Reduction In Heart Failure Events Research Articles

Effects of sodium-glucose co-transporter 2 inhibitors on heart failure events in chronic kidney disease: a systematic review and meta-analysis.

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors significantly reduce the risk for hospitalizations for heart failure (HF) in patients with diabetes, and HF; findings in patients with chronic kidney disease (CKD) are not uniform. We aimed to perform a meta-analysis exploring the effect of SGLT-2 inhibitors on HF events in patients with CKD and across subgroups defined by baseline kidney function. A systematic search in major electronic databases was performed. Randomized controlled trials providing data on the effect of SGLT-2 inhibitors on the primary outcome, time to hospitalization or urgent visit for worsening HF in patients with prevalent CKD at baseline or across subgroups stratified by baseline estimated glomerular-filtration-rate (eGFR) were included. Twelve studies (n=89,191 participants) were included in the meta-analysis. In patients with CKD, treatment with SGLT-2 inhibitors reduced the risk for HF events by 32% compared to placebo (hazard ratio [HR] 0.68; 95%CI 0.63-0.73). Reduction in HF events with SGLT-2 inhibitors was more prominent in patients with eGFR<60 ml/min/1.73m2 (HR 0.68; 95%CI 0.62-0.74) than in those with eGFR≥60 ml/min/1.73m2 (HR 0.76; 95%CI 0.69-0.83). Subgroup analysis according to type of SGLT-2 inhibitor showed a consistent treatment effect across all studied agents (p-subgroup-analysis=0.44). Sensitivity analysis including data from studies including only diabetic patients showed an even more pronounced effect in eGFR subgroup<60 ml/min/1.73m2 (HR 0.62; 95%CI 0.54-0.70). Treatment with SGLT-2 inhibitors led to a significant reduction in HF events in patients with CKD. Such findings may change the landscape of prevention of HF events in patients with advanced CKD. PROSPERO Registration number: CRD42022382857.

Abstract 12911: Life’s Essential 8 and Heart Failure: The Million Veteran Program

Background: Heart failure (HF) incidence has increased over past decades and is associated with poor quality of life, increased comorbidities, and high treatment costs. Prevention for HF warrant a major public health priority. Aim: To quantify the association of Life’s Essential 8 (LE8) score with HF. Methods: LE8 score (0-800) was developed based on the AHA guidelines among 348,311 Veterans who enrolled in the VA Million Veteran Program (MVP) (2011-2021) and free of HF at baseline. Cox proportional hazard models were used to calculate the hazard ratios (HR) with their 95% confidence intervals (CI) for first incident HF event, and HF subtypes (HF with reduced ejection fracture (HFrEF) and HF with preserved EF (HFpEF)) across categories of LE8 score. The population attributable fraction (PAF) was calculated to estimate the proportional reduction in HF events that would occur if LE8 was changed to the ideal level. Results: A total of 31,397 HF events were recorded over 1.8 million person-years of follow-up. LE8 score was negatively associated with incidence of HF, HFrEF and HRpEF, even after extensive adjustment for potential confounders ( Figure 1A ). The multivariate-adjusted HR for HF was 0.76 (95% CI: 0.73-0.78), 0.63 (0.61-0.65), 0.52 (0.50-0.54), 0.41 (0.39-0.43), 0.34 (0.32-0.36), 0.28 (0.27-0.30), and 0.23 (0.21-0.25), respectively, among Veterans whose LE8 score was 350-, 400-, 450-, 500-, 550-, 600- and ≥650, respectively, as compared to those with LE8 score &lt;350. The PAF for HF was 7.1%, 10.3%, 15.1%, 15.8%, 17.1%, 17.5% 18.4%, and 49.1% for not ideal sleep, diet, lipid, activity, BMI, smoking, glucose/HbA1c, and blood pressure, respectively, with an estimated joint PAF of 83.2% for total HF, 79.5% for HFrEF and 90.1% for HFpEF for not ideal of any LE8 ( Figure 1B ). Conclusion: Greater adherence to a healthy LE8 lifestyle could be a key component in prevention of HF among Veterans. Assuming everyone follows a lifestyle meet ideal LE8, majority of HF cases will be prevented.

#6355 EFFECTS OF SODIUM-GLUCOSE CO-TRANSPORTER 2 INHIBITORS ON HEART FAILURE IN CHRONIC KIDNEYDISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background and Aims Sodium-glucose co-transporter 2 (SGLT-2) inhibitors significantly reduce the risk for hospitalizations for heart failure (HF) in patients with diabetes, and HF; findings in patients with chronic kidney disease (CKD) are not uniform. Objectives: We aimed to perform a meta-analysis exploring the effect of SGLT-2 inhibitors on HF events in patients with CKD and across subgroups defined by baseline kidney function. Method A systematic search in major electronic databases was performed. Randomized controlled trials providing data on the effect of SGLT-2 inhibitors on the primary outcome, time to hospitalization or urgent visit for worsening HF in patients with prevalent CKD at baseline or across subgroups stratified by baseline estimated glomerular-filtration-rate (eGFR) were included. Results Twelve studies (n = 89,191 participants) were included in the meta-analysis. In patients with CKD, treatment with SGLT-2 inhibitors reduced the risk for HF events by 32% compared to placebo (hazard ratio [HR] 0.68;95%CI 0.63-0.73). Reduction in HF events with SGLT-2 inhibitors was more prominent in patients with eGFR&amp;lt;60 ml/min/1.73m2 (HR 0.68; 95%CI 0.62-0.74) than in those with eGFR&amp;gt; = 60 ml/min/1.73m2 (HR 0.76;95%CI 0.69-0.83). Subgroup analysis according to type of SGLT-2 inhibitor showed a consistent treatment effect across all studied agents (p subgroup-analysis = 0.44). Sensitivity analysis including data from studies including only diabetic patients showed an even more pronounced effect in eGFR subgroup&amp;lt;60ml/min/1.73m2 (HR 0.62; 95%CI 0.54-0.70). Conclusion Treatment with SGLT-2 inhibitors led to a significant reduction in HF events in patients with CKD. These findings may change the landscape of HF treatment in patients with advanced CKD.

EFFECTS OF SODIUM-GLUCOSE CO-TRANSPORTER 2 INHIBITORS ON HEART FAILURE IN CHRONIC KIDNEY DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Objective: Sodium-glucose co-transporter 2 (SGLT-2) inhibitors significantly reduce the risk for hospitalizations for heart failure (HF) in patients with diabetes, and HF; findings in patients with chronic kidney disease (CKD) are not uniform. Objectives: We aimed to perform a meta-analysis exploring the effect of SGLT-2 inhibitors on HF events in patients with CKD and across subgroups defined by baseline kidney function. Design and method: A systematic search in major electronic databases was performed. Randomized controlled trials providing data on the effect of SGLT-2 inhibitors on the primary outcome, time to hospitalization or urgent visit for worsening HF in patients with prevalent CKD at baseline or across subgroups stratified by baseline estimated glomerular-filtration-rate (eGFR) were included. Results: Twelve studies (n = 89,191 participants) were included in the meta-analysis. In patients with CKD, treatment with SGLT-2 inhibitors reduced the risk for HF events by 32% compared to placebo (hazard ratio [HR] 0.68; 95%CI 0.63-0.73). Reduction in HF events with SGLT-2 inhibitors was more prominent in patients with eGFR&lt;60 ml/min/1.73m2 (HR 0.68; 95%CI 0.62-0.74) than in those with eGFR&gt; = 60 ml/min/1.73m2 (HR 0.76; 95%CI 0.69-0.83). Subgroup analysis according to type of SGLT-2 inhibitor showed a consistent treatment effect across all studied agents (p subgroup-analysis = 0.44). Sensitivity analysis including data from studies including only diabetic patients showed an even more pronounced effect in eGFR subgroup&lt;60 ml/min/1.73m2 (HR 0.62; 95%CI 0.54-0.70). Conclusions: Treatment with SGLT-2 inhibitors led to a significant reduction in HF events in patients with CKD. These findings may change the landscape of HF treatment in patients with advanced CKD.

Stabilization of kidney function and reduction in heart failure events with sodium-glucose co-transporter 2 inhibitors: A meta-analysis and meta-regression analysis.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF) events regardless of diabetes status. However, factors associated with their efficacy in HF reduction remain unknown. This study aims to identify clinically relevant markers for the efficacy of SGLT2 inhibitors in HF risk reduction. We searched PubMed/MEDLINE and EMBASE for randomized placebo-controlled trials of SGLT2 inhibitors reporting a composite of HF hospitalization or cardiovascular death in participants with or without type 2 diabetes published until 28 February 2023. Random-effects meta-analysis and mixed-effects meta-regression were conducted to evaluate the association between the outcomes and clinical variables, including changes in glycated haemoglobin, body weight, systolic blood pressure, haematocrit and overall/chronic estimated glomerular filtration rate (eGFR) slope. Thirteen trials with 90 413 participants were included. SGLT2 inhibitors reduced the hazard ratio of the composite of HF hospitalization or cardiovascular death (hazard ratio 0.77; 95% confidence interval, 0.74-0.81; p < .0001). In meta-regression analysis, chronic eGFR slope (eGFR change after the initial dip) was significantly associated with the composite outcome (p = .017), and each 1 ml/min/1.73 m2 /year improvement in chronic eGFR slope led to a 14% reduction in the composite outcome. By contrast, changes in the other parameters showed no significant associations. Improvement in chronic eGFR slope, which reflects the stabilization of kidney function, is significantly associated with the efficacy of the SGLT2 inhibitor in HF, highlighting the cardiorenal axis role in the beneficial effects on HF. The chronic eGFR slope can be a surrogate marker of the effects of SGLT2 inhibitors on HF reduction.

Series: Cardiovascular outcome trials for diabetes drugs.

LEADER was a landmark cardiovascular outcome trial with the GLP-1 receptor agonist liraglutide, which demonstrated significant reductions in major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke), driven by a reduction in cardiovascular deaths and accompanied by a significant reduction in all-cause mortality. Shortly afterwards, the SUSTAIN-6 trial with once-weekly semaglutide demonstrated non-inferiority for MACE, with a nominal reduction in MACE that was driven by a reduction in the risk of non-fatal strokes. Since then, a further six cardiovascular trials have been published with GLP-1 receptor agonists, with major differences in study design and outcomes. Four trials have been performed with once-weekly formulations. The EXSCEL trial with once-weekly exenatide showed non-inferiority for MACE, but not superiority, with a reduction in all-cause mortality which was an exploratory outcome. The Harmony Outcomes trial with albiglutide demonstrated significant reductions in MACE, driven by reductions in fatal or non-fatal myocardial infarction. REWIND, with dulaglutide, also demonstrated significant reductions in MACE, this time driven by reductions in strokes. The AMPLITUDE-O trial with efpeglenatide showed significant reductions in MACE, but none of the individual components of MACE was significantly reduced as a secondary endpoint, and in contrast to other trials there was also a significant reduction in heart failure events. The fifth trial was the PIONEER 6 trial with the oral formulation of semaglutide, and this showed non-inferiority for MACE, but not superiority, with reductions in cardiovascular deaths and all-cause mortality which were secondary outcomes. Finally, FREEDOM-CVO with a subcutaneous mini-pump of exenatide showed non-inferiority for MACE and MACE plus hospitalisation for unstable angina. A reduction in albuminuria was seen in several of these trials, but there was no definite effect on eGFR or end-stage renal disease. Meta-analysis of the cardiovascular outcome trials with GLP-1 receptor agonists has demonstrated significant reductions in MACE, cardiovascular death, fatal or non-fatal stroke, fatal or non-fatal myocardial infarction, and all-cause mortality. It remains unclear why updated guidance from NICE on the management of T2DM in adults fails to acknowledge these evidence-based cardiovascular benefits.

Impact of Antihypertensive Drug Class on Outcomes in SPRINT.

The primary objective of this analysis is to assess if greater exposure to any major antihypertensive drug class was associated with reduced primary composite outcome events in SPRINT (Systolic Blood Pressure Intervention Trial). This is a secondary analysis of the SPRINT trial evaluating whether longitudinal, time varying exposure to any major antihypertensive drug class had any impact on primary outcome events, after adjusting for effects of randomization arm, time varying achieved systolic blood pressure, other drug class exposure, and baseline characteristics. Nine thousand two hundred fifty-two participants were included. After adjustments, exposure of one year or greater to thiazide-type diuretics or renin-angiotensin system blockers was associated with significantly fewer primary events than exposure of less than one year (hazard ratio, 0.78 [95% CI, 0.64-0.94]). There was no significant difference with longer versus shorter exposure to calcium channel blockers. Greater exposure to beta-blockers was associated with an increase in primary events compared with exposure of <1 year (hazard ratio, 1.35 [95% CI, 1.13-1.62]). Furthermore, thiazide-type diuretics were associated with a reduction in heart failure events and renin-angiotensin system blockers with reduced myocardial infarction. Both were associated with less cardiovascular deaths. The SPRINT trial demonstrated a lower target blood pressure led to reductions in adverse cardiovascular events. This analysis suggests greater exposure to thiazide-type diuretics and renin-angiotensin system blockers also contributed to reduced adverse cardiovascular events. Greater exposure to beta-blockers was associated with increased cardiovascular events.

Beta-Blocker Use in Hypertension and Heart Failure (A Secondary Analysis of the Systolic Blood Pressure Intervention Trial)

Given the concern that beta-blocker use may be associated with an increased risk for heart failure (HF) in populations with normal left ventricular systolic function, we evaluated the association between beta-blocker use and incident HF events, as well as loop diuretic initiation in the Systolic Blood Pressure Intervention Trial (SPRINT). SPRINT demonstrated that a blood pressure target of <120 mm Hg reduced cardiovascular outcomes compared with <140 mm Hg in adults with at least one cardiovascular risk factor and without HF. The lower rate of the composite primary outcome in the 120 mm Hg group was primarily driven by a reduction in HF events. Subjects on a beta blocker for the entire trial duration were compared with subjects who never received a beta blocker after 1:1 propensity score matching. A competing risk survival analysis by beta-blocker status was performed to estimate the effect of the drug on incident HF and was then repeated for a secondary end point of cardiovascular disease death. Among the 3,284 propensity score-matched subjects, beta-blocker exposure was associated with an increased HF risk (hazard ratio 5.86; 95% confidence interval 2.73 to 13.04; p <0.001). A sensitivity analysis of propensity score-matched cohorts with a history of coronary artery disease or atrial fibrillation revealed the same association (hazard ratio 3.49; 95% confidence interval 1.15 to 10.06; p = 0.028). In conclusion, beta-blocker exposure in this secondary analysis was associated with increased incident HF in subjects with hypertension without HF at baseline.

Heart Failure Events in a Clinical Trial on Arterial Hypertension: New Insights Into the SPRINT Trial.

[Figure: see text].

Heart failure events in a clinical trial of arterial hypertension. The acquittal of the SPRINT trial

Abstract Introduction The Systolic Blood Pressure Intervention Trial (SPRINT) was a randomized trial showing that intensive lowering of systolic blood pressure (BP), as compared to standard treatment (i.e. &amp;lt;120 vs &amp;lt;140 mm Hg) was associated with a reduced risk (HR 0.75 [95% CI 0.64–0.79], p&amp;lt;0.001) for the primary composite outcome (CE), defined as myocardial infarction, an acute coronary syndrome other than myocardial infarction, stroke, acute exacerbation of heart failure and cardiovascular death. primary outcome event in subjects at high cardiovascular risk. However, the primary endpoint events in the intensive treatment arm were only 76 fewer than in the standard treatment arm (243 vs 319 events), and he reduction in heart failure events was responsible for half of the effect (62 vs 100 events, i.e. 38 events fewer). Thus, several experts in hypertension argued that these results were mainly driven by a reduction of heart failure events, and questioned the main conclusion of the study. Aim To assess the effect of SPRINT intervention on a redefined CE: the primary SPRINT endpoint with HF events excluded. Material and methods We used limited SPRINT data, available from the NHLBI Biologic Specimen and Data Repository to assess the impact of BP intervention in SPRINT on a redefined CE excluding HF events. The Chi-square test, Cox proportional model and survival analysis were applied. Results Among 9361 SPRINT participants (mean age 67.9±9.5 years, 35.6% female, 20% with previous cardiovascular disease), there was 461 CE events. There were fewer CE events in the intensive treatment arm than in the standard treatment arm (204 [4.4%] vs 257 [5.5%], p=0.0117, respectively). Intensive systolic BP lowering was associated with lower risk for CE than standard treatment (HR 0.79 [95% CI 0.66–0.95], p=0.0115). Kaplan-Meier curves show that intensive treatment was associated with better outcome (Figure 1). Analyses in subgroups (age &amp;gt;75 vs &amp;lt;75 years, female vs male, black vs non-black, prior cardiovascular disease vs no cardiovascular disease, prior chronic kidney disease vs no chronic kidney disease) showed no difference in benefit of intensive treatment (p for interaction &amp;gt;0.05 in all subgroup). Conclusion The reduction in cardiovascular events by intensive BP lowering in SPRINT was not explained by a difference in heart failure events. This supports the concept that more intensive BP reduction may provide benefit in reducing cardiovascular event risk. Figure 1. Kaplan-Meier curves Funding Acknowledgement Type of funding source: None

Critical examination of mechanisms underlying the reduction in heart failure events with SGLT2 inhibitors: identification of a molecular link between their actions to stimulate erythrocytosis and to alleviate cellular stress.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of serious heart failure events, even though SGLT2 is not expressed in the myocardium. This cardioprotective benefit is not related to an effect of these drugs to lower blood glucose, promote ketone body utilization or enhance natriuresis, but it is linked statistically with their action to increase haematocrit. SGLT2 inhibitors increase both erythropoietin and erythropoiesis, but the increase in red blood cell mass does not directly prevent heart failure events. Instead, erythrocytosis is a biomarker of a state of hypoxia mimicry, which is induced by SGLT2 inhibitors in manner akin to cobalt chloride. The primary mediators of the cellular response to states of energy depletion are sirtuin-1 and hypoxia-inducible factors (HIF-1α/HIF-2α). These master regulators promote the cellular adaptation to states of nutrient and oxygen deprivation, promoting mitochondrial capacity and minimizing the generation of oxidative stress. Activation of sirtuin-1 and HIF-1α/HIF-2α also stimulates autophagy, a lysosome-mediated degradative pathway that maintains cellular homoeostasis by removing dangerous constituents (particularly unhealthy mitochondria and peroxisomes), which are a major source of oxidative stress and cardiomyocyte dysfunction and demise. SGLT2 inhibitors can activate SIRT-1 and stimulate autophagy in the heart, and thereby, favourably influence the course of cardiomyopathy. Therefore, the linkage between erythrocytosis and the reduction in heart failure events with SGLT2 inhibitors may be related to a shared underlying molecular mechanism that is triggered by the action of these drugs to induce a perceived state of oxygen and nutrient deprivation.

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium-glucose cotransporter 2 inhibitors.

In five large-scale trials involving >40 000 patients, sodium-glucose cotransporter 2 (SGLT2) inhibitors decreased the risk of serious heart failure events by 25-40%. This effect cannot be explained by control of hyperglycaemia, since it is not observed with antidiabetic drugs with greater glucose-lowering effects. It cannot be attributed to ketogenesis, since it is not causally linked to ketone body production, and the benefit is not enhanced in patients with diabetes. The effect cannot be ascribed to a natriuretic action, since SGLT2 inhibitors decrease natriuretic peptides only modestly, and they reduce cardiovascular death, a benefit that diuretics do not possess. Although SGLT2 inhibitors increase red blood cell mass, enhanced erythropoiesis does not favourably influence the course of heart failure. By contrast, experimental studies suggest that SGLT2 inhibitors may reduce intracellular sodium, thereby preventing oxidative stress and cardiomyocyte death. Additionally, SGLT2 inhibitors induce a transcriptional paradigm that mimics nutrient and oxygen deprivation, which includes activation of adenosine monophosphate-activated protein kinase, sirtuin-1, and/or hypoxia-inducible factors-1α/2α. The interplay of these mediators stimulates autophagy, a lysosomally-mediated degradative pathway that maintains cellular homeostasis. Autophagy-mediated clearance of damaged organelles reduces inflammasome activation, thus mitigating cardiomyocyte dysfunction and coronary microvascular injury. Interestingly, the action of hypoxia-inducible factors-1α/2α to both stimulate erythropoietin and induce autophagy may explain why erythrocytosis is strongly correlated with the reduction in heart failure events. Therefore, the benefits of SGLT2 inhibitors on heart failure may be mediated by a direct cardioprotective action related to modulation of pathways responsible for cardiomyocyte homeostasis.

Left Ventricular Reverse Remodeling in Cardiac Resynchronization Therapy and Long-TermOutcomes.

The aim of this study was to evaluate the association between improvement in left ventricular end-systolic volume (LVESV) with cardiac resynchronization therapy (CRT) and mortality and whether this relationship was modified by the presence of a left bundle branch block (LBBB) electrocardiographic pattern. Left ventricular reverse remodeling in patients receiving CRT has been shown to predict outcomes. However, the extent to which reverse remodeling contributes to long-term survival is not well understood. Changes in LVESV were assessed in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) patients receiving CRT with a defibrillator (CRT-D) and echocardiograms available at 1 year (n=752), stratified by LBBB, relative to long-term all-cause mortality, compared with those with implantable cardioverter-defibrillators (ICDs) only (n=684). In patients with LBBB, a reduction in LVESV of >35% (median) translated into significantly lower risk for long-term mortality (hazard ratio [HR]: 0.34; p<0.001), heart failure (HF) events (HR: 0.21; p<0.001), and HF or death (HR: 0.27; p<0.001) compared with patients with ICDs only. Patients with reductions in LVESV≤35% had a significantly lower risk for HF, and HF or death, and a nonsignificantly lower rate of death compared with those with ICDs only (HR:0.74; p=0.13). Risk reduction in HF events was uniform across all LVESV quartiles. In patients without LBBB, there was no survival benefit (HR: 0.68; p=0.271) despite an LVESV reduction greater than the median (>27.6%). CRT-D patients without LBBB with the least reverse remodeling (quartile 1) had a more than 3-fold increased risk for death compared with those with ICDs only (HR: 3.11; p<0.001). In patients with LBBB, CRT-D-induced reduction in LVESV at 1 year is associated with long-term survival benefit. Despite left ventricular reverse remodeling with CRT-D, there is no survival benefit and potential harm in patients without LBBB.

Prevention of Heart Failure in Patients with Diabetes: Role of Diabetes Medications

Type 2 diabetes mellitus (DM) is a major risk factor for the development of heart failure (HF). In patients with DM, preventing HF using diabetes medications should be an imperative for primary care physicians and cardiologists alike. Prior studies with DPP-IV inhibitors, thiazolidinediones (TZDs), and GLP-1 agonists have demonstrated either a neutral effect on HF or increased HF hospitalizations. Two recent large-scale randomized controlled trials (RCTs), EMPA-REG OUTCOME and CANVAS, compared sodium glucose transporter-2 inhibitor (SGLT-2i) to placebo. Use of SGLT-2i led to a substantial reduction in HF events and hospitalizations in patients with DM, with or without history of HF. Use of SGLT-2i therapy has been shown to reduce HF in patients with DM.

Left Ventricular Lead Location and Long-Term Outcomes in Cardiac Resynchronization Therapy Patients.

The authors aimed to evaluate the association of left ventricular (LV) lead location and long-term outcomesin MADIT-CRT (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy). There is limited data on the association of lead location with long-term clinical outcomes in patients with cardiac resynchronization therapy with defibrillator (CRT-D). The LV lead location was classified in 797 patients with CRT-D, in 569 patients with left bundle branch block (LBBB), in 228 patients with non-LBBB, and in 505 patients with an implantable cardioverter-defibrillator (ICD) only. Leads were classified into apical (n= 83) and non-apical (n= 486); with the non-apical LV leads further categorized into anterior (n= 99) and posterior/lateral (n= 387) within LBBB. All-cause mortality and heart failure (HF) events were assessed using Kaplan-Meier and Cox analyses. In CRT-D patients with LBBB and posterior/lateral LV lead location, there was an association with a significant reduction in long-term all-cause mortality (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.37 to 0.79; p=0.001), and HF events (HR: 0.44, 95% CI: 0.33 to 0.60; p< 0.001) compared to an ICD only, accompanied withbetter LV reverse remodeling. CRT-D patients with LBBB and an anterior LV lead location were shown to be associated with a significant reduction in HF events compared to an ICD only (anterior HR: 0.50, 95% CI: 0.30 to 0.82; p= 0.006); however, no association with mortality reduction was observed from CRT-D versus an ICD only. CRT-D wasnot associated with improved outcomes in non-LBBB patients, regardless of LV lead location. In mild HF patients with LBBB and an implanted CRT-D, lateral/posterior, and anterior LV lead locations are similarly associated with reduction in the risk of HF or death events compared to ICD alone. Mortality benefit derived from CRT-D is associated only with patients with lateral/posterior LV lead location. An apical LV lead location should be avoided due to the early risk of death whenever possible. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy [MADIT-CRT], NCT00180271; Multicenter Automatic Defibrillator Implantation Trial WithCardiac Resynchronization Therapy Post Approval Registry [MADIT-CRT-PAR], NCT01294449; and MADIT-CRT Long-Term International Follow-Up Registry - Europe, NCT02060110).

Comparison of Long-Term Survival Benefits With Cardiac Resynchronization Therapy in Patients With Mild Heart Failure With Versus Without Diabetes Mellitus (from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT

We have previously shown a reduction in HF events with cardiac resynchronization therapy with defibrillator (CRT-D) in patients with mild heart failure (HF) and diabetes mellitus (DM). It remains unknown whether HF remission in DM patients with CRT-D translates into reduced mortality. The effects of CRT-D versus an implantable cardioverter-defibrillator (ICD) alone to reduce long-term mortality were assessed in patients with left bundle branch block with DM (n = 386) and without DM (n = 982), enrolled in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). We further subdivided DM patients by insulin and noninsulin therapy. Kaplan-Meier survival analyses and multivariate cox proportional hazards regression models were utilized. At the 7-year follow-up, CRT-D was associated with a lower mortality in DM patients compared with ICD alone (21% vs 42%, p = 0.02), similar to non-DM patients (16 vs 24%, p = 0.014). CRT-D was associated with a 41% reduction in the risk of long-term all-cause mortality in DM patients (hazard ratio [HR] 0.59, 95% confidence interval 0.36 to 0.96, p = 0.033) and a similar reduction in non-DM patients (HR 0.69, 95% confidence interval 0.48 to 0.99, p = 0.045, treatment-diabetes interaction p = 0.611). Among DM patients, mortality benefit was evident in insulin-treated patients only (HR 0.40, p = 0.030). Reductions in HF events were present in all groups. In the MADIT-CRT, patients with mild HF with DM derive significant long-term survival benefit from CRT-D, similar to those without DM. The mortality benefit from CRT-D within the DM subgroup seems to be confined to patients with insulin treated diabetes.

Abstract 14932: Effects of Cardiac Resynchronization Therapy in Ischemic Cardiomyopathy Patients by Revascularization Procedures in MADIT-CRT

Background: The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) showed that patients with ischemic cardiomyopathy (ICM) had similar reductions in clinical events with implanted CRT-D vs. ICD-only when compared to patients with non-ischemic cardiomyopathy (NICM). Frequency of revascularizations may serve as a surrogate for severity of coronary artery disease in patients with ICM and severely reduced left ventricular ejection fraction. However, it is unknown whether the number of revascularizations plays a role in clinical outcomes in ICM patients implanted with CRT-D vs. ICD-only. Methods: Using a multivariable analysis of MADIT-CRT data, we evaluated the effect of CRT-D vs. ICD-only on combined heart failure (HF) or death and combined ventricular tachycardia (VT), ventricular fibrillation (VF) or death in ICM patients by the number of pre-enrollment revascularizations (1 or ≥ 2 revascularizations) compared to those with no need for revascularization. Follow-up over a median period of 5.6 years for HF/death and 4.0 years for VT/VF/death was assessed among 1374 ICM patients with a Left Bundle Branch Block (LBBB). Results: There was a significant and similar risk reduction with CRT-D vs. ICD-only in HF/death in all three sub-groups: ICM with no need for revascularization (HR 0.45 [0.26-0.80]; p &lt; 0.006), ICM with one revascularization (HR 0.46 [0.31-0.69]; p &lt;0.001), and ICM with 2 or more revascularization (HR 0.50 [0.30-0.84]; p = 0.008). However, significant risk reduction of VT/VF/death with CRT-D vs. ICD-only was only observed in patients with no need for revascularization (HR 0.52 [0.30-0.89]; p = 0.017), less so in those with ICM with one revascularization (HR 0.72 [0.49-1.06]; p = 0.10), and no reduction was seen in those with ICM with 2 or more revascularization (HR 0.94 [0.54-1.62]; p = 0.81). Conclusions: In ischemic cardiomyopathy patients, CRT-D vs. ICD-only is associated with a significant risk reduction in heart failure events or death irrespective of the frequency of pre-enrollment revascularization procedures; however, the benefit of CRT-D vs. ICD-only to reduce ventricular tachyarrhythmias is attenuated with the increasing number of revascularization procedures.

Abstract 12708: Similar Risk of Heart Failure Hospitalization in MADIT-RIT Programming Arms

Background: In MADIT-RIT (Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy), we reported a significant reduction in inappropriate ICD therapy and mortality with novel ICD programming, either a high-rate cut-off (VT zone ≥ 200 bpm, Arm B) or 60-sec delayed therapy in the VT zone 170-199 bpm (Arm C), as compared to conventional programming (VT zone&gt;170 bpm, Arm A). However, the effect of novel ICD programming on heart failure (HF) events has not been investigated. Methods: In MADIT-RIT patients (n=1500), we assessed risk of hospitalization with heart failure (HF) in the three programming arms. Brief summaries of each hospitalization were independently reviewed by three experienced cardiologists and HF events identified according to pre-specified criteria. Discrepancies were resolved by a fourth cardiologist. Kaplan-Meier cumulative probabilities and multivariable Cox hazards regression analyses were performed. Results: There was a similar probability of HF hospitalization (p=0.341) and HF hospitalization or death (p=0.207) in all three programming arms in MADIT-RIT (Figure). There were no differences in HF hospitalization in Arm B vs. A (HR=0.91, 95%CI: 0.63-1.33, p=0.629) or Arm C vs. A (HR=1.20, 95%CI: 0.84-1.72, p=0.310) after multivariable adjustments for age, NYHA class, diabetes, ICD vs. CRT-D, ejection fraction, and ischemic vs. non-ischemic cardiomyopathy. Similarly, there were no differences in HF or death in Arm B vs. A (HR=0.78, 95%CI: 0.56-1.10, p=0.154), or in Arm C vs. A (HR=1.06, 95%CI: 0.77-1.45, p=0.723) after multivariable adjustments. Risk of multiple hospitalizations was also the similar in the three programming arms. Conclusions: In MADIT-RIT, the mortality benefit seen with novel ICD programming was not accompanied by reduction in heart failure events. Conversely, greater mortality risk with conventional ICD programming was not associated with increased risk of heart failure hospitalization.

Rationale and design of the Aquapheresis Versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-HF) trial

In patients hospitalized with acutely decompensated heart failure, unresolved signs and symptoms of fluid overload have been consistently associated with poor outcomes. Regardless of dosing and type of administration, intravenous loop diuretics have not reduced heart failure events or mortality in patients with acutely decompensated heart failure. The results of trials comparing intravenous loop diuretics to mechanical fluid removal by isolated venovenous ultrafiltration have yielded conflicting results. Studies evaluating early decongestive strategies have shown that ultrafiltration removed more fluid and was associated with fewer heart failure-related rehospitalization than intravenous loop diuretics. In contrast, when used in the setting of worsening renal function, ultrafiltration was associated with poorer renal outcomes and no reduction in heart failure events. The AVOID-HF trial seeks to determine if an early strategy of ultrafiltration in patients with acutely decompensated heart failure is associated with fewer heart failure events at 90 days compared with a strategy based on intravenous loop diuretics. Study subjects from 40 highly experienced institutions are randomized to either early ultrafiltration or intravenous loop diuretics. In both treatment arms, fluid removal therapies are adjusted according to the patients' hemodynamic condition and renal function. The study was unilaterally terminated by the sponsor in the absence of futility and safety concerns after the enrollment of 221 subjects, or 27% of the originally planned sample size of 810 patients. The AVOID-HF trial's principal aim is to compare the safety and efficacy of ultrafiltration vs that of intravenous loop diuretics in patients hospitalized with acutely decompensated heart failure. Because stepped treatment approaches are applied in both ultrafiltration and intravenous loop diuretics groups and the primary end point is time to first heart failure event within 90 days, it is hoped that the AVOID-HF trial, despite its untimely termination by the sponsor, will provide further insight on how to optimally decongest patients with fluid-overloaded heart failure.

Survival with Cardiac-Resynchronization Therapy in Mild Heart Failure

BackgroundThe Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) showed that early intervention with cardiac-resynchronization therapy with a defibrillator (CRT-D) in patients with an electrocardiographic pattern showing left bundle-branch block was associated with a significant reduction in heart-failure events over a median follow-up of 2.4 years, as compared with defibrillator therapy alone.MethodsWe evaluated the effect of CRT-D on long-term survival in the MADIT-CRT population. Post-trial follow-up over a median period of 5.6 years was assessed among all 1691 surviving patients (phase 1) and subsequently among 854 patients who were enrolled in post-trial registries (phase 2). All reported analyses were performed on an intention-to-treat basis.ResultsAt 7 years of follow-up after initial enrollment, the cumulative rate of death from any cause among patients with left bundle-branch block was 18% among patients randomly assigned to CRT-D, as compared with 29% among those randomly assigned to defibrillator therapy alone (adjusted hazard ratio in the CRT-D group, 0.59; 95% confidence interval [CI], 0.43 to 0.80; P<0.001). The long-term survival benefit of CRT-D in patients with left bundle-branch block did not differ significantly according to sex, cause of cardiomyopathy, or QRS duration. In contrast, CRT-D was not associated with any clinical benefit and possibly with harm in patients without left bundle-branch block (adjusted hazard ratio for death from any cause, 1.57; 95% CI, 1.03 to 2.39; P=0.04; P<0.001 for interaction of treatment with QRS morphologic findings).ConclusionsOur findings indicate that in patients with mild heart-failure symptoms, left ventricular dysfunction, and left bundle-branch block, early intervention with CRT-D was associated with a significant long-term survival benefit. (Funded by Boston Scientific; ClinicalTrials.gov numbers, NCT00180271, NCT01294449, and NCT02060110.)