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Assessment of Omecamtiv Mecarbil for the Treatment of Patients With Severe Heart Failure: A Post Hoc Analysis of Data From the GALACTIC-HF Randomized Clinical Trial.
Felker, GM, Solomon, SD, Claggett, B, Diaz, R, McMurray, JJV, Metra, M, Anand, I, Crespo-Leiro, MG, Dahlström, U, Goncalvesova, E, et al
JAMA cardiology. 2022;(1):26-34
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Abstract
IMPORTANCE Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients' condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies. OBJECTIVE To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial. DESIGN, SETTING, AND PARTICIPANTS The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months. INTERVENTIONS Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo. MAIN OUTCOMES AND MEASURES The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability. RESULTS Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08; P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25]; P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo. CONCLUSIONS AND RELEVANCE In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02929329.
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A single bout of hybrid intradialytic exercise did not affect left-ventricular function in exercise-naïve dialysis patients: a randomized, cross-over trial.
Grigoriou, SS, Giannaki, CD, George, K, Karatzaferi, C, Zigoulis, P, Eleftheriadis, T, Stefanidis, I, Sakkas, GK
International urology and nephrology. 2022;(1):201-208
Abstract
INTRODUCTION Cardiovascular diseases are the leading cause of mortality in end-stage renal disease (ESRD) patients, especially those receiving hemodialysis (HD) therapy. HD has many side effects that are related to patients' hearts, such as recurrent myocardial ischemia and global or segmental left-ventricular dysfunction, which is associated with intradialytic hypotension, long-term loss of systolic function, and high incidence of cardiovascular events and death. Systematic exercise training has a beneficial effect on measures of cardiovascular fitness and reducing cardiovascular risk factors in ESRD. Whether there is an acute benefit of exercise during HD on left-ventricular function is not well known. The current study aimed to investigate whether a single bout of hybrid (aerobic and resistance) intradialytic exercise could affect left-ventricular function during HD sessions. METHODS Twenty-one exercise naïve and clinically stable HD patients participated in the study. All participants completed two different HD trials on two different days, separated by 1 week: (1) standard HD and (2) HD including a single bout of hybrid intradialytic exercise. Hybrid intradialytic training included the usual intradialytic cycling followed by resistance training using elastic bands and dumbbells. Echocardiographic assessment of left-ventricular function was completed before HD, half an hour before the end of HD, and 30 min after the end of HD. RESULTS Cohort data for left-ventricular function indices were not different between trials and did not change across time in either the standard HD or HD plus exercise trial. Cohort data for the change in ejection fraction from baseline to during HD did mask considerable inter-individual variability (HD - 0 ± 15; HD plus exercise (- 2 ± 20). Despite this, the variability was not mediated by the addition of intradialytic hybrid exercise. CONCLUSION A single bout of hybrid intradialytic exercise did not affect left-ventricular function during the HD therapy. It is important to determine whether chronic exercise training could beneficially affect left-ventricular function abnormalities often observed during the HD therapy. TRIAL REGISTRATION NUMBER The study is registered at ClinicalTrials.gov (NCT01721551) as a clinical trial.
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Associations of Empagliflozin With Left Ventricular Volumes, Mass, and Function in Patients With Heart Failure and Reduced Ejection Fraction: A Substudy of the Empire HF Randomized Clinical Trial.
Omar, M, Jensen, J, Ali, M, Frederiksen, PH, Kistorp, C, Videbæk, L, Poulsen, MK, Tuxen, CD, Möller, S, Gustafsson, F, et al
JAMA cardiology. 2021;(7):836-840
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IMPORTANCE Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve outcomes in patients with heart failure and a reduced ejection fraction (HFrEF). The association with cardiac remodeling has not been investigated. OBJECTIVE To investigate the outcome of the SGLT2i empagliflozin, compared with placebo, on cardiac remodeling in patients with HFrEF. DESIGN, SETTING, AND PARTICIPANTS This exploratory post hoc analysis included participants with stable HFrEF and ejection fractions of 40% or less, who were randomly enrolled in an investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trial in Denmark. Enrollment commenced on June 29, 2017, and continued through September 10, 2019, with the last participant follow-up on December 20, 2019. INTERVENTIONS Randomization (1:1) to empagliflozin (10 mg once daily) or matching placebo in addition to recommended heart failure therapy for 12 weeks. MAIN OUTCOMES AND MEASURES Efficacy measures were changes from baseline to week 12 in left ventricular end-systolic and end-diastolic volume indexes, left atrial volume index, and left ventricular ejection fraction adjusted for age, sex, type 2 diabetes, and atrial fibrillation. Secondary efficacy measures included changes in left ventricular mass index, global longitudinal strain, and relative wall thickness. RESULTS A total of 190 patients were randomized (95 each receiving empagliflozin and placebo), with a mean (SD) age of 64 (11) years; 162 were men (85.3%), 97 (51.1%) had ischemic HFrEF, 24 (12.6%) had type 2 diabetes, and the mean (SD) latest recorded left ventricular ejection fraction was 29% (8%). Of the 190, 186 completed the study. Empagliflozin significantly reduced left ventricular end-systolic volume index (-4.3 [95% CI, -8.5 to -0.1] mL/m2; P = .04), left ventricular end-diastolic volume index (-5.5 [95% CI, -10.6 to -0.4] mL/m2; P = .03), and left atrial volume index (-2.5 [95% CI, -4.8 to -0.1] mL/m2; P = .04) compared with placebo at 12 weeks' follow-up, with no change in left ventricular ejection fraction (1.2% [95% CI, -1.2% to 3.6%]; P = .32). These findings were consistent across subgroups. Of secondary efficacy measures, left ventricular mass index was significantly reduced by empagliflozin (-9.0 [95% CI, -17.2 to -0.8] g/m2; P = .03). CONCLUSIONS AND RELEVANCE In this small, randomized, short-term study, empagliflozin was associated with modest reductions in left ventricular and left atrial volumes with no association with ejection fraction. Effects beyond 12 weeks of SGLT2i use require further study. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03198585.
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Randomized, Controlled Trial to Evaluate the Effect of Dapagliflozin on Left Ventricular Diastolic Function in Patients With Type 2 Diabetes Mellitus: The IDDIA Trial.
Shim, CY, Seo, J, Cho, I, Lee, CJ, Cho, IJ, Lhagvasuren, P, Kang, SM, Ha, JW, Han, G, Jang, Y, et al
Circulation. 2021;(5):510-512
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Effect of l-arginine on cardiac reverse remodeling and quality of life in patients with heart failure.
Salmani, M, Alipoor, E, Navid, H, Farahbakhsh, P, Yaseri, M, Imani, H
Clinical nutrition (Edinburgh, Scotland). 2021;(5):3037-3044
Abstract
BACKGROUND & AIMS Heart failure (HF), as a major cardiac disease, is associated with considerable mortality, morbidities and poor quality of life. The aim of this study was to investigate the effect of l-arginine supplementation on cardiac outcomes and quality of life in patients with ischemic HF. METHODS This double-blind randomized controlled clinical trial was conducted in 50 patients with ischemic HF. Patients were randomly assigned to receive either 3 gr/d l-arginine or placebo, for 10 weeks. Cardiac function (based on echocardiography and six-minute walk test), blood pressure, and quality of life (based on the Minnesota living with heart failure questionnaire) were assessed. RESULTS The results showed significant improvements in ejection fraction (-6.5 ± 8.7 vs. -0.7 ± 7.8%, P = 0.037), left ventricular function (P = 0.043), diastolic dysfunction (P = 0.01) and marginally improvement in changes of left ventricular dimension during diastole (LVDd) (4 ± 6 vs. 0.3 ± 6.9 mm, P = 0.065) in the l-arginine compared to the placebo group. At the end of the study, physical aspect (5.7 ± 3.3 vs. 1.2 ± 6.1, P = 0.002) and total score (10 ± 6.7 vs. 4.1 ± 9.4, P = 0.011) of quality of life improved significantly in the l-arginine compared with the placebo group. Additionally, pre-to post-values of diastolic blood pressure, mean arterial pressure, LVDd, LV ejection fraction, left ventricular function, diastolic dysfunction as well as physical and total scores of quality of life improved significantly within the intervention, but not the placebo, group (all P < 0.05). CONCLUSION This study showed that 3 gr/d l-arginine supplementation for 10 weeks could improve cardiac recovery and function, and quality of life in patients with HF. This study was registered at the Iranian Clinical Trial Registration Center (www.irct.ir) with IRCT20170202032367N4 code.
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Extrapolating Long-term Event-Free and Overall Survival With Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis of a Phase 3 Randomized Clinical Trial.
Docherty, KF, Jhund, PS, Claggett, B, Ferreira, JP, Bengtsson, O, Inzucchi, SE, Køber, L, Kosiborod, MN, Langkilde, AM, Martinez, FA, et al
JAMA cardiology. 2021;(11):1298-1305
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IMPORTANCE Sodium glucose cotransporter 2 inhibitors reduce morbidity and mortality in patients with heart failure and reduced ejection fraction (HFrEF). Clinicians may find estimates of the projected long-term benefits of sodium glucose cotransporter 2 inhibitors a helpful addition to clinical trial results when communicating the benefits of this class of drug to patients. OBJECTIVE To estimate the projected long-term treatment effects of dapagliflozin in patients with HFrEF over the duration of a patient's lifetime. DESIGN, SETTING, AND PARTICIPANTS Exploratory analysis was performed of Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF), a phase 3 randomized, placebo-controlled clinical trial conducted at 410 sites in 20 countries. Patients with an ejection fraction less than or equal to 40% in New York Heart Association functional classification II to IV and elevated plasma levels of N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Mean (SD) duration of follow-up was 17.6 (5.2) months. INTERVENTIONS Dapagliflozin, 10 mg, once daily vs placebo in addition to standard therapy. MAIN OUTCOMES AND MEASURES The primary composite outcome was time to first hospitalization for heart failure, urgent heart failure visit requiring intravenous therapy, or cardiovascular death. The trial results were extrapolated to estimate the projected long-term treatment effects of dapagliflozin over the duration of a patient's lifetime for the primary outcome and the secondary outcome of death from any cause. RESULTS A total of 4744 patients (1109 women [23.4%]; 3635 men [76.6%]) were randomized in DAPA-HF, with a mean (SD) age of 66.3 (10.9) years. The extrapolated mean event-free survival for an individual aged 65 years from a primary composite end point event was 6.2 years for placebo and 8.3 years for dapagliflozin, representing an event-free survival time gain of 2.1 years (95% CI, 0.8-3.3 years; P = .002). When considering death from any cause, mean extrapolated life expectancy for an individual aged 65 years was 9.1 years for placebo and 10.8 years for dapagliflozin, with a gain in survival of 1.7 years (95% CI, 0.1-3.3; P = .03) with dapagliflozin. Similar results were seen when extrapolated across the age range studied. In analyses of subgroups of patients in DAPA-HF, consistent benefits were seen with dapagliflozin on both event-free and overall survival. CONCLUSIONS AND RELEVANCE These findings indicate that dapagliflozin provides clinically meaningful gains in extrapolated event-free and overall survival. These findings may be helpful in communicating the benefits of this treatment to patients with HFrEF. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03036124.
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Effects of canagliflozin on NT-proBNP stratified by left ventricular diastolic function in patients with type 2 diabetes and chronic heart failure: a sub analysis of the CANDLE trial.
Kusunose, K, Imai, T, Tanaka, A, Dohi, K, Shiina, K, Yamada, T, Kida, K, Eguchi, K, Teragawa, H, Takeishi, Y, et al
Cardiovascular diabetology. 2021;(1):186
Abstract
BACKGROUND Identification of the effective subtypes of treatment for heart failure (HF) is an essential topic for optimizing treatment of the disorder. We hypothesized that the beneficial effect of SGLT2 inhibitors (SGLT2i) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) might depend on baseline diastolic function. To elucidate the effects of SGLT2i in type 2 diabetes mellitus (T2DM) and chronic HF we investigated, as a post-hoc sub-study of the CANDLE trial, the effects of canagliflozin on NT-proBNP levels from baseline to 24 weeks, with the data stratified by left ventricular (LV) diastolic function at baseline. METHODS Patients (n = 233) in the CANDLE trial were assigned randomly to either an add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The primary endpoint was a comparison between the two groups of the changes from baseline to 24 weeks in NT-pro BNP levels, stratified according to baseline ventricular diastolic function. RESULTS The change in the geometric mean of NT-proBNP level from baseline to 24 weeks was 0.98 (95% CI 0.89-1.08) in the canagliflozin group and 1.07 (95% CI 0.97-1.18) in the glimepiride group. The ratio of change with canagliflozin/glimepiride was 0.93 (95% CI 0.82-1.05). Responder analyses were used to investigate the response of an improvement in NT-proBNP levels. Although the subgroup analyses for septal annular velocity (SEP-e') showed no marked heterogeneity in treatment effect, the subgroup with an SEP-e' < 4.7 cm/s indicated there was an association with lower NT-proBNP levels in the canagliflozin group compared with that in the glimepiride group (ratio of change with canagliflozin/glimepiride (0.83, 95% CI 0.66-1.04). CONCLUSIONS In the subgroup with a lower LV diastolic function, canagliflozin showed a trend of reduced NT-pro BNP levels compared to that observed with glimepiride. This study suggests that the beneficial effects of canagliflozin treatment may be different in subgroups classified by the severity of LV diastolic dysfunction.
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Effect of atorvastatin versus rosuvastatin on inflammatory biomarkers and LV function in type 2 diabetic patients with dyslipidemia.
Werida, R, Khairat, I, Khedr, NF
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:111179
Abstract
BACKGROUND Statins are potential drugs for decreasing risk of atherosclerotic cardiovascular complications in type 2 diabetic (T2D) patients. PURPOSE To examine the efficacy of both rosuvastatin (ROSUVA) and atorvastatin (ATORVA) on LV function and markers of inflammation in T2D patients with dyslipidemia. METHODS One hundred-sixty T2D patients were assigned to receive either atorvastatin (ATORVA group, n = 80, 40 mg) or rosuvastatin (ROSUVA group, n = 80, 10 mg), daily for 6 months. Blood was collected for biochemical analysis. The prevalence of left ventricular abnormalities was determined by echocardiography and two-dimensional Speckle-Strain to assess Global Longitudinal Strain (GLS). RESULTS ROSUVA vs. ATORVA resulted in significant (p < 0.001) reduction in HbA1c % (9.13 vs 2.35%), LDL-C (22.23% vs. 14.75%), triglycerides (13.56 % vs. 8.21 %), total cholesterol (16.10 % vs. 10.81 %), atherogenic index (18.08. % vs. 10.97%), hs-CRP (23.51 % vs.18.96%), sortilin (33.33 % % vs. 15.08 %), and leptin (31.81 % vs. 23.17 %) but increased adiponectin (97.99 % vs.76.47.1 %) and HDL-C (76.47 % vs. 0.21 %) compared with baseline, respectively. Negative correlations between adiponectin and each of hs-CRP, HbA1c%, total cholesterol, LDL-C, atherogenic index and leptin were found. Also, left ventricular functions were correlated with adiponectin, lipids, HbA1c% and hs-CRP. The areas under receiver operating characteristic curve (AUC) showed that hs-CRP, leptin, sortlin, leptin, and adiponectin were good predictors for cardiovascular events. CONCLUSION ROSUVA is more efficacious in improving lipid profile, atherogenic index and modulation of inflammatory biomarkers in dyslipidemic T2D patients compared with ATROVA. However, both statins are equivalent as cardioprotective agents in dyslipidemic T2D patients.
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Effect of Empagliflozin as an Add-On Therapy on Decongestion and Renal Function in Patients With Diabetes Hospitalized for Acute Decompensated Heart Failure: A Prospective Randomized Controlled Study.
Tamaki, S, Yamada, T, Watanabe, T, Morita, T, Furukawa, Y, Kawasaki, M, Kikuchi, A, Kawai, T, Seo, M, Abe, M, et al
Circulation. Heart failure. 2021;(3):e007048
Abstract
BACKGROUND Empagliflozin reduces the risk of hospitalization for heart failure in patients with type 2 diabetes and cardiovascular disease. We sought to elucidate the effect of empagliflozin as an add-on therapy on decongestion and renal function in patients with type 2 diabetes admitted for acute decompensated heart failure. METHODS The study was terminated early due to COVID-19 pandemic. We enrolled 59 consecutive patients with type 2 diabetes admitted for acute decompensated heart failure. Patients were randomly assigned to receive either empagliflozin add-on (n=30) or conventional glucose-lowering therapy (n=29). We performed laboratory tests at baseline and 1, 2, 3, and 7 days after randomization. Percent change in plasma volume between admission and subsequent time points was calculated using the Strauss formula. RESULTS There were no significant baseline differences in left ventricular ejection fraction and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide), hematocrit, or serum creatinine levels between the 2 groups. Seven days after randomization, NT-proBNP level was significantly lower in the empagliflozin group than in the conventional group (P=0.040), and hemoconcentration (≥3% absolute increase in hematocrit) was more frequently observed in the empagliflozin group than in the conventional group (P=0.020). The decrease in percent change in plasma volume between baseline and subsequent time points was significantly larger in the empagliflozin group than in the conventional group 7 days after randomization (P=0.017). The incidence of worsening renal function (an increase in serum creatinine ≥0.3 mg/dL) did not significantly differ between the 2 groups. CONCLUSIONS In this exploratory analysis, empagliflozin achieved effective decongestion without an increased risk of worsening renal function as an add-on therapy in patients with type 2 diabetes with acute decompensated heart failure. Registration: URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000026315.
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Empagliflozin does not change cardiac index nor systemic vascular resistance but rapidly improves left ventricular filling pressure in patients with type 2 diabetes: a randomized controlled study.
Rau, M, Thiele, K, Hartmann, NK, Schuh, A, Altiok, E, Möllmann, J, Keszei, AP, Böhm, M, Marx, N, Lehrke, M
Cardiovascular diabetology. 2021;(1):6
Abstract
BACKGROUND In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial) treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin significantly reduced heart failure hospitalization (HHF) in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The early separation of the HHF event curves within the first 3 months of the trial suggest that immediate hemodynamic effects may play a role. However, hitherto no data exist on early effects of SGLT2 inhibitors on hemodynamic parameters and cardiac function. Thus, this study examined early and delayed effects of empagliflozin treatment on hemodynamic parameters including systemic vascular resistance index, cardiac index, and stroke volume index, as well as echocardiographic measures of cardiac function. METHODS In this placebo-controlled, randomized, double blind, exploratory study patients with T2D were randomized to empagliflozin 10 mg or placebo for a period of 3 months. Hemodynamic and echocardiographic parameters were assessed after 1 day, 3 days and 3 months of treatment. RESULTS Baseline characteristics were not different in the empagliflozin (n = 22) and placebo (n = 20) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; day 1: 48.4 ± 34.7 g/24 h; p < 0.001) as well as urinary volume (1740 ± 601 mL/24 h to 2112 ± 837 mL/24 h; p = 0.011) already after one day compared to placebo. Treatment with empagliflozin had no effect on the primary endpoint of systemic vascular resistance index, nor on cardiac index, stroke volume index or pulse rate at any time point. In addition, echocardiography showed no difference in left ventricular systolic function as assessed by left ventricular ejections fraction and strain analysis. However, empagliflozin significantly improved left ventricular filling pressure as assessed by a reduction of early mitral inflow velocity relative to early diastolic left ventricular relaxation (E/e') which became significant at day 1 of treatment (baseline: 9.2 ± 2.6; day 1: 8.5 ± 2.2; p = 0.005) and remained apparent throughout the study. This was primarily attributable to reduced early mitral inflow velocity E (baseline: 0.8 ± 0.2 m/s; day 1: 0.73 ± 0.2 m/sec; p = 0.003). CONCLUSIONS Empagliflozin treatment of patients with T2D has no significant effect on hemodynamic parameters after 1 or 3 days, nor after 3 months, but leads to rapid and sustained significant improvement of diastolic function. Trial registration EudraCT Number: 2016-000172-19; date of registration: 2017-02-20 (clinicaltrialregister.eu).