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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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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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The effects of rice bran oil on left ventricular systolic function, cardiometabolic risk factors and inflammatory mediators in men with coronary artery disease: a randomized clinical trial.
Mahdavi-Roshan, M, Salari, A, Ghorbani, Z, Nikpey, Z, Haghighatkhah, M, Fakhr Mousavi, A, Gholipour, M, Pourfarzad, A
Food & function. 2021;(10):4446-4457
Abstract
BACKGROUND/OBJECTIVE In the current study, we aimed to explore the effects of rice bran oil (RBO) in adjunct to conventional medical therapy on left ventricular ejection fraction (LVEF), cardiometabolic risk factors, and inflammatory mediators in male patients with coronary artery disease (CAD). SUBJECTS/METHODS The present randomized controlled trial included 40 men diagnosed with CAD (mean age = 55.76 years) who were randomly allocated into two groups to receive either 30 grams per day of RBO (intervention group) or sunflower oil (control group) plus a standard diet for eight weeks. At the initial visit, demographic and anthropometric data and blood samples were collected. LVEF levels and serum concentrations of lipid profile, glucose, uric acid, hs-CRP, and TNF-α were investigated. RESULTS A total of 37 participants completed the study (n = 18 in the intervention group, n = 19 in the control group). Analysis of covariance (ANCOVA) adjusted for baseline values, age and body mass index revealed that RBO significantly improved LVEF (51.34%) and reduced triglyceride (125.01 mg dl-1), blood sugar (110.4 mg dl-1), total cholesterol (123.01 mg dl-1) and low density lipoprotein (56.88 mg dl-1) levels compared to sunflower oil ((45.56%), (155.93 mg dl-1), (128.94 mg dl-1), (163.93 mg dl-1) and (83.79 mg dl-1), respectively) following a 8-week trial (P-values < 0.05). Additionally, the test demonstrated that RBO consuming patients had significantly lower levels of serum uric acid (4.60 mg dl-1), TNF-α (6.99 ng L-1) and hs-CRP (2.11 mg L-1) compared to the control group ((5.92 mg dl-1), (15.23 ng L-1), (4.47 mg L-1), respectively) (P-value < 0.05). However, no significant changes were found regarding weight, blood pressure or serum HDL levels throughout the trial. CONCLUSION Consumption of 30 grams per day RBO within a standard diet could be considered an effective non-pharmacological approach in improving LVEF, cardiometabolic risk factors, and inflammatory state in CAD. However, future trials are recommended for more clarification.
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Early benefits of bariatric surgery on subclinical cardiac function: Contribution of visceral fat mobilization.
Piché, ME, Clavel, MA, Auclair, A, Rodríguez-Flores, M, O'Connor, K, Garceau, P, Rakowski, H, Poirier, P
Metabolism: clinical and experimental. 2021;:154773
Abstract
AIMS: We explored the early effects of bariatric surgery on subclinical myocardial function in individuals with severe obesity and preserved left ventricular (LV) ejection fraction. METHODS Thirty-eight patients with severe obesity [body mass index (BMI) ≥35 kg/m2] and preserved LV ejection fraction (≥50%) who underwent bariatric surgery (biliopancreatic diversion with duodenal switch [BPD-DS]) (Surgery group), 19 patients with severe obesity managed with usual care (Medical group), and 18 age and sex-matched non-obese controls (non-obese group) were included. Left ventricular global longitudinal strain (LV GLS) was evaluated with echocardiography speckle tracking imaging. Abnormal myocardial function was defined as LV GLS <18%. RESULTS Age of the participants was 42 ± 11 years with a BMI of 48 ± 8 kg/m2 (mean ± standard deviation); 82% were female. The percentage of total weight loss at 6 months after bariatric surgery was 26.3 ± 5.2%. Proportions of hypertension (61 vs. 30%, P = 0.0005), dyslipidemia (42 vs. 5%, P = 0.0001) and type 2 diabetes (40 vs. 13%, P = 0.002) were reduced postoperatively. Before surgery, patients with obesity displayed abnormal subclinical myocardial function vs. non-obese controls (LV GLS, 16.3 ± 2.5 vs. 19.6 ± 1.7%, P < 0.001). Six months after bariatric surgery, the subclinical myocardial function was comparable to non-obese (LV GLS, 18.2 ± 1.9 vs. 19.6 ± 1.7%, surgery vs. non-obese, P = NS). On the contrary, half of individuals with obesity managed medically worsened their myocardial function during the follow-up (P = 0.002). Improvement in subclinical myocardial function following bariatric surgery was associated with changes in abdominal visceral fat (r = 0.43, P < 0.05) and inflammatory markers (r = 0.45, P < 0.01), whereas no significant association was found with weight loss or change in insulin sensitivity (HOMA-IR) (P > 0.05). In a multivariate model, losing visceral fat mass was independently associated with improved subclinical myocardial function. CONCLUSIONS Bariatric surgery was associated with significant improvement in the metabolic profile and in subclinical myocardial function. Early improvement in subclinical myocardial function following bariatric surgery was related to a greater mobilization of visceral fat depot, linked to global fat dysfunction and cardiometabolic morbidity.
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Effects of Metformin on Left Ventricular Size and Function in Hypertensive Patients with Type 2 Diabetes Mellitus: Results of a Randomized, Controlled, Multicenter, Phase IV Trial.
Ono, K, Wada, H, Satoh-Asahara, N, Inoue, H, Uehara, K, Funada, J, Ogo, A, Horie, T, Fujita, M, Shimatsu, A, et al
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2020;(3):283-293
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BACKGROUND Metformin is the most widely used oral antihyperglycemic agent for patients with type 2 diabetes mellitus (T2DM). Despite the possible benefits of metformin on diabetes mellitus (DM) and heart failure (HF), acute or unstable HF remains a precaution for its use. OBJECTIVE The aim of the present prospective randomized controlled trial was to assess whether metformin treatment has beneficial effects on patients with T2DM with hypertension without overt HF. METHODS A total of 164 patients (92 males, 72 females; median age 66 years) were included in this study. Patients with T2DM with a history of hypertension were randomized 1:1 to treatment for 1 year with either metformin (metformin-treated group) or other hypoglycemic agents (control group). The primary endpoints were changes in brain natriuretic peptide (BNP) levels, left ventricular (LV) mass index, and indicators of LV diastolic function. We also evaluated changes in both clinical findings and blood laboratory examination data. RESULTS We observed no significant changes between baseline and 1-year post-treatment in LV mass index, BNP levels, or E/e' (early diastolic transmitral flow velocity/early diastolic mitral annular velocity; an indicator of LV diastolic function) in either the metformin-treated (n = 83) or the control (n = 81) groups. The metformin-treated group had a significant reduction of body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C), but the control group did not. We determined that renal function, including serum creatinine and estimated glomerular filtration rate, deteriorated significantly in the control group but not in the metformin-treated group. CONCLUSION LV mass and diastolic function were not affected after 1 year of metformin treatment in patients with T2DM. However, we observed benefits in terms of reductions in both BMI and LDL-C levels and preservation of renal function. TRIAL REGISTRATION UMIN000006504. Registered 7 October 2011.
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Efficacy and safety of sacubitril/valsartan compared with enalapril in patients with chronic heart failure and reduced ejection fraction: Results from PARADIGM-HF India sub-study.
Jain, AR, Aggarwal, RK, Rao, NS, Billa, G, Kumar, S
Indian heart journal. 2020;(6):535-540
Abstract
OBJECTIVES To determine efficacy and safety of sacubitril/valsartan compared with enalapril in Indian patients of PARADIGM-HF trial. METHODS A randomized, double-blind, active-controlled, phase III sub-study (NCT01035255) was conducted between April 2010 and May 2014. Patients with chronic heart failure (HF), aged >18 years with left ventricular ejection fraction ≤40% were randomized (1:1) to receive either sacubitril/valsartan 200 mg twice-daily or enalapril 10 mg twice-daily. The primary endpoint was to compare efficacy of sacubitril/valsartan to enalapril in delaying time-to-first occurrence of the composite endpoint (cardiovascular [CV] death or HF hospitalization). RESULTS The trial was stopped after a median follow-up of 27 months, because the boundary for benefit with sacubitril/valsartan had crossed. Among 637 Indian patients in PARADIGM-HF (sacubitril/valsartan, n = 322 and enalapril, n = 315), the primary outcome, CV death, and the first hospitalization for HF occurred in 21.81% and 24.76% (HR 0.89; 95% CI, 0.646-1.231), 17.45% and 20.63% (HR 0.87; 95% CI, 0.605-1.236), and 7.48% and 9.52% (HR 0.78; 95% CI, 0.461-1.350) patients in the sacubitril/valsartan and enalapril group, respectively. The all-cause mortality (19.0% vs. 21.9%) and adverse events (78.4% vs. 82.2%) were comparatively lower in the sacubitril/valsartan than enalapril group. No significant difference was seen between the benefits of treatment in Indian and the total PARADIGM-HF cohort (p value for interaction >0.05). CONCLUSION Results support the use of sacubitril/valsartan in Indian patients with chronic HF with reduced ejection fraction with treatment benefits similar to global PARADIGM-HF cohort.
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Benefits of 1-Year Lifestyle Modification Program on Exercise Capacity and Diastolic Function Among Coronary Artery Disease Men With and Without Type 2 Diabetes.
Piché, ME, Poirier, P, Marette, A, Mathieu, P, Lévesque, V, Bibeau, K, Larose, É, Després, JP
Metabolic syndrome and related disorders. 2019;(3):149-159
Abstract
BACKGROUND To assess the benefits of a 1-year lifestyle modification program on exercise capacity and diastolic function in men with left ventricular (LV) diastolic dysfunction (LVDD) and coronary artery disease (CAD), according to glucose tolerance status. METHODS Fifty-three men (62 ± 8 years; BMI: 27.3 ± 3.5 kg/m2) with LVDD and CAD were enrolled in a 1-year lifestyle modification program based on dietary management and increased physical activity. Patients were classified by using a 75 grams oral glucose tolerance test as having normal glucose tolerance (n = 16), prediabetes (n = 23), or type 2 diabetes mellitus (T2DM) (n = 14). Cardiac morphology and function, visceral fat, and cardiac fat depots were measured using magnetic resonance imaging, whereas exercise capacity [cardiorespiratory fitness (CRF)] (VO2peak) was assessed with a maximal treadmill test. RESULTS The 1-year lifestyle modification program was associated with reductions in body weight, and visceral and cardiac fat levels (all P < 0.05). CRF increased by 13% (24.9 ± 4.1 vs. 28.2 ± 4.8 mL O2/kg/min, P < 0.0001). Moreover, half of patients (53%) improved LV diastolic function in response to the lifestyle intervention. Multiple regression analyses revealed that age (partial R2 = 26.9, P < 0.0001) and presence of T2DM (partial R2 = 5.9, P = 0.04) were the stronger predictors of change in diastolic function, while favorable change in LV remodeling index was the best predictor of improvement in LV diastolic function after the lifestyle intervention (R2 = 21.9, P = 0.002). CONCLUSIONS Irrespective of glucose tolerance status, a 1-year lifestyle modification program in men with LVDD and CAD is associated with significant improvements in exercise capacity and LV diastolic function in more than half of patients.
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Impact of dapagliflozin on left ventricular diastolic function of patients with type 2 diabetic mellitus with chronic heart failure.
Soga, F, Tanaka, H, Tatsumi, K, Mochizuki, Y, Sano, H, Toki, H, Matsumoto, K, Shite, J, Takaoka, H, Doi, T, et al
Cardiovascular diabetology. 2018;(1):132
Abstract
BACKGROUND The objective of this study was to investigate the impact of sodium glucose cotransporter type 2 (SGLT2) inhibitors on left ventricular (LV) diastolic function of type 2 diabetes mellitus (T2DM) patients with heart failure (HF). METHODS This trial was a prospective multicenter study of 58 T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least one antidiabetic drugs other than SGLT2 inhibitors started the administration of 5 mg/day of dapagliflozin. The physical examinations, blood tests, and echocardiography were performed at baseline and 6 months after administration of dapagliflozin. The primary endpoint was defined as a change in mitral inflow E and mitral e' annular velocities (E/e') between baseline and 6 months after the administration of dapagliflozin. The secondary end points consisted of a change in brain natriuretic peptide (BNP), LV mass index (LVMI) and left atrial volume index (LAVI). RESULTS E/e' significantly decreased from 9.3 to 8.5 cm/s (p = 0.020) 6 months after administration of dapagliflozin. LAVI and LVMI significantly decreased from 31 to 26 mL/m2 (p = 0.001), and from 75.0 to 67.0 g/m2 (p < 0.001), respectively, 6 months after administration of dapagliflozin. No significant change was observed in BNP (from 27.9 to 28.9 pg/mL; p = 0.132) 6 months after administration of dapagliflozin, except for a significant decrease from 168.8 to 114.3 pg/mL (p = 0.012) in patients with BNP ≥ 100 pg/mL. CONCLUSION This prospective multicenter trial showed the beneficial effect of SGLT2 inhibitors on LV diastolic functional parameters for T2DM patients with HF. Our findings may thus offer a new insight into the management of T2DM patients. Trial registration UMIN000019789, Registered 28 September 2014, Date of registration: 11/14/2015, Date of enrolment of the first participant to the trial: 6/15/2016, Date of enrolment of the last participant to the trial: 12/9/2017.
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The combined effect of subcutaneous granulocyte- colony stimulating factor and myocardial contrast echocardiography with intravenous infusion of sulfur hexafluoride on post-infarction left ventricular function, the RIGENERA 2.0 trial: study protocol for a randomized controlled trial.
Leone, AM, D'Amario, D, Teofili, L, Basile, E, Cannata, F, Graziani, F, Marzilli, M, Russo, AM, Tarantini, G, Ceconi, C, et al
Trials. 2016;:97
Abstract
BACKGROUND Several clinical trials and recent meta-analyses have demonstrated that administration of recombinant human granulocyte-colony stimulating factor (G-CSF) is safe and, only in patients with large acute myocardial infarction (AMI), is associated with an improvement in left ventricular ejection fraction. Moreover, the mobilization and engraftment of the bone marrow-derived cells may differ significantly among patients, interfering with the restoration of left ventricular function after treatment. Therefore, the clinical potential application of the G-CSF has not yet been fully elucidated. METHODS/DESIGN The RIGENERA 2.0 trial is a multicenter, phase II, placebo-controlled, randomized, open-label, with blinded evaluation of endpoints (PROBE) trial in which 120 patients with an acute ST-elevation myocardial infarction (STEMI) undergoing successful revascularization but with residual myocardial dysfunction will be enrolled. In cases where there is a left ventricular ejection fraction (LVEF) ≤ 45% the patient will be electronically randomized (1:1 ratio) to receive either subcutaneous recombinant human G-CSF (group 1) or placebo (group 2) both added on top of optimal standard of care. Both groups will undergo myocardial contrast echocardiography with intravenous infusion of sulfur hexafluoride (MCE) whilst undergoing the echocardiogram. The primary efficacy endpoint is the evaluation of the LVEF at 6 months after AMI assessed by cardiac magnetic resonance. Secondary efficacy endpoints are the evaluation of LVEF at 6 months after AMI assessed by echocardiography, left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) assessed by cardiac magnetic resonance and echocardiography at 6 months, together with the incidence of major adverse clinical events (MACE) defined as death, myocardial infarction, sustained cardiac arrhythmias, cardiogenic shock, stroke and re-hospitalization due to heart failure at 1 year. DISCUSSION The RIGENERA 2.0 trial will test whether G-CSF administration and MCE, through the enhancement of the bone marrow-derived cells homing in the myocardium, determines an improvement in regional and global contractile function, myocardial perfusion and infarct extension in patients with large AMI. The results of the present study are expected to envision routine clinical use of this safe, affordable and reproducible approach in patients with successful revascularization after AMI. TRIAL REGISTRATION ClinicalTrials.gov: NCT02502747 (29 June 2015); EudraCT: 2015-002189-21 (10 July 2015).
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Determinants of Improvement In Left Ventricular Diastolic Function Following a 1-Year Lifestyle Modification Program in Abdominally Obese Men with Features of the Metabolic Syndrome.
Leclerc, J, Arsenault, M, Després, JP, Brassard, P, Gaudreault, V, Bergeron, J, Alméras, N, Tremblay, A, Auclair, A, Ross, MK, et al
Metabolic syndrome and related disorders. 2016;(10):483-491
Abstract
BACKGROUND Abdominal obesity and presence of the metabolic syndrome (MetS) are associated with cardiac abnormalities. Among those, left ventricular diastolic dysfunction (LVDD) is the most frequently encountered in clinical practice. Few studies evaluated the reversibility of LVDD by an approach promoting lifestyle modifications in abdominally obese subjects with MetS. METHODS We assessed the impact of a 1-year lifestyle modification program combining nutritional and physical activity counseling on LVDD and metabolic profile of abdominally obese men with MetS. Echocardiograms, oral glucose tolerance test, lipids profile, dual energy X-ray absorptiometry, computed tomography scans (visceral obesity assessment), heart rate variability (HRV), as well as maximal and submaximal exercise tests were performed in participants before and after a 1-year program combining healthy eating and a physical activity/exercise program. RESULTS Fifty-one abdominally obese men participated in this study. At baseline, 86% of the participants had LVDD (n = 44). After the 1-year program, LVDD improved in 57% of participants (n = 29, P < 0.0001). All metabolic, adiposity, and exercise tolerance measures improved from baseline (P < 0.0001), but were not associated with improvement in LVDD. Participants who improved LVDD had better exercise performance at baseline. Exercise tolerance during the submaximal exercise test, parasympathetic cardiac autonomic activity, and fasting insulin predicted 50% of LVDD improvements. CONCLUSIONS There was a significant improvement in LVDD after a 1-year lifestyle intervention program in abdominally obese men with MetS, such an improvement being associated with increased exercise tolerance, enhanced HRV, and reduced insulin levels.