Total Heart Failure Hospitalizations Research Articles

Effects of an outpatient intervention comprising nurse-led non-invasive assessments, telemedicine support and remote cardiologists' decisions in patients with heart failure (AMULET study): a randomised controlled trial.

AimPrevention of heart failure (HF) hospitalisations and deaths constitutes a major therapeutic aim in patients with HF. The role of telemedicine in this context remains equivocal. We investigated whether an outpatient telecare based on nurse‐led non‐invasive assessments supporting remote therapeutic decisions (AMULET telecare) could improve clinical outcomes in patients after an episode of acute HF during 12‐month follow‐up.Methods and resultsIn this prospective randomised controlled trial, patients with HF and left ventricular ejection fraction (LVEF) ≤49%, after an episode of acute HF within the last 6 months, were randomly assigned to receive either an outpatient telecare based on nurse‐led non‐invasive assessments (n = 300) (AMULET model) or standard care (n = 305). The primary composite outcome of unplanned HF hospitalisation or cardiovascular death occurred in 51 (17.1%) patients in the telecare group and 73 (23.9%) patients in the standard care group up to 12 months after randomization [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.48–0.99; P = 0.044]. The implementation of AMULET telecare, as compared to standard care, reduced the risk of first unplanned HF hospitalisation (HR 0.62, 95% CI 0.42–0.91; P = 0.015) as well as the risk of total unplanned HF hospitalisations (HR 0.64, 95% CI 0.41–0.99; P = 0.044).There was no difference in cardiovascular mortality between the study groups (HR 1.03, 95% CI 0.54–1.67; P = 0.930).ConclusionsAMULET telecare as compared to standard care significantly reduced the risk of HF hospitalisation or cardiovascular death during 12‐month follow‐up among patients with HF and LVEF ≤49% after an episode of acute HF.

Prognostic impact of percentage of ventricular pacing in patients requiring pacemaker implantation after transcatheter aortic valve replacement

Abstract Background Despite the continuous developments of transcatheter aortic valve implantation (TAVI), around 15% of the patients (P) who undergo this procedure require permanent pacemaker (PM). Right ventricular pacing (RVP), particularly with a cumulative percentage of ventricular pacing (CVp) above 40%, has been associated with detrimental effects on ventricular function and an increased risk of cardiovascular events in non-TAVI patients. Aim To evaluate the long-term prognostic significance of RVP, regarding overall mortality and the combined endpoint of overall mortality/heart failure hospitalization in P requiring a PM after TAVI. Methods We retrospectively examined P who underwent TAVI with a self-expanding valve from 2009 to 2020 at our institution. All P had pre-procedural clinical evaluation, cardiac computed tomographic angiography, transthoracic echocardiography and electrocardiography performed. CVp was determined from stored PM data. P with previous PM were excluded. Post-TAVI PM implantation was defined as a device implantation during hospital stay or during the first month after discharge. Results 474P, 57% male, mean age 81.7±6.5 years with a mean left ventricular ejection fraction of 51.5±14.6% were analysed. Mean follow-up was 18.7 months. Mean STS score and mean Euroscore II were, respectively, 6.89% and 5.76%. Mean gradient was 51.67 mmHg and mean aortic valve area 0.71 cm2. After TAVI, 104P (21.9%) required PM implantation, with a mean CVp of 65.3±43.4%. Post-TAVI PM was not associated with a worse outcome - overall mortality: HR 1.13, 95% CI 0.72 – 1.78, p=0.57; combined mortality/heart failure hospitalization: HR 1.22, 95% CI 0.87 – 1.70, p=0.24. The follow-up Kaplan-Meier curves according to the need for PM post-TAVI were similar: log rank p=0.24. A CVp cut-off of 40% was not associated with any of the study endpoints - overall mortality: HR 1.72, 95% CI 0.38–7.86, p=0.48; combined mortality/heart failure hospitalization: HR 1.32, 95% CI 0.45–3.91, p=0.61. Also, a CVp cut-off of 40% did not provide an accurate risk stratification as survival free of events was similar between these P and those below this cut-off (log rank p=0.11) and in comparison, with P without PM (log rank p=0.65). Conclusions In P submitted to TAVI with a self-expanding valve, the need for PM implantation is common, but not associated with increased risk of total mortality or heart failure hospitalization during a 18 months follow-up period. A CVp cut-off of 40% showed poor discriminative ability regarding long-term events in this population. Funding Acknowledgement Type of funding sources: None.

Efficacy of intravenous ferric carboxymaltose in patients with acute heart failure and iron deficiency with and without anaemia: a subgroup analysis of AFFIRM-AHF

Abstract Background Iron deficiency is associated with increased morbidity and mortality in patients with acute heart failure (HF), even in the absence of anaemia. Purpose This prespecified subanalysis of the AFFIRM-AHF trial investigated the effects of ferric carboxymaltose (FCM) on recurrent HF hospitalisations and cardiovascular (CV) mortality in patients with and without anaemia defined as baseline haemoglobin (Hb) <12 g/dL, ≥12 g/dL. Methods In total, 1108 patients (558 FCM, 550 placebo) were included in the modified intention-to-treat AFFIRM-AHF analysis. The primary outcome was a composite of total HF hospitalisations and CV death, evaluated up to 52 weeks post-randomisation. Results Of the 1108 patients, 228 and 329 in the FCM group and 236 and 314 in the placebo group had Hb <12 g/dL and ≥12 g/dL at baseline, respectively. For patients with a baseline Hb ≥12 g/dL, the total number of HF hospitalisations and CV death was 156 and 201 in the FCM and placebo groups, respectively, with a rate ratio (95% confidence interval) of 0.67 (0.48–0.93; p=0.016). For patients with Hb <12 g/dL, this was 136 and 171 in the FCM and placebo groups, respectively (0.97 [0.66–1.41; p=0.862]). This treatment effect was consistent for all secondary outcomes in patients in the FCM group vs placebo, for both Hb subgroups (Figure). Conclusion Iron deficiency treatment with FCM following acute HF reduced the risk of HF hospitalisations and CV death, irrespective of Hb level at baseline. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Vifor Pharma Ltd. Figure 1

Potential Implications of Expanded US Food and Drug Administration Labeling for Sacubitril/Valsartan in the US

The US Food and Drug Administration (FDA) expanded labeling for sacubitril/valsartan for use in individuals with chronic heart failure (HF) with left ventricular ejection fraction (LVEF) lower than normal. The population-level implications of implementation of sacubitril/valsartan at higher LVEF ranges is unknown. While the Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction (PARAGON-HF) trial did not meet its primary end point, the trial may provide useful information in projecting expected clinical events among treated individuals. To quantify newly eligible treatment candidates for sacubitril/valsartan under the expanded FDA labeling and to apply treatment effects and the number needed to treat (NNT) to prevent 1 worsening HF event derived from subgroups of the PARAGON-HF trial who fall under the revised FDA label. Newly eligible treatment candidates were estimated by mapping the LVEF distribution from 559 520 adult patients hospitalized between 2014 and 2019 in the Get With The Guidelines-Heart Failure registry to adults self-identifying with HF in the National Health and Nutrition Examination Survey (2015 to 2018). The NNT with 3 years of treatment for 3 end points of interest (total HF hospitalizations, total HF hospitalizations and cardiovascular death, and total HF hospitalizations and urgent HF visits and cardiovascular death) were estimated from the PARAGON-HF trial. Data were analyzed from February to June 2021. Number of worsening HF events prevented or postponed if eligible patients were treated with sacubitril/valsartan for 3 years. Of an estimated 4 682 098 adults, the mean (SE) age was 66.3 (0.8) years, 1 995 037 (42.6%) were women, and 748 045 (16.0%) were Black. The potential number of adults projected to be newly eligible varied by the definition of FDA labeling of lower than normal LVEF from 643 161 (95% CI, 534 433-751 888; LVEF of 41% to 50%) to 1 838 756 (95% CI, 1 527 911-2 149 601; LVEF of 41% to 60%). In the PARAGON-HF trial, the NNT to prevent a worsening HF event (range, 7 to 12 patients) was consistent irrespective of specific LVEF range selected. Comprehensive implementation of sacubitril/valsartan among newly eligible patients was empirically estimated to prevent up to 69 268 (95% CI, 57 558-80 978) worsening HF events (LVEF of 41% to 50%) to 182 592 (95% CI, 151 725-213 460) worsening HF events (LVEF of 41% to 60%). The expanded FDA labeling is positioned to substantially increase the potential HF population eligible for sacubitril/valsartan by up to 1.8 million individuals and has the potential to prevent or postpone as many as 180 000 worsening HF events, depending on the definition of normal LVEF.

Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure

BackgroundEmpagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with reduced ejection fraction. Its interplay with systolic blood pressure (SBP) is not known. ObjectivesThe goal of this study was to evaluate the interplay of SBP and the effects of empagliflozin in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction). MethodsStudy patients (N = 3,730) were randomly assigned to groups according to SBP at baseline (<110 mm Hg, n = 928; 110-130 mm Hg, n = 1,755; >130 mm Hg, n = 1,047). This study explored the influence of SBP on the effects of empagliflozin on cardiovascular death or HF hospitalization (primary outcome), as well as on total HF hospitalizations, rate of decline in estimated glomerular filtration rate, renal outcomes, and empagliflozin’s effects and significance on SBP. ResultsOver a median of 16 months considering only patients receiving placebo, baseline SBP and the risk of cardiovascular death or hospitalization for HF (P trend = 0.0015) were inversely related. Corrected for placebo, a slight early increase was observed in SBP at <110 mm Hg, no change at 110-130 mm Hg, and a slight reduction at >130 mm Hg. These between-group differences were of borderline significance (P for interaction trend = 0.05-0.10) after 4 and 12 weeks but were not significant later. SBP at baseline did not influence the effect of empagliflozin to reduce the risk of HF events or renal endpoints. When treated with empagliflozin, patients with SBP <110 mm Hg did not have an increased rate of symptomatic hypotension. ConclusionsEmpagliflozin was effective and safe, with no meaningful interaction between SBP and the effects of empagliflozin in the EMPEROR-Reduced trial. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)

Effect of Empagliflozin on Worsening Heart Failure Events in Patients With Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial.

Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with preserved ejection fraction, but additional data are needed about its effect on inpatient and outpatient heart failure events. We randomly assigned 5988 patients with class II through IV heart failure with an ejection fraction of >40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to usual therapy, for a median of 26 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points. Empagliflozin reduced the combined risk of cardiovascular death, hospitalization for heart failure, or an emergency or urgent heart failure visit requiring intravenous treatment (432 versus 546 patients [empagliflozin versus placebo, respectively]; hazard ratio, 0.77 [95% CI, 0.67-0.87]; P<0.0001). This benefit reached statistical significance at 18 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio, 0.71 [95% CI, 0.52-0.96]; P=0.028) and the total number of all hospitalizations that required a vasopressor or positive inotropic drug (hazard ratio, 0.73 [95% CI, 0.55-0.97]; P=0.033). Compared with patients in the placebo group, fewer patients in the empagliflozin group reported outpatient intensification of diuretics (482 versus 610; hazard ratio, 0.76 [95% CI, 0.67-0.86]; P<0.0001), and patients assigned to empagliflozin were 20% to 50% more likely to have a better New York Heart Association functional class, with significant effects at 12 weeks that were maintained for at least 2 years. The benefit on total heart failure hospitalizations was similar in patients with an ejection fraction of >40% to <50% and 50% to <60%, but was attenuated at higher ejection fractions. In patients with heart failure with preserved ejection fraction, empagliflozin produced a meaningful, early, and sustained reduction in the risk and severity of a broad range of inpatient and outpatient worsening heart failure events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.

Vericiguat: A Novel Oral Soluble Guanylate Cyclase Stimulator for the Treatment of Heart Failure.

To review the efficacy and safety of vericiguat indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization following hospitalization or need for outpatient intravenous diuretics in adult patients with chronic symptomatic HF and ejection fraction (EF) less than 45%. A literature search through MEDLINE with search terms MK1242, BAY 1021189, and vericiguat was conducted. Product labeling and English-language studies assessing pharmacokinetics, pharmacodynamics, efficacy, or safety of vericiguat were included. Preclinical and clinical studies describing the efficacy and safety of vericiguat were included. The phase 3 VICTORIA clinical trial demonstrated a lower composite primary outcome of death from cardiovascular causes or first hospitalization in the vericiguat group compared to placebo. Total hospitalizations for HF in the vericiguat group were significantly less compared to placebo. The composite secondary outcome of death from any cause or first HF hospitalization was significantly less in the vericiguat group. The addition of vericiguat offers a new treatment option for those in whom rehospitalization or recurrent outpatient intravenous diuretic treatment is a concern. Given high rates of nonadherence in HF patients, vericiguat represents an additional treatment option, especially for patients who do not tolerate available HF therapies. Vericiguat is a novel soluble guanylate cyclase stimulator that is safe and effective for reducing the risk of cardiovascular death and HF hospitalization in adults with symptomatic chronic HF and reduced EF.

Clinical outcomes of upgrade to versus de novo cardiac resynchronization therapy in mild heart failure patients with atrioventricular block

BackgroundIndication for de novo cardiac resynchronization therapy (CRT) has been recommended in mild heart failure (HF) patients with left ventricular (LV) ejection fraction (LVEF) <50% and atrioventricular block (AVB). In contrast, the indication of CRT upgrade from right ventricular pacing (RVP) has been limited to severe HF patients with LVEF≤35% and AVB. This study examined LV volumetric responses and clinical outcomes in mild HF patients with AVB who underwent CRT upgrade, compared with those of de novo CRT patients. MethodsThis retrospective study focused on patients with CRT due to AVB, mild HF at New York Heart Association class II and LVEF<50%. A total of 58 patients were divided into two groups: (1) 27 patients with CRT upgrade from RVP>40% (Upgrade group, UG), and (2) 31 patients with de novo CRT implantation (De novo group, DG). The echocardiographic assessment was performed at baseline and six months after CRT. The study endpoint was a combined endpoint with total mortality, HF hospitalization, or ventricular tachyarrhythmia events. ResultsAt six months after CRT, the LV end-systolic volume (LVESV) was significantly reduced in both groups (from 144.3±39.4 mL to 111.1±33.5 mL in UG, p<0.01; from 134.5±36.6 mL to 123.5±45.6 mL in DG, p<0.05); however, a significant improvement in LVEF was obtained in UG but not in DG (from 31.7±6.8% to 39.7±8.5% in UG, p<0.01; from 34.2±7.3% to 36.0±9.7% in DG, p=0.15). Consequently, the changes in LVESV and LVEF were significantly greater in UG than in DG. During the follow-up of 989 days, the survival rate for the composite events were similar between both groups (p=0.18). ConclusionsLV reverse remodeling was significantly greater in UG than DG, and the incidence of clinical composite events at mid-term follow-up was equivalent between UG and DG. CRT upgrade could be an acceptable indication in mild HF patients dependent on RVP.

Sacubitril-valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction.

AimsPatients with heart failure and preserved ejection fraction (HFpEF) frequently have difficult-to-control hypertension. We examined the effect of neprilysin inhibition on ‘apparent resistant hypertension’ in patients with HFpEF in the PARAGON-HF trial, which compared the effect of sacubitril–valsartan with valsartan.Methods and resultsIn this post hoc analysis, patients were categorized according to systolic blood pressure at the end of the valsartan run-in (n = 4795). ‘Apparent resistant hypertension’ was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite treatment with valsartan, a calcium channel blocker, and a diuretic. ‘Apparent mineralocorticoid receptor antagonist (MRA)-resistant’ hypertension was defined as systolic blood pressure ≥140 mmHg (≥135 mmHg if diabetes) despite the above treatments and an MRA. The primary outcome in the PARAGON-HF trial was a composite of total hospitalizations for heart failure and death from cardiovascular causes. We examined clinical endpoints and the safety of sacubitril–valsartan according to the hypertension category. We also examined reductions in blood pressure from the end of valsartan run-in to Weeks 4 and 16 after randomization. Overall, 731 patients (15.2%) had apparent resistant hypertension and 135 (2.8%) had apparent MRA-resistant hypertension. The rate of the primary outcome was higher in patients with apparent resistant hypertension [17.3; 95% confidence interval (CI) 15.6–19.1 per 100 person-years] compared to those with a controlled systolic blood pressure (13.4; 12.7–14.3 per 100 person-years), with an adjusted rate ratio of 1.28 (95% CI 1.05–1.57). The reduction in systolic blood pressure at Weeks 4 and 16, respectively, was greater with sacubitril–valsartan vs. valsartan in patients with apparent resistant hypertension [−4.8 (−7.0 to −2.5) and 3.9 (−6.6 to −1.3) mmHg] and apparent MRA-resistant hypertension [−8.8 (−14.0 to −3.5) and −6.3 (−12.5 to −0.1) mmHg]. The proportion of patients with apparent resistant hypertension achieving a controlled systolic blood pressure by Week 16 was 47.9% in the sacubitril–valsartan group and 34.3% in the valsartan group [adjusted odds ratio (OR) 1.78, 95% CI 1.30–2.43]. In patients with apparent MRA-resistant hypertension, the respective proportions were 43.6% vs. 28.4% (adjusted OR 2.63, 95% CI 1.18–5.89).ConclusionSacubitril–valsartan may be useful in treating apparent resistant hypertension in patients with HFpEF, even in those who continue to have an elevated blood pressure despite treatment with at least four antihypertensive drug classes, including an MRA.Clinical trial registrationPARAGON-HF: ClinicalTrials.gov Identifier NCT01920711.

Untying the Gordian knot of sex and heart failure therapy

Untying the Gordian knot of sex and heart failure therapy

Integrating High-Sensitivity Troponin T and Sacubitril/Valsartan Treatment in HFpEF: The PARAGON-HF Trial

ObjectivesThis study examined the relationship among high-sensitivity troponin-T (hs-TnT), outcomes, and treatment with sacubitril/valsartan in patients with heart failure (HF) and preserved ejection fraction (HFpEF). Backgroundhs-TnT is a marker of myocardial injury in HF. MethodsThe PARAGON-HF trial randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. We compared the risk of the composite outcome of cardiovascular death (CVD) and total HF hospitalization (HHF) according to hs-TnT. We also assessed the effect of allocated treatment on hs-TnT. Resultshs-TnT was available in 1,141 patients (24%) at run-in (median value: 17 ng/L) and 1,260 (26%) at randomization, with 58.3% having hs-TnT >14 ng/L (upper limit of normal). During a median follow-up of 34 months, there were 393 outcome events (82 CVD, 311 HHF). Adjusting for demographics, comorbidities, left ventricular ejection fraction (LVEF), and N-terminal pro B-type natriuretic peptide (NT-proBNP), log-hs-TnT at randomization was an independent predictor of the composite outcome (HR: 1.38; 95% CI: 1.19-1.59; P < 0.001). Compared with valsartan, sacubitril/valsartan significantly reduced hs-TnT by 9% at week 16 (P < 0.001). Patients whose hs-TnT decreased from randomization to 16 weeks to at or below the median value of 17 ng/L subsequently had a lower risk of CVD/HHF compared with those with persistently elevated hs-TnT (P = 0.046). Patients with higher baseline hs-TnT (>17 ng/L) appeared to have a greater benefit from sacubitril/valsartan treatment when accounting for other potential effect modifiers (P interaction = 0.07). ConclusionsHigher baseline hs-TnT was associated with increased risk of CVD/HHF, whereas hs-TnT decrease at 16 weeks led to lower subsequent risk of CVD/HHF compared with those who had persistently elevated values. Sacubitril/valsartan significantly reduced hs-TnT compared with valsartan. hs-TnT may be helpful in identifying patients with HFpEF who are more likely to benefit from sacubitril/valsartan.

Influence of study discontinuation during the run-in period on the estimated efficacy of sacubitril/valsartan in the PARAGON-HF trial.

The 4822 patients randomized in the PARAGON-HF trial were a subset of 5746 initially eligible patients who entered sequential run-in periods. We identified patient factors associated with study discontinuation during the run-in period and estimated the implications of these discontinuations for the overall study result. We utilized multivariable logistic regression models to identify patient factors associated with study discontinuation during the run-in period. The efficacy of sacubitril/valsartan in a broader cohort approximating the full run-in population was estimated by weighting randomized patients according to the inverse probability of run-in completion. A total of 924 (16.1%) subjects failed to complete the run-in period. In multivariable models, non-completion was associated with region other than Central Europe, lower systolic blood pressure, lower serum sodium, lower haemoglobin, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide, higher New York Heart Association functional class, prior heart failure (HF) hospitalization, and lack of prior use of renin-angiotensin system inhibitors or beta-blocker. In repeat analysis of the effect of randomized treatment in PARAGON-HF giving greater weight to participants resembling those who failed to complete the run-in period, the incidence of HF hospitalizations and cardiovascular death was higher, and sacubitril/valsartan treatment reduced the composite of total HF hospitalizations and cardiovascular death compared with valsartan (rate ratio 0.86; 95% confidence interval 0.74-1.00). Patients with more advanced HF were at higher risk for non-completion of the run-in period in PARAGON-HF. Re-analysis of study outcomes accounting for the effect of run-in non-completion did not alter the estimated treatment effects of sacubitril/valsartan vs. valsartan.

Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial.

AimsThe aim of this article is to explore the influence of region and race/ethnicity on the effects of empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial.Methods and resultsOf 3730 patients, 1353 (36.3%) were enrolled in Europe, 1286 (34.5%) in Latin America, 425 (11.4%) in North America, and 493 (13.2%) in Asia; 2629 (70.5%) were White, 257 (6.9%) Black, and 672 (18.0%) Asian. Placebo event rates (per 100 patient-years) for cardiovascular death or heart failure (HF) hospitalization varied by region (Asia 27.7, North America 26.4, Latin America 21.4, and Europe 17.5) and race/ethnicity (Black 34.4, Asian 24.3, and White 18.7); driven by differences in HF hospitalization. The ratio of total HF hospitalization to cardiovascular death varied from 5.4 in Asia and 4.8 in North America to 2.1 in Europe; and from 4.8 in Black and 4.2 in Asian to 2.2 in White patients. Groups with the highest ratio had the greatest reduction in the primary outcome with empagliflozin. Inclusion of outpatient worsening HF episodes added more events in Europe vs. other regions; enhanced the placebo event rates in Europe vs. other regions; and increased the relative risk reduction with empagliflozin in Europe from 6% to 26%.ConclusionsThere were notable differences in the placebo event rates for major HF events across diverse regions and race/ethnic groups. The benefit of empagliflozin was most pronounced in groups with the highest ratio of HF hospitalization to cardiovascular death. Regional differences were attenuated when the definition of HF events was expanded to include outpatient worsening HF events.

321-OR: Effects of Canagliflozin (CANA) on Hospitalization for Heart Failure (HHF) by Baseline EGFR: Pooled Analysis from the CANVAS Program and CREDENCE

People with type 2 diabetes (T2D) are at high risk for CV events, including HHF, especially as kidney function declines. We examined the effects of CANA on risk of HHF by baseline eGFR in patients with T2D and high CV risk and/or chronic kidney disease from the CANVAS Program and CREDENCE. Patient-level data from the CANVAS Program (N = 10,142) and CREDENCE (N = 4401) were pooled. Cox proportional hazards model for the time to first/second HHF events and proportional means model based on cumulative mean function for recurrent HHF events were used to assess effects overall as well as within baseline eGFR strata ( 60 mL/min/1.73 m2). HHF events were independently and blindly adjudicated. In 14,540 participants with baseline eGFR values over a median follow-up of 130 weeks, 672 HHF events occurred; 357 (53%) were single events. CANA decreased the time to first HHF event (HR 0.58, 95% CI 0.48, 0.70; Figure), consistently regardless of baseline eGFR (interaction P = 0.84), and time to second HHF event (HR 0.67, 95% CI 0.46, 0.96; too few events to stratify by eGFR). CANA also decreased total HHF events overall (mean event ratio 0.63, 95% CI 0.54, 0.73) and across eGFR subgroups (interaction P = 0.51). In individuals with T2D in the CANVAS Program and CREDENCE, CANA decreased the risk of first and recurrent HHF events, with consistent benefits independent of baseline eGFR. Disclosure M. N. Kosiborod: Consultant; Self; Amgen Inc., Applied Therapeutics, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk, Sanofi, Vifor Pharma Management Ltd., Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH. J. Gogate: Employee; Self; Janssen Research & Development, LLC. J. Seufert: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi, Speaker’s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk, Sanofi. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. Funding Janssen Scientific Affairs, LLC

FC 021EFFICACY OF INTRAVENOUS FERRIC CARBOXYMALTOSE IN PATIENTS WITH IRON DEFICIENCY FOLLOWING ACUTE HEART FAILURE, ACCORDING TO BASELINE EGFR: A SUBGROUP ANALYSIS OF THE AFFIRM-AHF TRIAL

Abstract Background and Aims In the AFFIRM-AHF trial, treatment with intravenous (IV) ferric carboxymaltose (FCM) reduced the risk of heart failure (HF) hospitalisations vs placebo in patients with iron deficiency after an episode of acute HF. Of these patients, 41% had a medical history of chronic kidney disease (CKD). This prespecified subanalysis of AFFIRM-AHF data was performed to investigate the effect of renal function on FCM efficacy. Methods In AFFIRM-AHF, patients stabilised following hospitalisation for acute HF with concomitant iron deficiency (defined as ferritin &amp;lt;100 μg/L, or 100–299 μg/L with transferrin saturation &amp;lt;20%) were randomised to receive either IV FCM or placebo before discharge for the index hospitalisation. In this analysis, patients who had received at least one dose of the study drug, and who had at least one post-randomisation data point and a baseline value for estimated glomerular filtration rate (eGFR; calculated using the CKD-EPI formula and baseline creatinine value), were stratified into tertiles according to baseline eGFR. The primary outcome was a composite of total HF hospitalisations and CV death. Secondary outcomes included total HF hospitalisations, CV death, time to first HF hospitalisation or CV death, composite of total CV hospitalisations and CV death, and days lost due to HF hospitalisations or CV death. All outcomes were evaluated up to 52 weeks post-randomisation. Results Of the 1,108 patients included in primary AFFIRM-AHF analyses, 967 (FCM: 487; placebo: 480) had a baseline eGFR value and were included in this analysis. In both groups, 60% of patients had an eGFR &amp;lt;60 mL/min/1.73 m2 following the index acute HF episode. Patients were divided into eGFR tertiles 1, 2 and 3, with corresponding respective baseline eGFR values of &amp;lt;42.96, 42.96 to &amp;lt;64.32, and ≥64.32 mL/min/1.73 m2. At baseline, the mean age, proportion of females, and proportions of patients with ischaemic HF aetiology, a documented history of HF, and a medical history of percutaneous coronary intervention, coronary artery bypass graft and/or cardiac resynchronisation therapy, were highest in eGFR tertile 1 and lowest in eGFR tertile 3. In eGFR tertiles 1, 2 and 3, the number of total HF hospitalisations and CV deaths in the FCM group vs placebo group were, respectively, 115 vs 152, 76 vs 83, and 56 vs 79, with respective annualised rate ratios (95% confidence interval [CI]) of 0.76 (0.50, 1.16), 0.76 (0.48, 1.22) and 0.69 (0.42, 1.12) (Figure). In eGFR tertile 3, the total number of CV hospitalisations and CV deaths was significantly lower in the FCM group vs the placebo group (69 vs 107; rate ratio [95% CI] 0.60 [0.39, 0.93]), with a nominally lower number of total HF hospitalisations with FCM vs placebo (44 vs 66; rate ratio [95% CI] 0.62 [0.38, 1.01]). In the time to first event analysis, FCM significantly reduced HF hospitalisation or CV death vs placebo in eGFR tertile 3 (hazard ratio [95% CI] 0.64 [0.42, 0.98]). In eGFR tertiles 1 and 2, differences between FCM and placebo arms for secondary endpoints did not reach statistical significance. The p-trend for treatment by baseline eGFR subgroup was non-significant for the primary outcome (0.941) and also for the secondary outcomes specified here. Conclusion In patients with iron deficiency who were stabilised after an episode of acute HF, numerically fewer primary and secondary events, endpoints or outcomes were consistently observed with FCM vs placebo across the eGFR tertiles. In addition, no significant interaction between kidney function and FCM efficacy was noted. Given that this analysis was limited by small patient numbers following subgroup stratification, further studies in larger cohorts with CKD may help to clarify the effect of IV FCM in this patient population.

Efficacy of intravenous ferric carboxymaltose for iron deficiency following acute heart failure (AHF) in patients with previously diagnosed HF: a subgroup analysis of AFFIRM-AHF

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Vifor Pharma OnBehalf The AFFIRM-AHF Investigators Introduction AFFIRM-AHF is the first randomised clinical trial to evaluate the effect of intravenous ferric carboxymaltose (IV FCM) (vs placebo) on morbidity and mortality in patients with an episode of acute heart failure (HF) and concomitant iron deficiency. Purpose To determine the effect of FCM versus placebo on efficacy outcomes in the subgroup of the AFFIRM-AHF cohort with a documented history of HF. Methods This subgroup analysis evaluated patients previously diagnosed with HF. Primary outcome was a composite of total HF hospitalisations and CV death. Secondary outcomes included total HF hospitalisations, CV death, time to first HF hospitalisation or CV death, composite of total CV hospitalisations and CV death, and days lost due to HF hospitalisations or CV death. All outcomes were evaluated up to 52 weeks post-randomisation. Results In AFFIRM-AHF, 73% and 70% of patients randomly assigned to FCM and placebo, respectively, had a documented history of HF. Baseline demographics and clinical characteristics were comparable between treatment groups for this subgroup. There were significantly fewer primary events in patients assigned to FCM compared to placebo: 249 vs 336, respectively (rate ratio [RR] 0.72, 95% CI: 0.55–0.95; p = 0.022). 186 total HF hospitalisations occurred in FCM group and 267 in placebo (RR 0.67, 95% CI: 0.52–0.88; p = 0.004). The composite of first HF hospitalisation or CV death occurred in 149 (37%) assigned FCM and in 179 (44%) patients assigned placebo (hazard ratio [HR] 0·76, 95% CI: 0·61–0·95; p = 0·014). Conclusion In patients with a documented history of HF and iron deficiency who were stabilised after an episode of AHF, treatment with FCM significantly reduced the risk of a composite of total HF hospitalisation and CV death. Primary and Secondary outcomesFCM (n = 405)Placebo (n = 385)RR or HR (95% CI)P valueNo. of eventsRate per 100 patient-yrNo. of eventsRate per 100 patient-yrPrimary outcomeTotal HF hospitalisations and CV death24971.85336101.3RR: 0.72 (0.55-0.95)0.022Secondary outcomesTotal CV hospitalisationsand CV death30888.87401120.57RR: 0.74 (0.58-0.95)0.020Time to CV death63346.5568332.58HR: 0.91 (0.65-1.29)0.602Total HF hospitalisations18653.6726780.28RR: 0.67 (0.52-0.88)0.004Time to first HF hospitalisation or CV death149291.76179257.93HR: 0.76 (0.61-0.95)0.014Days lost due to HF hospitalisation and CV death4.5*526.328.3*955.55RR: 0.58 (0.38-0.90)0.015*Data point is the mean number of days lost per subject.

Dapagliflozin and Recurrent Heart Failure Hospitalizations in Heart Failure With Reduced Ejection Fraction: An Analysis of DAPA-HF.

Background:Patients with heart failure (HF) and reduced ejection fraction will experience multiple hospitalizations for heart failure during the course of their disease. We assessed the efficacy of dapagliflozin on reducing the rate of total (ie, first and repeat) hospitalizations for heart failure in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure).Methods:The total number of HF hospitalizations and cardiovascular deaths was examined by using the proportional-rates approach of Lei-Wei-Yang-Ying and a joint frailty model for each of recurrent HF hospitalizations and time to cardiovascular death. Variables associated with the risk of recurrent hospitalizations were explored in a multivariable Lei-Wei-Yang-Ying model.Results:Of 2371 participants randomly assigned to placebo, 318 experienced 469 hospitalizations for HF; of 2373 assigned to dapagliflozin, 230 patients experienced 340 admissions. In a multivariable model, factors associated with a higher risk of recurrent HF hospitalizations included higher heart rate, higher N-terminal pro-B-type natriuretic peptide, and New York Heart Association class. In the Lei-Wei-Yang-Ying model, the rate ratio for the effect of dapagliflozin on recurrent HF hospitalizations or cardiovascular death was 0.75 (95% CI, 0.65–0.88), P=0.0002. In the joint frailty model, the rate ratio for total HF hospitalizations was 0.71 (95% CI, 0.61–0.82), P<0.0001, whereas, for cardiovascular death, the hazard ratio was 0.81 (95% CI, 0.67–0.98), P=0.0282.Conclusions:Dapagliflozin reduced the risk of total (first and repeat) HF hospitalizations and cardiovascular death. Time-to-first event analysis underestimated the benefit of dapagliflozin in HF and reduced ejection fraction.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Worsening Heart Failure Episodes Outside a Hospital Setting in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial

ObjectivesThis study sought to evaluate the frequency and prognostic implications of urgent heart failure (HF) visits in a large global clinical trial of HF with preserved ejection fraction (HFpEF). BackgroundEpisodes of worsening HF managed without hospitalization are common and prognostically important in HF with reduced ejection fraction (EF). The significance of these ambulatory worsening HF events in HFpEF is uncertain. MethodsPARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) randomly assigned 4,796 patients with HFpEF (≥45%) to treatment with sacubitril/valsartan vs. valsartan with a primary composite endpoint of total HF hospitalizations and cardiovascular death. Urgent ambulatory HF visits requiring intravenous diuretic treatment were prospectively collected and adjudicated by a blinded committee. We examined the effect of study treatment on a prespecified expanded composite of cardiovascular death and worsening HF events (including HF hospitalizations and urgent HF visits) and the effect of each type of HF event on subsequent mortality. ResultsOf 884 first worsening HF events, 66 (7.5%) were urgent HF visits. Patients whose first episode of worsening HF event was an urgent visit had similar age, comorbidities, baseline N-terminal prohormone of B-type natriuretic peptide, and Meta-Analysis Global Group in Chronic Heart Failure risk scores to those in whom the first HF event was a hospitalization (all comparisons p > 0.05). Regardless of the treatment setting, patients with a first episode of worsening HF had higher rates of subsequent death (19.2 per 100 patient-years; 95% confidence interval [CI]: 16.9 to 21.8 for HF hospitalization and 10.1 per 100 patients-years; 95% CI: 5.4 to 18.7 for urgent HF visit) compared with those who did not experience worsening HF (death rate 4.0 per 100 patient-years; 95% CI: 3.6 to 4.4). Including total urgent HF visits in the composite study endpoint added 95 total events and would have shortened the trial duration needed for event accrual. The addition of urgent HF visits in a prespecified composite endpoint reinforced the treatment efficacy of sacubitril/valsartan compared with valsartan (rate ratio 0.86; 95% CI: 0.75 to 0.99; p = 0.040). ConclusionsLike HF hospitalizations, worsening HF events treated in the ambulatory setting are prognostically important in HFpEF. Inclusion of these events in the composite primary endpoint underscores the benefit of sacubitril/valsartan compared with valsartan in PARAGON-HF. (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)

Burden of Heart Failure Signs and Symptoms, Prognosis, and Response to Therapy: The PARAGON-HF Trial

ObjectivesThis study investigated the prognostic importance of heart failure (HF) signs and symptoms in patients with heart failure and preserved ejection fraction (HFpEF), and the effect of sacubitril/valsartan on HF signs and symptoms. BackgroundIn patients with HFpEF, worsening of HF symptoms, as a marker of cardiac decompensation, is frequently the reason for hospitalization. In this heterogenous disease entity, the prognostic value of HF signs and symptoms with regard to cardiovascular (CV) outcomes is poorly defined. MethodsThe authors examined the association between baseline HF signs and symptoms (rest dyspnea, exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, fatigue, edema, jugular venous distension, rales, and third heart sound) as well as burden of these HF signs and symptoms (classified as ≤2 and ≥3 HF signs and symptoms) and the primary composite of total HF hospitalizations and CV death, its components, and all-cause death in 4,725 patients enrolled in PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HFpEF) with available signs and symptoms at randomization. Response to sacubitril/valsartan on the basis of the presence of signs and symptoms was evaluated. Effects of sacubitril/valsartan on signs and symptoms over time were assessed using binary repeated-measures logistic regression. ResultsPatients with high (≥3) burden of HF signs and symptoms (n = 1,772 [38%]) were more commonly women, had slightly lower left ventricular ejection fractions, higher body mass index, and more advanced New York Heart Association functional class compared with patients with low (≤2) burden (n = 2,953 [62%]) (p < 0.001 for all). Levels of N-terminal pro–B-type natriuretic peptide did not differ significantly between groups (p = 0.14). Greater burden of signs and symptoms was associated with higher risk for total HF hospitalizations and CV death (rate ratio [RR]: 1.50; 95% confidence interval [CI]: 1.30 to 1.74) and all-cause death (RR: 1.41; 95% CI: 1.21 to 1.65). Among individual signs and symptoms, orthopnea (RR: 1.29; 95% CI: 1.04 to 1.61) and rales (RR: 1.52; 95% CI: 1.10 to 2.10) were most predictive of the primary endpoint. Treatment response to sacubitril/valsartan was not significantly modified by burden of HF signs and symptoms (p for interaction = 0.08), though patients with orthopnea appeared to derive greater benefit from sacubitril/valsartan (RR: 0.67; 95% CI: 0.49 to 0.90) than those without orthopnea (RR: 0.97; 95% CI: 0.82 to 1.14; p for interaction = 0.04). Compared with valsartan, sacubitril/valsartan did not significantly decrease overall burden of HF signs and symptoms over time (odds ratio: 0.84; 95% CI: 0.67 to 1.07) but did reduce exertional dyspnea (odds ratio: 0.76; 95% CI: 0.63 to 0.93). ConclusionsHigh burden of HF signs and symptoms, particularly the presence of orthopnea and rales, portends a higher risk for adverse CV events in patients with HF with preserved ejection fraction. Sacubitril/valsartan did not significantly decrease the burden of HF signs and symptoms over time but did reduce exertional dyspnea relative to valsartan. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)

Serum potassium and outcomes in heart failure with preserved ejection fraction: a post-hoc analysis of the PARAGON-HF trial.

The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan. The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4-5 mmol/L and >5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P< 0.001, and for hyperkalaemiaHR 1.21, 95% CI 1.02-1.44; P= 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up. Both hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.