5, P = .04, respectively, Figure B). Conclusions: In comparison to RASB continuation, RASB discontinuation and nonuse was associated with higher baseline and serial serum creatinine levels during treatment for ADHF, but not with changes in SBP. Furthermore, RASB discontinuation and nonuse in ADHF were associated with an increased risk of adverse clinical outcomes. Given the persistent elevation of serum creatinine and unchanged blood pressures these findings question the practice of withholding RASB in the setting of renal insufficiency and marginal blood pressure in ADHF.
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090 The Effect of Neurohormonal Blockade in Patients Supported with LVAD Priya P. Mehta1, Mark N. Belkin1, Sirtaz Adatya1, Nitasha Sarswat1, Gene Kim1, Jayant Raikhelkar1, Takeyoshi Ota1, Daniel Burkhoff2, Valluvan Jeevanandam1, Gabriel Sayer1, Nir Uriel1; 1University of Chicago, Chicago, Illinios; 2Columbia University, Chicago, Illinios Background: Neurohormonal blockade (NHB) is the mainstay of medical therapy for patients with heart failure with reduced ejection fraction. The role of NHB in patients with left ventricular assist devices (LVADs) is not well described. This study aims to assess the relationship between neurohormonal blockade and hemodynamics in LVAD patients. Methods: In this prospective study, LVAD patients undergoing a hemodynamic ramp study for speed optimization were enrolled. Complete hemodynamic data were collected at baseline prior to ramp study. Patients were divided into four groups: normal (central venous pressure (CVP) < 12 mmHg and pulmonary capillary wedge pressure (PCWP) < 18 mmHg), right ventricular failure (RVF) (CVP ≥ 12 and PCWP < 18), left ventricular failure (LVF) (CVP < 12 and PCWP ≥ 18), and biventricular failure (BiVF) (CVP ≥ 12 and PCWP ≥ 18). The use of beta blockers (BB), angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), angiotensin receptor neprilysin inhibitors (ARNI) and aldosterone antagonists (AA) was compared across the groups. Categorical variables were compared using ChiSquared Test and Fisher’s Exact Test and continuous variables were compared using Independent T-tests and Mann-Whitney U Test. Results: Of 90 patients enrolled, 54 had normal hemodynamics, 10 had LVF, 11 had RVF, and 15 had BiVF. No intergroup differences were detected in the baseline characteristics, including gender, race, age, device type, and comorbidities. In the group with normal hemodynamics, 67% were taking ACEi or ARB, as compared to 33% in the BiVF group, 30% in the LVF group, and 73% in the RVF group (P = .02; Figure). AA, ARNI and BB use was not significantly different between the groups. Only a small percentage of patients in each group was on triple therapy with no significant intergroup differences. Among patients taking an ACEi/ARB, PCWP was 12.5 ± 5.6 vs 15.6 ± 6.0 mmHg for those not on ACEi/ARB (P = .01). There was no difference in mean arterial pressure (90 ± 11 vs. 89 ± 13 mmHg; P = .67) or CVP between these two groups (8.2 ± 4.7 vs. 9.9 ± 5.6 mmHg; P = .12). Conclusions: Greater ACEi/ARB use was observed in patients with normal hemodynamics and right heart failure as compared to those with elevated left-sided pressures. In addition, lower PCWP is seen in patients taking ACEi/ ARB compared to those who are not. Further studies are warranted to evaluate the impact of medical therapy on LVAD outcomes.
092 MANP: Structural Insights of a Novel GC-A Receptor and cGMP Activator with Cardiorenal Enhancing and Aldosterone Suppressing Actions in Vivo Shinobu Sugihara1, Tomoko Ichiki1, Yang Chen1,2, Gail J. Harty1, Denise M. Heublein1, Seethalakshimi R. Iyer1, Brenda K. Huntley1, S. Jeson M. Sangaralingham1, Daniel J. McCormick1, Alessia Buglioni1, John C. Burnett Jr1; 1Mayo clinic, Rochester, Minnesota; 2 Biochemistry and Molecular Biology Graduate Program, Mayo Graduate School, Rochester, Minnesota Introduction: M-atrial natriuretic peptide (MANP) is a novel Mayo Clinic engineered 40 amino acid (AA) guanylyl cyclase A (GC-A) receptor activating peptide based on the cardiac hormone ANP. Importantly, MANP possesses a unique 12 AA carboxyl terminal (CT) extension which contributes to increased resistance to neprilysin degradation and enhanced activation of 3′,5′-cyclic guanosine monophosphate (cGMP), which results in greater hemodynamic, natriuretic and aldosterone- suppressing actions than native ANP in models of hypertension and hypertensive heart failure. We investigated which key AAs in the CT may be critical in mediating MANP’s biological actions to optimize peptide design. We therefore engineered 6 MANP variants with modified
089 Implications of Renin-Angiotensin-System Blocker Discontinuation in Advanced Decompensated Heart Failure Douglas Darden1, Mark H. Drazner1, Wilfried Mullens2, Matthias Dupont2, W.H. Wilson Tang3, Justin L. Grodin1; 1University of Texas Southwestern, Dallas, Texas; 2Ziekenhuis Oost Limburg, Genk, Belgium; 3Cleveland Clinic, Cleveland, Ohio Introduction: The impact of renin-angiotensin-system blocker (RASB) use, or lack of, on renal function, blood pressure, and clinical outcomes during treatment for acute decompensated heart failure (ADHF) needs further clarification. Hypothesis: In comparison to patients with RASB use, discontinuing or non-use of a RASB will associate with worsening renal function, hypotension, and adverse long-term outcomes. Methods: Participants with an LVEF ≤ 40% in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization (ESCAPE) trial were included. Mixed effects models compared RASB use on serial serum creatinine and systolic blood pressure (SBP) measurements. Cox-proportional hazard models tested the association between RASB use and outcomes adjusted for age, male sex, potassium, SBP < 140 mmHg and baseline creatinine. Outcomes were validated in an independent ADHF cohort admitted to the Cleveland Clinic (n = 253). Results: Patients in the ESCAPE cohort (N = 402, age 56 ± 14 y, 74% male, 49% ischemic, LVEF 19 ± 6 %, and creatinine 1.5 ± 0.6 mg/ dL) were separated into 4 groups based on RASB use at baseline and discharge: continued (n = 316), discontinued (n = 21), initiated (n = 42), and non-use (n = 23). RASB discontinuation or non-use was associated with higher serial serum creatinine levels than RASB continuation or initiation (P < .001 for both) but not with SBP measurements (P > .3 for both). In comparison to RASB continuation, RASB discontinuation and nonuse was associated with ~75% increased risk of a 180-day composite of death, transplant, or re-hospitalization (HR 1.87, 95% CI 1.09–3.20, P = .02 and HR 1.72 1.04–2.82, P = .03, respectively, Figure A). Similarly in the validation cohort, RASB discontinuation and non-use versus RASB continuation were associated with ~65% and ~75% risk for 180-day death, transplant, LVAD, or re-hospitalization (HR 1.85, 95% CI 1.02– 3.34, P = .04 and HR 95% CI 1.64, 95% CI 1.03–2.5, P = .04, respectively, Figure B). Conclusions: In comparison to RASB continuation, RASB discontinuation and nonuse was associated with higher baseline and serial serum creatinine levels during treatment for ADHF, but not with changes in SBP. Furthermore, RASB discontinuation and nonuse in ADHF were associated with an increased risk of adverse clinical outcomes. Given the persistent elevation of serum creatinine and unchanged blood pressures these findings question the practice of withholding RASB in the setting of renal insufficiency and marginal blood pressure in ADHF.
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HFSA
S37
090 The Effect of Neurohormonal Blockade in Patients Supported with LVAD Priya P. Mehta1, Mark N. Belkin1, Sirtaz Adatya1, Nitasha Sarswat1, Gene Kim1, Jayant Raikhelkar1, Takeyoshi Ota1, Daniel Burkhoff2, Valluvan Jeevanandam1, Gabriel Sayer1, Nir Uriel1; 1University of Chicago, Chicago, Illinios; 2Columbia University, Chicago, Illinios Background: Neurohormonal blockade (NHB) is the mainstay of medical therapy for patients with heart failure with reduced ejection fraction. The role of NHB in patients with left ventricular assist devices (LVADs) is not well described. This study aims to assess the relationship between neurohormonal blockade and hemodynamics in LVAD patients. Methods: In this prospective study, LVAD patients undergoing a hemodynamic ramp study for speed optimization were enrolled. Complete hemodynamic data were collected at baseline prior to ramp study. Patients were divided into four groups: normal (central venous pressure (CVP) < 12 mmHg and pulmonary capillary wedge pressure (PCWP) < 18 mmHg), right ventricular failure (RVF) (CVP ≥ 12 and PCWP < 18), left ventricular failure (LVF) (CVP < 12 and PCWP ≥ 18), and biventricular failure (BiVF) (CVP ≥ 12 and PCWP ≥ 18). The use of beta blockers (BB), angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), angiotensin receptor neprilysin inhibitors (ARNI) and aldosterone antagonists (AA) was compared across the groups. Categorical variables were compared using ChiSquared Test and Fisher’s Exact Test and continuous variables were compared using Independent T-tests and Mann-Whitney U Test. Results: Of 90 patients enrolled, 54 had normal hemodynamics, 10 had LVF, 11 had RVF, and 15 had BiVF. No intergroup differences were detected in the baseline characteristics, including gender, race, age, device type, and comorbidities. In the group with normal hemodynamics, 67% were taking ACEi or ARB, as compared to 33% in the BiVF group, 30% in the LVF group, and 73% in the RVF group (P = .02; Figure). AA, ARNI and BB use was not significantly different between the groups. Only a small percentage of patients in each group was on triple therapy with no significant intergroup differences. Among patients taking an ACEi/ARB, PCWP was 12.5 ± 5.6 vs 15.6 ± 6.0 mmHg for those not on ACEi/ARB (P = .01). There was no difference in mean arterial pressure (90 ± 11 vs. 89 ± 13 mmHg; P = .67) or CVP between these two groups (8.2 ± 4.7 vs. 9.9 ± 5.6 mmHg; P = .12). Conclusions: Greater ACEi/ARB use was observed in patients with normal hemodynamics and right heart failure as compared to those with elevated left-sided pressures. In addition, lower PCWP is seen in patients taking ACEi/ ARB compared to those who are not. Further studies are warranted to evaluate the impact of medical therapy on LVAD outcomes.
092 MANP: Structural Insights of a Novel GC-A Receptor and cGMP Activator with Cardiorenal Enhancing and Aldosterone Suppressing Actions in Vivo Shinobu Sugihara1, Tomoko Ichiki1, Yang Chen1,2, Gail J. Harty1, Denise M. Heublein1, Seethalakshimi R. Iyer1, Brenda K. Huntley1, S. Jeson M. Sangaralingham1, Daniel J. McCormick1, Alessia Buglioni1, John C. Burnett Jr1; 1Mayo clinic, Rochester, Minnesota; 2 Biochemistry and Molecular Biology Graduate Program, Mayo Graduate School, Rochester, Minnesota Introduction: M-atrial natriuretic peptide (MANP) is a novel Mayo Clinic engineered 40 amino acid (AA) guanylyl cyclase A (GC-A) receptor activating peptide based on the cardiac hormone ANP. Importantly, MANP possesses a unique 12 AA carboxyl terminal (CT) extension which contributes to increased resistance to neprilysin degradation and enhanced activation of 3′,5′-cyclic guanosine monophosphate (cGMP), which results in greater hemodynamic, natriuretic and aldosterone- suppressing actions than native ANP in models of hypertension and hypertensive heart failure. We investigated which key AAs in the CT may be critical in mediating MANP’s biological actions to optimize peptide design. We therefore engineered 6 MANP variants with modified