Body mass index and cardiorenal outcomes in the EMPEROR-Preserved trial: Principal findings and meta-analysis with the DELIVER trial.

AIMS: Both low and high body mass index (BMI) are associated with poor heart failure outcomes. Whether BMI modifies benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure with preserved ejection fraction (HFpEF) requires further investigation. METHODS AND RESULTS: Using EMPEROR-Preserved data, the effects of empagliflozin versus placebo on the risks for the primary outcome (hospitalization for heart failure [HHF] or cardiovascular [CV] death), change in estimated glomerular filtration rate (eGFR) slopes, change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), and secondary outcomes across baseline BMI categories (<25 kg/m2, 25 to <30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2 and ≥40 kg/m2) were examined, and a meta-analysis conducted with DELIVER. Forty-five percent had a BMI of ≥30 kg/m2. For the primary outcome, there was a consistent treatment effect of empagliflozin versus placebo across the BMI categories with no formal interaction (p trend = 0.19) by BMI categories. There was also no difference in the effects on secondary outcomes including total HHF (p trend = 0.19), CV death (p trend = 0.20), or eGFR slope with slower declines with empagliflozin regardless of BMI (range 1.12-1.71 ml/min/1.73 m2 relative to placebo, p trend = 0.85 for interaction), though there was no overall impact on the composite renal endpoint. The difference in weight change between empagliflozin and placebo was -0.59, -1.48, -1.54, -0.87, and - 2.67 kg in the lowest to highest BMI categories (p trend = 0.016 for interaction). A meta-analysis of data from EMPEROR-Preserved and DELIVER showed a consistent effect of SGLT2i versus placebo across BMI categories for the outcome of HHF or CV death. There was a trend toward greater absolute KCCQ-CSS benefit at 32 weeks with empagliflozin at higher BMIs (p = 0.08). CONCLUSIONS: Empagliflozin treatment resulted in broadly consistent cardiac effects across the range of BMI in patients with HFpEF. SGLT2i treatment yields benefit in patients with HFpEF regardless of baseline BMI.

Insulin-like growth factor binding protein-7 concentrations in chronic heart failure: Results from the EMPEROR programme.

AIMS: Insulin-like growth factor binding protein-7 (IGFBP7) is a biomarker of tissue senescence with a role in cardio-renal pathophysiology. The role of IGFBP7 as a prognostic biomarker across the full ejection fraction (EF) spectrum of heart failure (HF) remains less well understood. We examined associations between IGFBP7 and risk of cardio-renal outcomes regardless of EF and the effect of empagliflozin treatment on IGFBP7 concentrations among individuals with HF. METHODS AND RESULTS: IGFBP7 was measured in 1125 study participants from the EMPEROR-Reduced and EMPEROR-Preserved trials. Cox regression was used to study associations with outcomes. Study participants with IGFBP7 levels in the highest tertile had a higher-risk clinical profile. In Cox proportional hazards models adjusted for clinical variables, N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin T, baseline IGFBP7 values in the highest tertile predicted an increased risk of HF hospitalization or cardiovascular death (hazard ratio [HR] 2.00, 95% confidence interval [CI] 1.28-3.10, p = 0.002, p for trend <0.001) and higher risk of the renal composite endpoint (HR 4.66, 95% CI 1.61-13.53, p = 0.005, p for trend = 0.001), regardless of EF. Empagliflozin reduced risk for cardiovascular death/HF hospitalization irrespective of baseline IGFBP7 (p for trend across IGFBP7 tertiles = 0.26). Empagliflozin treatment was not associated with meaningful change in IGFBP7 at 12 or 52 weeks. CONCLUSION: Across the entire left ventricular EF spectrum in the EMPEROR Programme, concentrations of the senescence-associated biomarker IGFBP7 were associated with higher risk clinical status and predicted adverse cardio-renal outcomes even in models adjusted for conventional biomarkers. Empagliflozin did not significantly affect IGFBP7 levels over time.

Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction.

BACKGROUND: Cardiovascular events frequently recur after acute myocardial infarction, and low cholesterol efflux - a process mediated by apolipoprotein A1, which is the main protein in high-density lipoprotein - has been associated with an increased risk of cardiovascular events. CSL112 is human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity. Whether infusions of CSL112 can reduce the risk of recurrent cardiovascular events after acute myocardial infarction is unclear. METHODS: We conducted an international, double-blind, placebo-controlled trial involving patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors. Patients were randomly assigned to receive either four weekly infusions of 6 g of CSL112 or matching placebo, with the first infusion administered within 5 days after the first medical contact for the acute myocardial infarction. The primary end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes from randomization through 90 days of follow-up. RESULTS: A total of 18,219 patients were included in the trial (9112 in the CSL112 group and 9107 in the placebo group). There was no significant difference between the groups in the risk of a primary end-point event at 90 days of follow-up (439 patients [4.8%] in the CSL112 group vs. 472 patients [5.2%] in the placebo group; hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.05; P = 0.24), at 180 days of follow-up (622 patients [6.9%] vs. 683 patients [7.6%]; hazard ratio, 0.91; 95% CI, 0.81 to 1.01), or at 365 days of follow-up (885 patients [9.8%] vs. 944 patients [10.5%]; hazard ratio, 0.93; 95% CI, 0.85 to 1.02). The percentage of patients with adverse events was similar in the two groups; a higher number of hypersensitivity events was reported in the CSL112 group. CONCLUSIONS: Among patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors, four weekly infusions of CSL112 did not result in a lower risk of myocardial infarction, stroke, or death from cardiovascular causes than placebo through 90 days. (Funded by CSL Behring; AEGIS-II ClinicalTrials.gov number, NCT03473223.).

Carbohydrate antigen 125 concentrations across the ejection fraction spectrum in chronic heart failure: The EMPEROR programme.

AIM: Vascular congestion may lead to an increase of carbohydrate antigen 125 (CA-125). The role of CA-125 as a biomarker of congestion or for prognosis across the full ejection fraction (EF) spectrum of chronic heart failure (HF) remains unknown. METHODS AND RESULTS: Serum CA-125 was measured in 1111 study participants from the EMPEROR-Reduced and EMPEROR-Preserved trials. Congestive signs and symptoms were evaluated across CA-125 tertiles. Cox regression was used to study the association with outcomes. The primary outcome was a composite of first HF hospitalization or cardiovascular (CV) death. No significant association was present between baseline CA-125 levels and congestive signs or symptoms. In the overall population, higher CA-125 levels were not associated with an increased risk of primary outcome (tertile 3 vs. tertile 1: hazard ratio [HR] 1.34; 95% confidence interval [CI] 0.91-1.96; p-trend = 0.11). However, higher CA-125 levels were associated with an increased risk of primary outcome in patients with HF and reduced EF (HFrEF; tertile 3 vs. tertile 1: HR 2.25 [95% CI 1.30-3.89]), but not among patients with preserved EF (HFpEF; tertile 3 vs. tertile 1: HR 0.68 [95% CI 0.38-1.21]); interaction-p = 0.02). Patients in the upper CA-125 tertile also showed the steepest estimated glomerular filtration rate decline over time (p-trend = 0.03). The effect of empagliflozin to reduce the risk of CV death or HF hospitalization appeared to be attenuated in those with lower baseline CA-125 levels (interaction-p-trend = 0.09). CONCLUSION: Across the range of EF in patients with chronic HF enrolled in the EMPEROR trials, the majority of whom did not have clinical evidence of congestion, CA-125 concentrations were not significantly associated with congestive signs or symptoms. CA-125 concentrations may predict HF hospitalization/CV death in patients with HFrEF, but not those with HFpEF. CLINICAL TRIAL REGISTRATION: EMPEROR-Reduced (NCT03057977), EMPEROR-Preserved (NCT03057951).

Empagliflozin and risk of lower respiratory tract infection in heart failure with mildly reduced and preserved ejection fraction: An EMPEROR-Preserved analysis.

AIMS: Lower respiratory tract infections (LRTI) are common worldwide. Patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) have a high risk of developing LRTI. Prior studies were able to show that sodium-glucose cotransporter 2 inhibitors may reduce the incidence of LRTI in patients with type 2 diabetes. The aim of this study was to evaluate patient characteristics and prognosis according to LRTI status and to assess the effect of empagliflozin on LRTI in 5988 patients with HFmrEF/HFpEF enrolled in the EMPEROR-Preserved trial randomized to either empagliflozin or placebo over a median follow-up of 26 months. METHODS AND RESULTS: Time-updated models were used to study the mortality risk after a LRTI. Cox regression was used to study the effect of empagliflozin on incident LRTI. Throughout the follow-up, 699 of 5988 (11.7%) patients developed LRTI: these were older, were more frequently hospitalized within the previous year, had type 2 diabetes, chronic kidney disease, and had higher N-terminal pro-B-type natriuretic peptide levels than patients without incident LRTI. Patients who developed LRTI had a 2.7-fold higher risk of subsequent mortality compared to patients without LRTI. The incidence of LRTI was 5.2 (95% confidence interval [CI] 4.6-5.8) events per 100 person-years in the empagliflozin group and 6.2 (95% CI 5.6-6.9) events per 100 person-years in the placebo group (hazard ratio 0.83, 95% CI 0.71-0.96, p = 0.014). The total number of LRTI events was reduced in the empagliflozin group (incidence rate ratio 0.80, 95% CI 0.68-0.94, p = 0.008). No effect of empagliflozin was observed on COVID-19 incidence. CONCLUSION: In EMPEROR-Preserved, LRTI was frequent and associated with a poor prognosis. Empagliflozin was associated with a reduced risk of LRTI compared to placebo.

Quantifying the benefit-risk trade-off for individual patients in a clinical trial: principles and antithrombotic case study.

BACKGROUND: A treatment's overall favorable benefit-risk profile does not imply that every individual patient will benefit from the treatment. OBJECTIVES: To describe a statistical methodology for quantifying the benefit-risk trade-off in individual patients. METHODS: The method requires a large randomized controlled trial containing a primary efficacy outcome and a primary safety outcome, for instance, the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in Myocardial Infarction 50 placebo-controlled trial of vorapaxar in 17 779 patients following myocardial infarction. Multivariate regression models predict each individual patient's risk of ischemic events (benefit) and major bleeding events (harm) based on their profile. Hence, each patient's predicted benefit from vorapaxar (reduction in ischemic events) and predicted risk (increase in bleeding events) were estimated. The relative importance of ischemic and bleeding events based on links to all-cause mortality was quantified, although the limitations of such weightings are noted. RESULTS: Overall results demonstrated both clear benefit and harm from vorapaxar. Substantial interindividual variation in both benefit and risk facilitated distinguishing patients with a favorable benefit-risk trade-off from those who did not. Such findings were applied to recommend vorapaxar in as many as 98.3% of patients in which a favorable mortality-weighted benefit-risk trade-off was present, in 77.2% of patients with ischemic benefit 20% greater than bleeding risk, or in as few as 45.5% of patients if an annual decrease in ischemic risk of ≥0.5% was also required. CONCLUSION: While overall randomized controlled trials of treatment benefit vs risk are valuable, models determining each individual patient's estimated absolute benefit and risk provide more useful insight regarding patient-specific benefit-risk trade-offs to better enable personalized therapeutic decision-making.

Early changes in estimated glomerular filtration rate post-initiation of empagliflozin in EMPEROR-Preserved.

AIMS: Renal function (estimated glomerular filtration rate [eGFR]) changes early after the introduction of empagliflozin have not been described in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to describe early eGFR changes, assess its determinants and its clinical impact on cardiovascular and renal outcomes in patients with HFpEF enrolled in EMPEROR-Preserved. METHODS AND RESULTS: Estimated glomerular filtration rate changes (absolute and relative) from randomization to week 4 were calculated and landmark analyses performed. Initial eGFR change was available in 5836 patients (97.5% of the population). Empagliflozin induced a mean eGFR change of -3.2 ml/min/1.73 m2 versus placebo from baseline to week 4. After week 4, in the empagliflozin group, the risk of the primary outcome (composite of heart failure hospitalization or cardiovascular death), cardiovascular, all-cause mortality and sustained ≥50% eGFR decrease or end-stage renal disease (ESRD) did not differ by eGFR change levels. In contrast, in the placebo group, patients included in the tertile with most profound eGFR decrease (i.e. ≥5.1% from baseline) had a higher risk of the primary outcome (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.17-1.82), cardiovascular mortality (HR 1.38, 95% CI 1.01-1.89) and sustained ≥50% eGFR decrease or ESRD (HR 2.20, 95% CI 1.20-4.04) versus tertile with eGFR increase. CONCLUSION: An initial relatively small eGFR decrease may be expected after empagliflozin initiation. Such small eGFR decrease was not associated with adverse cardiovascular outcomes with empagliflozin. In contrast, eGFR decrease was associated with poor cardiovascular outcomes with placebo.

Effects of empagliflozin on collagen biomarkers in patients with heart failure: Findings from the EMPEROR trials.

AIMS: Extracellular matrix remodelling is one of the key pathways involved in heart failure (HF) progression. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may have a role in attenuating myocardial fibrosis. The impact of SGLT2i on blood markers of collagen turnover in humans is not fully elucidated. This study aimed to investigate the effect of empagliflozin on serum markers of collagen turnover in patients enrolled in the EMPEROR-Preserved and EMPEROR-Reduced trials. METHODS AND RESULTS: Overall, 1084 patients (545 in empagliflozin and 539 in placebo) were included in the analysis. Procollagen type I carboxy-terminal propeptide (PICP), a fragment of N-terminal type III collagen (PRO-C3), procollagen type I amino-terminal peptide (PINP), a fragment of C-terminal type VIa3 collagen (PRO-C6), a fragment of type I collagen (C1M), and a fragment of type III collagen (C3M) were measured in serum at baseline, 12 and 52 weeks. A mixed model repeated measurements model was used to evaluate the effect of empagliflozin versus placebo on the analysed biomarkers. Higher baseline PICP, PRO-C6 and PINP levels were associated with older age, a more severe HF presentation, higher levels of natriuretic peptides and high-sensitivity troponin T, and the presence of comorbid conditions such as chronic kidney disease and atrial fibrillation. Higher PICP levels were associated with the occurrence of the study primary endpoint (a composite of HF hospitalization or cardiovascular death), and PRO-C6 and PINP were associated with the occurrence of sustained worsening of kidney function. On the other hand, PRO-C3, C1M, and C3M were not associated with worse HF severity or study outcomes. Compared to placebo, empagliflozin reduced PICP at week 12 by 5% and at week 52 by 8% (week 12: geometric mean ratio = 0.95, 95% confidence interval [CI] 0.91-0.99, p = 0.012; week 52: geometric mean ratio = 0.92, 95% CI 0.88-0.97, p = 0.003). Additionally, empagliflozin reduced PRO-C3 at week 52 by 7% (week 12: geometric mean ratio = 0.98, 95% CI 0.95-1.02, p = 0.42; week 52: geometric mean ratio = 0.93, 95% CI 0.89-0.98, p = 0.003), without impact on other collagen markers. CONCLUSION: Our observations are consistent with experimental observations that empagliflozin down-regulates profibrotic signalling. The importance of such an effect for the clinical benefits of SGLT2i in HF remains to be elucidated.

Growth differentiation factor-15 and the effect of empagliflozin in heart failure: Findings from the EMPEROR program.

AIMS: Growth differentiation factor-15 (GDF-15) is upregulated in part in response to cardiomyocyte stretch and stress, and it exerts a protective role that is mediated by its action to suppress signalling through insulin-like growth factor (IGF) and enhance signalling through adenosine monophosphate-activated protein kinase (AMPK). Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in heart failure, which has been experimentally linked to AMPK. This study aimed at evaluating the associations of GDF-15 with baseline characteristics, the prognostic significance of GDF-15, and the effect of empagliflozin on GDF-15 in patients with heart failure with a reduced and preserved ejection fraction. METHODS AND RESULTS: Growth differentiation factor-15 was determined in serum samples from the EMPEROR-Reduced and EMPEROR-Preserved trials. Cox regression and mixed models for repeated measures were used to study the association with outcomes and the effect of empagliflozin on GDF-15, respectively. We studied 1124 patients (560 placebo and 564 empagliflozin) with median GDF-15 levels at baseline of 2442 (interquartile range 1603-3780) pg/ml. Patients with higher GDF-15 levels were typically older men with more severe symptoms, higher N-terminal pro-B-type natriuretic peptide levels, worse kidney function and who were prescribed metformin. Baseline levels of GDF-15 were well correlated with levels of IGF-binding protein 7 (rho = 0.64). Higher levels of GDF-15 were independently associated with an increased risk of cardiovascular death, heart failure hospitalizations, and worse kidney outcomes. When considered as a continuous variable, for each doubling in GDF-15, the adjusted hazard ratio for cardiovascular death or heart failure hospitalization was 1.40 (95% confidence interval 1.15-1.71; p < 0.001). The relative effect of empagliflozin on cardiovascular death and hospitalization for heart failure was most pronounced in patients with higher baseline levels of GDF-15 (interaction p-trend = 0.031). At week 52, when compared with placebo, empagliflozin increased GDF-15 by an additional 8% (p = 0.020), an effect that was primarily seen in patients not receiving metformin, a known AMPK activator. CONCLUSIONS: Growth differentiation factor-15 is a marker of worse heart failure severity, is an independent predictor of major heart failure outcomes and may be associated with more pronounced benefits of empagliflozin. GDF-15 is increased among metformin users, and empagliflozin was associated with an increase in GDF-15 levels, primarily in patients not receiving metformin.

Efficacy and Safety of Empagliflozin According to Background Diuretic Use in HFrEF: Post-Hoc Analysis of EMPEROR-Reduced.

BACKGROUND: The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial established the efficacy of empagliflozin in reducing heart failure (HF) outcomes among patients with heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: The authors examined the outcomes of EMPEROR-Reduced as a function of background diuretic therapy. METHODS: The EMPEROR-Reduced trial was a double-blind, randomized controlled trial of placebo vs empagliflozin 10 mg among 3,730 HFrEF patients. Herein, the population was stratified into 4 groups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. RESULTS: A total of 3,656 patients from the EMPEROR-Reduced trial were available for analysis. Of those patients, 482 (13.2%) were receiving no diuretic therapy, and 731 (20.0%), 1,411 (38.6%), and 1,032 (28.2%) were receiving <40 mg, 40 mg, and >40 mg, respectively. The efficacy of empagliflozin on the primary outcome (time to first event of hospitalization for HF or cardiovascular [CV] death) was consistent regardless of background diuretic therapy (>40 mg: HR: 0.88 [95% CI: 0.71-1.10]; 40 mg: HR: 0.65 [95% CI: 0.51-0.82]; <40 mg: HR: 0.65 [95% CI: 0.46-0.92]); no diuretic agents: HR: 0.78 [95% CI: 0.47-1.29]; Ptrend test = 0.192). Baseline diuretic doses did not influence the effect of empagliflozin on body weight, systolic blood pressure, NT-proBNP, or hematocrit at 52 weeks. The safety profile of empagliflozin vs placebo was unaffected by baseline diuretic dose; however, independently of treatment allocation, total rates of adverse events were higher among patients with higher baseline doses of diuretic agents. CONCLUSIONS: Empagliflozin exhibits a consistent effect on time to CV death or HF hospitalization and an unaltered safety profile regardless of baseline diuretic therapy. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Optimal timing of influenza vaccination among patients with acute myocardial infarction - Findings from the IAMI trial.

Influenza vaccination reduces the risk of adverse cardiovascular events.The IAMI trial randomly assigned 2571 patients with acute myocardial infarction (AMI) to receive influenza vaccine or saline placebo during their index hospital admission. It was conducted at 30 centers in 8 countries from October 1, 2016 to March 1, 2020. In this post-hoc exploratory sub-study, we compare the trial outcomes in patients receiving early season vaccination (n = 1188) and late season vaccination (n = 1344).The primary endpoint wasthe composite of all-cause death, myocardial infarction (MI), or stent thrombosis at 12 months. Thecumulative incidence of the primary and key secondary endpoints by randomized treatment and early or late vaccination was estimated using the Kaplan-Meier method. In the early vaccinated group, the primary composite endpoint occurred in 36 participants (6.0%) assigned to influenza vaccine and 49 (8.4%) assigned to placebo (HR 0.69; 95% CI 0.45 to 1.07), compared to 31 participants (4.7%) assigned to influenza vaccine and 42 (6.2%) assigned to placebo (HR 0.74; 95% CI 0.47 to 1.18) in the late vaccinated group (P = 0.848 for interaction on HR scale at 1 year). We observed similar estimates for the key secondary endpoints of all-cause death and CV death. There was no statistically significant difference in vaccine effectiveness against adverse cardiovascular events by timing of vaccination. The effect of vaccination on all-cause death at one year was more pronounced in the group receiving early vaccination (HR 0.50; 95% CI, 0.29 to 0.86) compared late vaccination group (HR 0.75; 35% CI, 0.40 to 1.40) but there was no statistically significant difference between these groups (Interaction P = 0.335). In conclusion,there is insufficient evidence from the trial to establish whether there is a difference in efficacy between early and late vaccinationbut regardless of vaccination timing we strongly recommend influenza vaccination in all patients with cardiovascular diseases.

Transcatheter Aortic-Valve Replacement in Low-Risk Patients at Five Years.

BACKGROUND: A previous analysis in this trial showed that among patients with severe, symptomatic aortic stenosis who were at low surgical risk, the rate of the composite end point of death, stroke, or rehospitalization at 1 year was significantly lower with transcatheter aortic-valve replacement (TAVR) than with surgical aortic-valve replacement. Longer-term outcomes are unknown. METHODS: We randomly assigned patients with severe, symptomatic aortic stenosis and low surgical risk to undergo either TAVR or surgery. The first primary end point was a composite of death, stroke, or rehospitalization related to the valve, the procedure, or heart failure. The second primary end point was a hierarchical composite that included death, disabling stroke, nondisabling stroke, and the number of rehospitalization days, analyzed with the use of a win ratio analysis. Clinical, echocardiographic, and health-status outcomes were assessed through 5 years. RESULTS: A total of 1000 patients underwent randomization: 503 patients were assigned to undergo TAVR, and 497 to undergo surgery. A component of the first primary end point occurred in 111 of 496 patients in the TAVR group and in 117 of 454 patients in the surgery group (Kaplan-Meier estimates, 22.8% in the TAVR group and 27.2% in the surgery group; difference, -4.3 percentage points; 95% confidence interval [CI], -9.9 to 1.3; P = 0.07). The win ratio for the second primary end point was 1.17 (95% CI, 0.90 to 1.51; P = 0.25). The Kaplan-Meier estimates for the components of the first primary end point were as follows: death, 10.0% in the TAVR group and 8.2% in the surgery group; stroke, 5.8% and 6.4%, respectively; and rehospitalization, 13.7% and 17.4%. The hemodynamic performance of the valve, assessed according to the mean (±SD) valve gradient, was 12.8±6.5 mm Hg in the TAVR group and 11.7±5.6 mm Hg in the surgery group. Bioprosthetic-valve failure occurred in 3.3% of the patients in the TAVR group and in 3.8% of those in the surgery group. CONCLUSIONS: Among low-risk patients with severe, symptomatic aortic stenosis who underwent TAVR or surgery, there was no significant between-group difference in the two primary composite outcomes. (Funded by Edwards Lifesciences; PARTNER 3 ClinicalTrials.gov number, NCT02675114.).

Recurrent Events in Cardiovascular Trials: JACC State-of-the-Art Review.

Many randomized trials in cardiovascular disease have repeat nonfatal events (such as hospitalizations) occurring during patient follow-up; yet, it remains common practice to have time-to-first event as the primary outcome. We explore the value of analyses that include repeat events. Do they help us understand the effect of treatment and total disease burden? Do they enhance statistical power? Should they become a trial's primary analysis? It may also be difficult to choose which of the various statistical methods for analyzing repeat events to use, and we provide a nontechnical guide to what each method is doing. We compare several methods for repeat events: Lin Wei Yang Ying, negative binomial, joint frailty, win ratio, and area under the curve. We illustrate their performance in 5 large cardiovascular trials and compare them with time-to-first-event analyses. We review their use in recently published heart failure trials and make recommendations for their use in future trials.

Blinded Withdrawal of Long-Term Randomized Treatment With Empagliflozin or Placebo in Patients With Heart Failure.

BACKGROUND: It is not known whether the benefits of sodium-glucose cotransporter 2 inhibitors in heart failure persist after years of therapy. METHODS: In the EMPEROR-Reduced (Empagliflozin Outcome Trials in Chronic Heart Failure With Reduced Ejection Fraction) and EMPEROR-Preserved (Empagliflozin Outcome Trials in Chronic Heart Failure With Preserved Ejection Fraction) trials, patients with heart failure were randomly assigned (double-blind) to placebo or empagliflozin 10 mg/day for a median of 16 and 26 months, respectively. At the end of the trials, 6799 patients (placebo 3381, empagliflozin 3418) were prospectively withdrawn from treatment in a blinded manner, and, of these, 3981 patients (placebo 2020, empagliflozin 1961) underwent prespecified in-person assessments after ≈30 days off treatment. RESULTS: From 90 days from the start of closeout to the end of double-blind treatment, the annualized risk of cardiovascular death or hospitalization for heart failure was lower in empagliflozin-treated patients than in placebo-treated patients (10.7 [95% CI, 9.0-12.6] versus 13.5 [95% CI, 11.5-15.6] events per 100 patient-years, respectively; hazard ratio 0.76 [95% CI, 0.60-0.96]). When the study drugs were withdrawn for ≈30 days, the annualized risk of cardiovascular death or hospitalization for heart failure increased in patients withdrawn from empagliflozin but not in those withdrawn from placebo (17.0 [95% CI, 12.6-22.1] versus 14.1 [95% CI, 10.1-18.8] events per 100 patient-years for empagliflozin and placebo, respectively). The hazard ratio for the change in risk in the patients withdrawn from empagliflozin was 1.75 (95% CI, 1.20-2.54), P=0.0034, whereas the change in the risk in patients withdrawn from placebo was not significant (hazard ratio 1.12 [95% CI, 0.76-1.66]); time period-by-treatment interaction, P=0.068. After withdrawal, the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score declined by 1.6±0.4 in patients withdrawn from empagliflozin versus placebo (P<0.0001). Furthermore, withdrawal of empagliflozin was accompanied by increases in fasting glucose, body weight, systolic blood pressure, estimated glomerular filtration rate, N-terminal pro-hormone B-type natriuretic peptide, uric acid, and serum bicarbonate and decreases in hemoglobin and hematocrit (all P<0.01). These physiological and laboratory changes were the inverse of the effects of the drug seen at the start of the trials during the initiation of treatment (≈1-3 years earlier) in the same cohort of patients. CONCLUSIONS: These observations demonstrate a persistent effect of empagliflozin in patients with heart failure even after years of treatment, which dissipated rapidly after withdrawal of the drug. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT03057977 and NCT03057951.

Long-term outcomes among stable post-acute myocardial infarction patients living in rural versus urban areas: insights from the prospective, observational TIGRIS registry.

BACKGROUND: Insights on the differences in clinical outcomes, quality of life (QoL) and health resource utilisation (HRU) with different levels of care available to post-acute myocardial infarction (AMI) populations in rural and urban settings are limited. METHODS: The long-Term rIsk, clinical manaGement, and healthcare Resource utilisation of stable coronary artery dISease (TIGRIS), a prospective, observational registry, enrolled 8452 patients aged ≥50 years 1-3 years post-AMI from June 2013 to November 2014 from 24 countries in Asia Pacific/Australia, Europe, North America and South America. Differences in QoL (measured using the EuroQol Research Foundation instrument) and HRU between patients in rural and urban settings were evaluated in this post hoc analysis. The incidence of clinical endpoints (cardiovascular (CV) death, AMI, unstable angina with urgent revascularisation and stroke; bleeding; and all-cause mortality) was analysed. Data were collected at baseline and every 6 months for 24 months. RESULTS: There were fewer hospitalisations and visits to general practitioners (GPs) and cardiologists in the rural versus urban populations (adjusted event rate ratio (ERR)=0.90 (95% CI, 0.82 to 1.00, p=0.04); ERR=0.84 (95% CI, 0.78 to 0.92, p<0.001); ERR=0.86 (95% CI, 0.81 to 0.92, p<0.001), respectively). No statistically significant differences were observed between rural and urban populations in all-cause death, AMI, unstable angina with urgent revascularisation, CV death, stroke, major bleeding events and health-related QoL. The adjusted incidence rate ratio was 0.92 (95% CI, 0.74 to 1.15) for the composite of CV death, AMI and stroke. CONCLUSIONS: Living in rural areas was associated with fewer GP/cardiologist visits and hospitalisations; no significant differences in clinical outcomes and QoL were observed. TRIAL REGISTRATION NUMBER: NCT01866904.

Vascular Disease Burden, Outcomes and Benefits with Empagliflozin in Heart Failure: Insights From the EMPEROR-Reduced Trial.

BACKGROUND: The presence of ischemic heart disease impacts prognosis in patients affected by heart failure and reduced ejection fraction (HFrEF). It is not well known how the extent of vascular disease impacts prognoses and responses to therapy in this setting. METHODS: In this post hoc analysis of the EMPEROR-Reduced trial, outcomes and the effects of empagliflozin, were assessed in study participants according to the extent (none vs mono1 vs poly [≥ 2] vascular bed) of vascular disease. Vascular disease was defined as investigator-reported coronary artery disease (CAD), peripheral artery disease (PAD) and cerebrovascular disease at baseline. Cox proportional-hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Incidence rates are presented per 100 person-years (py) of follow-up. RESULTS: Of the 3730 study participants enrolled, 1324 (35.5%) had no vascular disease, 1879 (50.4%) had monovascular disease, and 527 (14.1%) had polyvascular disease. Participants with polyvascular disease tended to be older and male and to have had histories of hypertension, diabetes and smoking. In the placebo arm, a significantly higher risk for cardiovascular death existed in those with polyvascular disease (HR 1.57, 95% CI1.02, 2.44, compared to those with no vascular disease). In adjusted analysis, the benefit of empagliflozin in cardiovascular death or hospitalization due to HF, HF hospitalization, cardiovascular death, renal composite endpoint, estimated glomerular filtration slope changes, and health status scores were seen across the 3 groups (interaction P > 0.05 for all) but were attenuated in those with polyvascular disease. Adverse events were higher in those with polyvascular disease, but no major differences were noted between empagliflozin or placebo assignment in the 3 groups. CONCLUSION: In patients with HFrEF, the extent of vascular disease is associated with the risk for adverse cardiovascular outcomes. Empagliflozin offers cardiovascular and renal benefits in HFrEF across the extent of vascular disease, but this benefit is attenuated in those with polyvascular disease.

Underutilization of Mineralocorticoid Antagonists in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: It is unknown how the efficacy and safety of mineralocorticoid receptor antagonists vary according to duration of heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: In this study, we sought to evaluate the safety and efficacy of eplerenone according to duration of HFrEF. METHODS: In the EMPHASIS-HF trial, 3 patient groups were created according to HFrEF duration: <1 year, 1 to <5 years, and ≥5 years. The primary outcome was the composite of heart failure (HF) hospitalization or cardiovascular death. Outcomes were adjusted for prespecified prognostic variables and examined with the use of Cox regression models. RESULTS: The numbers of patients in each group were: 975, <1 year; 769, 1 to <5 years; and 988, ≥5 years. Patients with longer-standing HF were older and more frequently had cardiovascular and noncardiovascular comorbidities. The rate of the primary outcome (per 100 person-years) increased with HFrEF duration: 9.8 (95% CI: 8.4-11.4) for <1 year, 13.5 (95% CI: 11.6-15.7) for 1 to <5 years, and 17.6 (95% CI: 15.6-19.8) for ≥5 years. The benefits of eplerenone were consistent across HF duration: HRs for the primary outcome were 0.57 (95% CI: 0.42-0.79) for <1 year, 0.81 (95% CI: 0.60-1.10) for 1 to <5 years, and 0.61 (95% CI: 0.48-0.78) for ≥5 years; Pinteraction = 0.24. The absolute benefit was greatest in the longest-duration group: the number needed to treat for the primary outcome was 14 for <1 year, 13 for 1 to <5 years, and 10 for ≥5 years duration. CONCLUSIONS: Patients with longer-standing HFrEF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent regardless of HFrEF duration. (A Comparison of Outcomes in Patients in NYHA Class II Heart Failure When Treated With Eplerenone or Placebo in Addition to Standard Heart Failure Medicines [EMPHASIS-HF]; NCT00232180).

Liver tests, cardiovascular outcomes and effects of empagliflozin in patients with heart failure and preserved ejection fraction: The EMPEROR-Preserved trial.

AIM: The prognostic implication of elevated liver tests in heart failure with preserved ejection fraction (HFpEF) is uncertain. This analysis investigates the association of liver markers with hospitalization for heart failure (HHF) and cardiovascular death (CVD), and the treatment effect of empagliflozin across the range of liver marker levels. METHODS AND RESULTS: The double-blind, placebo-controlled EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure with Preserved Ejection Fraction) enrolled 5988 patients with HFpEF (ejection fraction >40%). Patients in New York Heart Association class II-IV and elevated N-terminal pro-B-type natriuretic peptide were randomized to receive empagliflozin 10 mg daily or placebo in addition to usual therapy. Patients with significant liver disease were excluded. The primary endpoint was time to first adjudicated HHF or CVD. We explored the association of liver function abnormalities with heart failure outcomes in patients on placebo, the effects of empagliflozin on liver tests and the treatment effects of empagliflozin on heart failure outcomes across categories of liver laboratory values. High alkaline phosphatase (p trend < 0.0001), low albumin (p trend < 0.0001) and high bilirubin (p = 0.02) were associated with poorer outcomes for HHF or CVD, while high aspartate aminotransferase was not, and high alanine aminotransferase was associated with better outcomes. Empagliflozin had no significant effects on liver tests compared to placebo except for albumin which was significantly increased. The treatment effect of empagliflozin on outcomes was not modified by liver tests. CONCLUSION: Abnormalities of liver function tests are associated differently with heart failure outcomes. Salutary effects of empagliflozin on liver tests were not observed although albumin increased. The treatment benefits of empagliflozin were not affected by baseline values of liver parameters.

Rationale and design of a randomized study comparing the Watchman FLX device to DOACs in patients with atrial fibrillation.

BACKGROUND: Percutaneous left atrial appendage (LAA) closure (LAAC) was developed as a nonpharmacologic alternative to oral anticoagulants (OACs) in patients with atrial fibrillation (AF) who are at an increased risk for stroke or systemic embolism. The Watchman device permanently seals off the LAA to prevent thrombi from escaping into the circulation. Previous randomized trials have established the safety and efficacy of LAAC compared to warfarin. However, direct OACs (DOACs) have become the preferred pharmacologic strategy for stroke prevention in patients with AF, and there is limited data comparing Watchman FLX to DOACs in a broad AF patient population. CHAMPION-AF is designed to prospectively determine whether LAAC with Watchman FLX is a reasonable first-line alternative to DOACs in patients with AF who are indicated for OAC therapy. STUDY DESIGN: A total of 3,000 patients with a CHA2DS2-VASc score ≥2 (men) or ≥3 (women) were randomized to Watchman FLX or DOAC in a 1:1 allocation at 142 global clinical sites. Patients in the device arm were to be treated with DOAC and aspirin, DOAC alone, or DAPT for at least 3 months postimplant followed by aspirin or P2Y12 inhibitor for 1-year. Control patients were required to take an approved DOAC for the duration of the trial. Clinical follow-up visits are scheduled at 3- and 12-months, and then annually through 5 years; LAA imaging is required at 4 months in the device group. Two primary end points will be evaluated at 3 years: (1) composite of stroke (ischemic/hemorrhagic), cardiovascular death, and systemic embolism compared for noninferiority, and (2) nonprocedural bleeding (International Society on Thrombosis and Haemostasis [ISTH] major and clinically relevant nonmajor bleeding) tested for superiority in the device arm against DOACs. The third primary noninferiority end point is the composite of ischemic stroke and systemic embolism at 5 years. Secondary end points include 3- and 5-year rates of (1) ISTH-defined major bleeding and (2) the composite of cardiovascular death, all stroke, systemic embolism, and nonprocedural ISTH bleeding. CONCLUSIONS: This study will prospectively evaluate whether LAAC with the Watchman FLX device is a reasonable alternative to DOACs in patients with AF. CLINICAL TRIAL REGISTRATION: NCT04394546.

Remodeling dental anatomy vs sham therapy for chronic temporomandibular disorders. A placebo-controlled randomized clinical trial.

BACKGROUND: Evidence regarding the etiology or effective treatments for chronic orofacial pain, the majority diagnosed as temporomandibular disorder (TMD), is limited. PURPOSE: To investigate whether occlusal equilibration therapy (ET) and decreasing the (higher) angle of the lateral guidance on the nonworking-side leads to a reduction in chronic TMDs intensity. METHODS: It was conducted a randomized, explanatory, single blind with blinded assessment, placebo-controlled trial with strong protection against bias involving patients with chronic TMDs. Participants were randomly assigned to receive equilibration therapy or sham therapy. ET in this study consisted of minimal invasive occlusal remodeling to obtain balanced occlusion with reduction of the steeper angle of lateral mandibular movement with respect to the Frankfort plane. The primary outcome was a change in the pain intensity score (on a 0-10 point scale, with 0 indicating no pain and 10 the worst possible pain) at month 6. Secondary outcomes include maximum unassisted mouth opening and psychological distress. RESULTS: A total of 77 participants underwent randomization, 39 of whom received ET and 38 sham therapy. The trial was stopped early for efficacy, according to preestablished rules when 67 participants (n = 34, n = 33, respectively) had completed the analysis. At month 6, the mean unadjusted pain intensity score was 2.1 in the ET and 3.6 in the sham therapy group (adjusted mean difference, -1.54; 95% confidence interval [CI] -0.5 to -2.6; P = 0.004; ANCOVA model). The mean increase in maximum unassisted mouth opening (main secondary outcome) was significantly higher in the real therapy group (adjusted mean difference 3.1 mm, 95% CI 0.5-5.7, p = 0.02). CONCLUSION: ET significantly reduced the intensity of facial pain associated with chronic TMDs and increased maximum unassisted mouth opening, as compared with sham therapy, over the course of 6 months. There were no serious adverse events. Funded by the Instituto de Salud Carlos III from the Ministry of Science and Innovation of the Government of Spain and European Regional Development Fund, Grant nº PI11/02507; "una manera de hacer Europa".