Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Early- and mid-term outcomes after transcatheter aortic valve implantation. Data from a single-center registry

Introduction : Transcatheter aortic valve implantation (TAVI) is a less invasive treatment option for elderly, high-risk patients with symptomatic severe aortic stenosis (AS) than aortic valve replacement. More importantly, TAVI improves survival and quality of life as compared to medical treatment in inoperable patients. Aim: To assess early- and mid-term clinical outcomes after TAVI. Material and methods: All consecutive high-risk patients with severe symptomatic AS undergoing TAVI from November 2008 to August 2014 were enrolled. The clinical and procedural characteristics, as well as clinical outcomes including mortality during 12-month follow-up, were assessed. Results : A total of 101 consecutive patients underwent TAVI for native aortic valve stenosis (100%). Patients were elderly, with a median age of 81.0 (76.0–84.0) years, 60.4% were female and 83.2% presented with NYHA III/IV. Median baseline EuroSCORE I and STS scores were 14.0 (10.0–22.5)% and 12.0 (5.0–24.0)%, respectively. The main periprocedural and in-hospital complications were minor vascular complications, bleeding requiring blood transfusions, and the need for a permanent pacemaker. In-hospital, 30-day, 6-month and 12-month mortality rates were 6.9%, 10.9%, 15.8% and 17.8%, respectively. Conclusions : A mortality rate of < 20% after 12 months seems acceptable given the high-risk population enrolled

Balloon aortic valvuloplasty for severe aortic stenosis may reduce mitral regurgitation in mid-term follow-up

INTRODUCTION: Mitral regurgitation (MR) is a frequent complication in patients with severe aortic stenosis (AS). MATERIAL AND METHODS: Echocardiographic assessment of MR was performed at baseline, at 30 days and at 6 months after balloon aortic valvuloplasty (BAV). RESULTS: Data of 271 patients were included in our final analysis, of which 21.2% (n = 85) had at least moderate MR at baseline (in 19 (22.3%) subjects MR was diagnosed as primary). Both groups showed similar severity of AS, but patients in the MR group had a greater left ventricle (LV) size (p = 0.003 for LVESD, p = 0002 for LVEDD) and slightly lower LV ejection fraction (p = 0.04). Mitral regurgitation parameters significantly improved both at 30 days and 6 months after BAV in the MR group (MR jet area: 7.2 (4.5–9.9) vs. 3.6 (2.3–7.2) cm(2), and 7.2 (4.5–9.9) vs. 3.2 (2.1–6.7) cm(2); %MR/left atrial area 34.5 (23.4–42.7) vs. 17.5 (9.3–29.5) and 34.5 (23.4–42.7) vs. 14.5 (8.3–24.5), p < 0.001 for all). In multivariate logistic regression analysis, the change at 30 days, from baseline, in the LVESD (OR = 1.87; 95% CI: 1.23–2.87; p < 0.001) and LVEF (OR = 0.95; 95% CI: 0.87–1.01; p < 0.001); MR jet area (OR = 2.2, 95% CI: 1.5–4.6; p < 0.001) and the presence of primary MR (OR = 3.2, 95% CI: 1.04–5.98; p < 0.001) were retained as independent predictors of significant persisting MR at 6 months. CONCLUSIONS: Balloon aortic valvuloplasty may reduce MR in mid-term follow-up. Predictors of persistent MR at 6 months after BAV included an increase of LVESD and MR jet area and decrease of LVEF at 30 days

Diabetes Mellitus and Prevention of Late Myocardial Infarction After Coronary Stenting in the Randomized Dual Antiplatelet Therapy Study

BACKGROUND: Patients with diabetes mellitus (DM) are at high risk for recurrent ischemic events after coronary stenting. We assessed the effects of continued thienopyridine among patients with DM participating in the Dual Antiplatelet Therapy (DAPT) Study as a prespecified analysis. METHODS AND RESULTS: After coronary stent placement and 12 months treatment with open-label thienopyridine plus aspirin, 11 648 patients free of ischemic or bleeding events and who were medication compliant were randomly assigned to continued thienopyridine or placebo, in addition to aspirin, for 18 more months. After randomization, patients with DM (n=3391), in comparison with patients without DM (n=8257), had increased composite outcome of death, myocardial infarction (MI), or stroke (6.8% versus 4.3%, P CONCLUSIONS: In patients with DM, continued thienopyridine beyond 1 year after coronary stenting is associated with reduced risk of MI, although this benefit is attenuated in comparison with patients without DM. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00977938

Stent Thrombosis in Drug-Eluting or Bare-Metal Stents in Patients Receiving Dual Antiplatelet Therapy

OBJECTIVES This study sought to compare rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE) (composite of death, myocardial infarction, or stroke) after coronary stenting with drug-eluting stents (DES) versus bare-metal stents (BMS) in patients who participated in the DAPT (Dual Antiplatelet Therapy) study, an international multicenter randomized trial comparing 30 versus 12 months of dual antiplatelet therapy in subjects undergoing coronary stenting with either DES or BMS. BACKGROUND Despite antirestenotic efficacy of coronary DES compared with BMS, the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Many clinicians perceive BMS to be associated with fewer adverse ischemic events and to require shorter-duration dual antiplatelet therapy than DES. METHODS Prospective propensity-matched analysis of subjects enrolled into a randomized trial of dual antiplatelet therapy duration was performed. DES- and BMS-treated subjects were propensity-score matched in a many-to-one fashion. The study design was observational for all subjects 0 to 12 months following stenting. A subset of eligible subjects without major ischemic or bleeding events were randomized at 12 months to continued thienopyridine versus placebo; all subjects were followed through 33 months. RESULTS Among 10,026 propensity-matched subjects, DES-treated subjects (n = 8,308) had a lower rate of stent thrombosis through 33 months compared with BMS-treated subjects (n = 1,718, 1.7% vs. 2.6%; weighted risk difference -1.1%, p = 0.01) and a noninferior rate of MACCE (11.4% vs. 13.2%, respectively, weighted risk difference -1.8%, p = 0.053, noninferiority p < 0.001). CONCLUSIONS DES-treated subjects have long-term rates of stent thrombosis that are lower than BMS-treated subjects. (The Dual Antiplatelet Therapy Study [DAPT study]; NCT00977938)

Antiplatelet therapy duration following bare metal or drug-eluting coronary stents: the dual antiplatelet therapy randomized clinical trial

IMPORTANCE Despite antirestenotic efficacy of coronary drug-eluting stents (DES) compared with bare metal stents (BMS), the relative risk of stent thrombosis and adverse cardiovascular events is unclear. Although dual antiplatelet therapy (DAPT) beyond 1 year provides ischemic event protection after DES, ischemic event risk is perceived to be less after BMS, and the appropriate duration of DAPT after BMS is unknown. OBJECTIVE To compare (1) rates of stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE; composite of death, myocardial infarction, or stroke) after 30 vs 12 months of thienopyridine in patients treated with BMS taking aspirin and (2) treatment duration effect within the combined cohorts of randomized patients treated with DES or BMS as prespecified secondary analyses. DESIGN, SETTING, AND PARTICIPANTS International, multicenter, randomized, double-blinded, placebo-controlled trial comparing extended (30-months) thienopyridine vs placebo in patients taking aspirin who completed 12 months of DAPT without bleeding or ischemic events after receiving stents. The study was initiated in August 2009 with the last follow-up visit in May 2014. INTERVENTIONS Continued thienopyridine or placebo at months 12 through 30 after stent placement, in 11,648 randomized patients treated with aspirin, of whom 1687 received BMS and 9961 DES. MAIN OUTCOMES AND MEASURES Stent thrombosis, MACCE, and moderate or severe bleeding. RESULTS Among 1687 patients treated with BMS who were randomized to continued thienopyridine vs placebo, rates of stent thrombosis were 0.5% vs 1.11% (n = 4 vs 9; hazard ratio [HR], 0.49; 95% CI, 0.15-1.64; P = .24), rates of MACCE were 4.04% vs 4.69% (n = 33 vs 38; HR, 0.92; 95% CI, 0.57-1.47; P = .72), and rates of moderate/severe bleeding were 2.03% vs 0.90% (n = 16 vs 7; P = .07), respectively. Among all 11,648 randomized patients (both BMS and DES), stent thrombosis rates were 0.41% vs 1.32% (n = 23 vs 74; HR, 0.31; 95% CI, 0.19-0.50; P < .001), rates of MACCE were 4.29% vs 5.74% (n = 244 vs 323; HR, 0.73; 95% CI, 0.62-0.87; P < .001), and rates of moderate/severe bleeding were 2.45% vs 1.47% (n = 135 vs 80; P < .001). CONCLUSIONS AND RELEVANCE Among patients undergoing coronary stent placement with BMS and who tolerated 12 months of thienopyridine, continuing thienopyridine for an additional 18 months compared with placebo did not result in statistically significant differences in rates of stent thrombosis, MACCE, or moderate or severe bleeding. However, the BMS subset may have been underpowered to identify such differences, and further trials are suggested. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00977938

Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure

BACKGROUND The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016 -002299-28.)