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Cardioprotective Effects of Mesenchymal Precursor Cells in Patients With Advanced Chronic Heart Failure Due to Left Ventricular Systolic Dysfunction
The 19th Annual Scientific Meeting HF, 8399 patients (NYHA II-IV, EF #40%) were randomized to LCZ696 (200 mg BID) or enalapril (10 mg BID). Primary outcome was composite of CV death or HF hospitalization. 1991 patients had NT-proBNP O1000 pg/ml measured (core lab) at baseline (prior to run-in) and then had NT-proBNP assessed 1 & 8 months after randomization. Primary outcome was compared in patients with 1 month value !1000 vs $1000 pg/ml (partition value used in NIH GUIDE-IT trial), whether treated with LZC696 or enalapril. Results: Median (IQR) NT-proBNP for the study group was 1498 (854,2854). After 1 month, 36.5% of LCZ696 treated fell to !1000 vs 20.8% in enalapril treated (odds ratio 2.18[1.71,2.78], p!0.0001); reductions were maintained at 8 months in 78% of LCZ696 vs 60% of enalapril treated (Figure 1A). In patients with a fall in NT-proBNP to !1000 pg/ml at 1 month, the risk of a subsequent primary endpoint was 56% (risk ratio 0.44 [0.33,0.59], p !0.0001) lower than in patients without a fall in NT-proBNP to !1000 pg/ml at 1 month, adjusting for and regardless of treatment group (p-interaction 50.98) (Figure 1B). Conclusions: Patients attaining NT-proBNP !1000 pg/ml, whether with an ARNI or ACEI, had a lower subsequent rate of CV death or HF hospitalization. Treatment with LCZ696 was twice as likely to reduce NT-proBNP to this level as treatment with enalapril.
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improvement in 30-day all-cause readmission was 84%. The probability of an absolute reduction in 30-day all-cause readmission by 1% (i.e. from 15% - 14%) was 71%, and by 2% was 54%. Conclusions: Although the credible interval of the RD included the null value, the effects of ivabradine on 30-day readmission using a Bayesian framework suggest ivabradine is likely associated with an absolute reduction in 30-day readmission for patients on guidelines-based drug therapy plus ivabradine when used in appropriate patients with chronic systolic HF.
252 Cardioprotective Effects of Mesenchymal Precursor Cells in Patients With Advanced Chronic Heart Failure Due to Left Ventricular Systolic Dysfunction Emerson C. Perin1, Kenneth Borow2, Lee Golden3, Oscar Marroquin1, Paul Huang4, Jay Traverse5, Silviu Itescu3, Timothy Henry6; 1Texas Heart Institute, Houston, TX; 2 Borow Consulting Group, Bryn Mawr, PA; 3Mesoblast Inc., New York, NY; 4Heart and Vascular Institute, Seatlle, WA; 5Minneapolis Heart Institute Foundation, Minneapolis, MN; 6Cedars-Sinai Heart Institute, Los Angeles, CA Background: In a randomized, placebo-controlled dose-escalating study (n560) of allogeneic mesenchymal precursor cells (MPCs) given transendocardially in class II/III heart failure (HF) patients with LVEF!40%, consistent benefits were seen in cardiac remodeling variables and HF-MACE (composite of cardiac-related death, resuscitated cardiac death, or non-fatal decompensated HF events) in the highest dose group of 150 million (M) MPCs. Objective: We evaluated the therapeutic effect of 150M MPCs in advanced HF patients defined by baseline LV systolic dysfunction. Methods: We performed a post-hoc analysis in 30 patients from the above completed trial (n515 controls; n515 MPC-treated patients) who were stratified into 2 groups based on baseline LVESV 100 mL, a level O3 standard deviations above normal. We measured cardiac remodeling variables at 6 months by echocardiography. HF-MACE was assessed by Kaplan-Meier time-to-first event analysis over 36 months. Results: At 6 months, control patients with baseline LVESV O100 mL (n57) had extensive adverse LV remodeling (mean change from baseline: +46 mL LVESV, +41mL LVEDV and -6.4% LVEF). In contrast, 150M MPC-treated patients with baseline LVESV O100 mL (n511) showed significant improvement in these variables (control-corrected changes from baseline: -54mL LVESV [p!0.02], -51mL LVEDV [p! 0.03] and +8.1% LVEF [p!0.05]). Control (n58) and MPC-treated patients (n54) with LVESV 100 mL (5/7); the annualized HF-MACE rate was 24% in this group. No HF-MACE occurred in any MPC-treated patient (p50.0007 by log rank) over 36 months; the 7 control patients with baseline LVESV O100 mL had 11 total HF-MACE versus 0 in the 11 MPC-treated patients (p!0.001). Conclusion: The therapeutic benefits of 150M MPCs on LV remodeling and HF-MACE were more evident in advanced HF patients with baseline LVESV O100 mL. This may be an optimal target group for the cardioprotective benefits of 150M MPC treatment.
253 Figure 1.
Patiromer Reduces Serum K+ in Hyperkalemic Patients with HF and CKD on RAAS Inhibitors: Results from OPAL-HK and AMETHYST-DN Bertram Pitt1, Matthew Weir2, David Bushinsky3, Martha Mayo4, Dahlia Garza4, Yuri Stasiv4, Susan Arthur4, Lance Berman4, George Bakris5; 1Univ. of Michigan, Ann Arbor, MI; 2Univ. of Maryland, Baltimore, MD; 3Univ. of Rochester, Rochester, NY; 4Relypsa, Inc., Redwood City, CA; 5Univ. of Chicago, Chicago, IL
Effect of Ivabradine on Readmission: A Post-Hoc Bayesian Analysis of 30-day Readmission Rates in the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT) Stanmira Krotneva1, Anuraag R. Kansal1, K. Jack Ishak1, Adrian Kielhorn2, Harshali Patel2, Jeffery S. Borer3; 1Evidera, Montreal, QC, Canada; 2Amgen Inc., Thousand Oaks, CA; 3State University of New York Downstate Medical Center, New York, NY
Introduction: Renin angiotensin-aldosterone system (RAAS) inhibitors reduce mortality in patients with heart failure (HF) with and without chronic kidney disease (CKD), yet hyperkalemia can limit RAAS inhibitor use in these patients. We evaluated the effect of patiromer, an investigational potassium (K+) binder, on serum K+ in hyperkalemic patients with HF and CKD on RAAS inhibitors based on data from two studies. Methods: OPAL-HK was a 12-week, 2-part, randomized, single-blind study (n5243); AMETHYST-DN was a 52-week, randomized, open-label study (n5304). Eligible patients had estimated glomerular filtration rate (eGFR) 15-59 mL/min/ 1.73m2, were on $1 RAAS inhibitor and, in AMETHYST-DN, had Type 2 diabetes. Patients with NYHA Class IV HF were excluded. Entry serum K+ was 5.1-!6.5 mEq/L (OPAL-HK) and O5.0-!6.0 mEq/L (AMETHYST-DN). Patiromer was titrated, if needed, to achieve and maintain serum K+ #5.0 mEq/L (AMETHYST-DN) or !5.1 mEq/L (OPAL-HK). In a posthoc subgroup analysis, efficacy data from patients with HF were pooled over the first 4 weeks and analysed for serum K+ change from baseline (primary endpoint) by central laboratory serum K+ strata: !5.5 mEq/L (mild) and $5.5 mEq/L (moderate-severe). Results: Of HF patients, 123 had mild and 84 had moderate-severe hyperkalemia. Mild and moderate-severe hyperkalemia patients were primarily male (63% and 60%, respectively) and $65 yr (67% and 64%, respectively). At baseline (Day 1) mean6SD eGFR was 40616 and 34616 mL/min/1.73m2, respectively, and mean6SE serum K+ was 5.260.03 and 5.860.05 mEq/L, respectively. In patients with mild and moderate-severe hyperkalemia, respectively, mean serum K+ was reduced by 0.22 mEq/L and 0.68 mEq/L at the first post-baseline visit (Day 3) and continued to improve (Fig). Mean serum K+ reductions to !5.0 mEq/L were observed by Day 3 in mild and by Week 1 in moderate-severe hyperkalemia patients. By Week 4, mean (95% CI) serum K+ change from baseline was -0.55 mEq/L ( 0.65, 0.45) in mild and -1.33 mEq/L (-1.46, -1.19) in moderate-severe hyperkalemia patients; both P!0.001. In a pooled analysis of adverse events (AEs) over the first 4 weeks, constipation was the most common AE (6.3%; none severe), and 7 patients discontinued due to AEs. Conclusions: Patiromer significantly reduced serum K+ in hyperkalemic patients
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Introduction: Heart failure (HF) is the leading cause of hospital readmissions. Reducing costly readmissions is a priority for improving healthcare quality. The US Hospital Readmissions Reduction Program provides reduction in Medicare reimbursement penalties for hospitals that reduce the number of patients returning within 30 days of discharge after hospitalization for HF. Data from the SHIFT study showed ivabradine plus guidelines-based drug therapy reduced total number of hospitalizations by 25%. We used SHIFT study data to examine the effect of ivabradine on the incidence of 30-day readmission in patients with HF using a Bayesian framework. Methods: SHIFT was a randomized, placebo-controlled study in 6505 patients with chronic systolic HF in sinus rhythm with heart rate $ 70bpm. Adjudicated hospital admission data were collected, including cause, admission, and discharge dates. In this post-hoc analysis, the subset of patients hospitalized for worsening of HF were analyzed by a logistic regression model in a Bayesian framework to derive a point estimate and 95% credible intervals (CI) for the rate difference (RD) between ivabradine and placebo in 30-day all-cause readmission. The posterior distribution was used to estimate the probabilities for observing a range of pre-specified RDs. Results: In patients with an initial HF hospitalization receiving guidelines-based drug therapy plus placebo (N 5 623) or such therapy plus ivabradine (N 5 479), observed all-cause 30-day readmission rates were 15.89% (95% CI 13.15 - 18.84) and 13.79% (95% CI 10.82 - 17.00), respectively. RD between ivabradine and placebo for 30-day all-cause readmission was -2.10 (-6.27, 2.10). The probability of
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improvement in 30-day all-cause readmission was 84%. The probability of an absolute reduction in 30-day all-cause readmission by 1% (i.e. from 15% - 14%) was 71%, and by 2% was 54%. Conclusions: Although the credible interval of the RD included the null value, the effects of ivabradine on 30-day readmission using a Bayesian framework suggest ivabradine is likely associated with an absolute reduction in 30-day readmission for patients on guidelines-based drug therapy plus ivabradine when used in appropriate patients with chronic systolic HF.
252 Cardioprotective Effects of Mesenchymal Precursor Cells in Patients With Advanced Chronic Heart Failure Due to Left Ventricular Systolic Dysfunction Emerson C. Perin1, Kenneth Borow2, Lee Golden3, Oscar Marroquin1, Paul Huang4, Jay Traverse5, Silviu Itescu3, Timothy Henry6; 1Texas Heart Institute, Houston, TX; 2 Borow Consulting Group, Bryn Mawr, PA; 3Mesoblast Inc., New York, NY; 4Heart and Vascular Institute, Seatlle, WA; 5Minneapolis Heart Institute Foundation, Minneapolis, MN; 6Cedars-Sinai Heart Institute, Los Angeles, CA Background: In a randomized, placebo-controlled dose-escalating study (n560) of allogeneic mesenchymal precursor cells (MPCs) given transendocardially in class II/III heart failure (HF) patients with LVEF!40%, consistent benefits were seen in cardiac remodeling variables and HF-MACE (composite of cardiac-related death, resuscitated cardiac death, or non-fatal decompensated HF events) in the highest dose group of 150 million (M) MPCs. Objective: We evaluated the therapeutic effect of 150M MPCs in advanced HF patients defined by baseline LV systolic dysfunction. Methods: We performed a post-hoc analysis in 30 patients from the above completed trial (n515 controls; n515 MPC-treated patients) who were stratified into 2 groups based on baseline LVESV 100 mL, a level O3 standard deviations above normal. We measured cardiac remodeling variables at 6 months by echocardiography. HF-MACE was assessed by Kaplan-Meier time-to-first event analysis over 36 months. Results: At 6 months, control patients with baseline LVESV O100 mL (n57) had extensive adverse LV remodeling (mean change from baseline: +46 mL LVESV, +41mL LVEDV and -6.4% LVEF). In contrast, 150M MPC-treated patients with baseline LVESV O100 mL (n511) showed significant improvement in these variables (control-corrected changes from baseline: -54mL LVESV [p!0.02], -51mL LVEDV [p! 0.03] and +8.1% LVEF [p!0.05]). Control (n58) and MPC-treated patients (n54) with LVESV 100 mL (5/7); the annualized HF-MACE rate was 24% in this group. No HF-MACE occurred in any MPC-treated patient (p50.0007 by log rank) over 36 months; the 7 control patients with baseline LVESV O100 mL had 11 total HF-MACE versus 0 in the 11 MPC-treated patients (p!0.001). Conclusion: The therapeutic benefits of 150M MPCs on LV remodeling and HF-MACE were more evident in advanced HF patients with baseline LVESV O100 mL. This may be an optimal target group for the cardioprotective benefits of 150M MPC treatment.
253 Figure 1.
Patiromer Reduces Serum K+ in Hyperkalemic Patients with HF and CKD on RAAS Inhibitors: Results from OPAL-HK and AMETHYST-DN Bertram Pitt1, Matthew Weir2, David Bushinsky3, Martha Mayo4, Dahlia Garza4, Yuri Stasiv4, Susan Arthur4, Lance Berman4, George Bakris5; 1Univ. of Michigan, Ann Arbor, MI; 2Univ. of Maryland, Baltimore, MD; 3Univ. of Rochester, Rochester, NY; 4Relypsa, Inc., Redwood City, CA; 5Univ. of Chicago, Chicago, IL
Effect of Ivabradine on Readmission: A Post-Hoc Bayesian Analysis of 30-day Readmission Rates in the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT) Stanmira Krotneva1, Anuraag R. Kansal1, K. Jack Ishak1, Adrian Kielhorn2, Harshali Patel2, Jeffery S. Borer3; 1Evidera, Montreal, QC, Canada; 2Amgen Inc., Thousand Oaks, CA; 3State University of New York Downstate Medical Center, New York, NY
Introduction: Renin angiotensin-aldosterone system (RAAS) inhibitors reduce mortality in patients with heart failure (HF) with and without chronic kidney disease (CKD), yet hyperkalemia can limit RAAS inhibitor use in these patients. We evaluated the effect of patiromer, an investigational potassium (K+) binder, on serum K+ in hyperkalemic patients with HF and CKD on RAAS inhibitors based on data from two studies. Methods: OPAL-HK was a 12-week, 2-part, randomized, single-blind study (n5243); AMETHYST-DN was a 52-week, randomized, open-label study (n5304). Eligible patients had estimated glomerular filtration rate (eGFR) 15-59 mL/min/ 1.73m2, were on $1 RAAS inhibitor and, in AMETHYST-DN, had Type 2 diabetes. Patients with NYHA Class IV HF were excluded. Entry serum K+ was 5.1-!6.5 mEq/L (OPAL-HK) and O5.0-!6.0 mEq/L (AMETHYST-DN). Patiromer was titrated, if needed, to achieve and maintain serum K+ #5.0 mEq/L (AMETHYST-DN) or !5.1 mEq/L (OPAL-HK). In a posthoc subgroup analysis, efficacy data from patients with HF were pooled over the first 4 weeks and analysed for serum K+ change from baseline (primary endpoint) by central laboratory serum K+ strata: !5.5 mEq/L (mild) and $5.5 mEq/L (moderate-severe). Results: Of HF patients, 123 had mild and 84 had moderate-severe hyperkalemia. Mild and moderate-severe hyperkalemia patients were primarily male (63% and 60%, respectively) and $65 yr (67% and 64%, respectively). At baseline (Day 1) mean6SD eGFR was 40616 and 34616 mL/min/1.73m2, respectively, and mean6SE serum K+ was 5.260.03 and 5.860.05 mEq/L, respectively. In patients with mild and moderate-severe hyperkalemia, respectively, mean serum K+ was reduced by 0.22 mEq/L and 0.68 mEq/L at the first post-baseline visit (Day 3) and continued to improve (Fig). Mean serum K+ reductions to !5.0 mEq/L were observed by Day 3 in mild and by Week 1 in moderate-severe hyperkalemia patients. By Week 4, mean (95% CI) serum K+ change from baseline was -0.55 mEq/L ( 0.65, 0.45) in mild and -1.33 mEq/L (-1.46, -1.19) in moderate-severe hyperkalemia patients; both P!0.001. In a pooled analysis of adverse events (AEs) over the first 4 weeks, constipation was the most common AE (6.3%; none severe), and 7 patients discontinued due to AEs. Conclusions: Patiromer significantly reduced serum K+ in hyperkalemic patients
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Introduction: Heart failure (HF) is the leading cause of hospital readmissions. Reducing costly readmissions is a priority for improving healthcare quality. The US Hospital Readmissions Reduction Program provides reduction in Medicare reimbursement penalties for hospitals that reduce the number of patients returning within 30 days of discharge after hospitalization for HF. Data from the SHIFT study showed ivabradine plus guidelines-based drug therapy reduced total number of hospitalizations by 25%. We used SHIFT study data to examine the effect of ivabradine on the incidence of 30-day readmission in patients with HF using a Bayesian framework. Methods: SHIFT was a randomized, placebo-controlled study in 6505 patients with chronic systolic HF in sinus rhythm with heart rate $ 70bpm. Adjudicated hospital admission data were collected, including cause, admission, and discharge dates. In this post-hoc analysis, the subset of patients hospitalized for worsening of HF were analyzed by a logistic regression model in a Bayesian framework to derive a point estimate and 95% credible intervals (CI) for the rate difference (RD) between ivabradine and placebo in 30-day all-cause readmission. The posterior distribution was used to estimate the probabilities for observing a range of pre-specified RDs. Results: In patients with an initial HF hospitalization receiving guidelines-based drug therapy plus placebo (N 5 623) or such therapy plus ivabradine (N 5 479), observed all-cause 30-day readmission rates were 15.89% (95% CI 13.15 - 18.84) and 13.79% (95% CI 10.82 - 17.00), respectively. RD between ivabradine and placebo for 30-day all-cause readmission was -2.10 (-6.27, 2.10). The probability of