Clinical outcomes associated with proton pump inhibitor use among clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial infarction

We examined clinical outcomes with proton pump inhibitors (PPI) use within CYP2C19 genotype groups during clopidogrel treatment following acute myocardial infarction (AMI). 2062 patients were genotyped for CYP2C19*2 and *17 variants in TRIUMPH. 12 month clinical outcomes were analyzed among patients discharged on clopidogrel within CYP2C19*2 carrier, CYP2C19*17 carrier, and CYP2C19*1 homozygote genotype groups. PPI use was not associated with a difference in mortality. Among clopidogrel-treated Caucasians following AMI, PPI use was associated with a significantly higher rate of cardiac rehospitalization (HR 1.62, 95% CI 1.19-2.19; P=0.002) compared with no PPI use. PPI users who were carriers of the CYP2C19*17 variant experienced significantly higher rates of cardiac rehospitalization (HR 2.05, 95% CI 1.26-3.33; P=0.003), carriers of the CYP2C19*2 variant had a trend toward increased 1-year cardiac rehospitalization (HR 1.69, 95% CI 0.95-2.99; P=0.07), while no significant differences were observed among CYP2C19*1 homozygotes. These results indicate that the risks associated with PPI use among clopidogrel-treated Caucasian post-MI patients are impacted by CYP2C19 genotype, and suggest knowledge of genotype may be useful for personalizing PPI use among patients following AMI to reduce rehospitalization.J P Depta, P A Lenzini, D E Lanfear, T Y Wang, J A Spertus, R G Bach and S Cresc

Adrenergic-pathway gene variants influence beta-blockerrelated outcomes after acute coronary syndrome in a race-specific manner

Overcoming racial differences in acute coronary syndrome (ACS) outcomes is a strategic goal for U.S. health care. Genetic polymorphisms in the adrenergic pathway seem to explain some outcome differences by race in other cardiovascular diseases treated with β-adrenergic receptor blockade (BB). Whether these genetic variants are associated with survival among ACS patients treated with BB, and if this differs by race, is unknown.β-adrenergic receptor blockade after ACS is a measure of quality care, but the effectiveness across racial groups is less clear.A prospective cohort of 2,673 ACS patients (2,072 Caucasian; 601 African-American) discharged on BB from 22 U.S. hospitals were followed for 2 years. Subjects were genotyped for polymorphisms in ADRB1, ADRB2, ADRA2C, and GRK5. We used proportional hazards regression to model the effect of genotype on mortality, stratified by race and adjusted for baseline factors.The overall 2-year mortality rate was 7.5% for Caucasians and 16.7% for African Americans. The prognosis associated with different genotypes in these BB-treated patients differed by race. In Caucasians, ADRA2C 322-325 deletion carriers had significantly lower mortality as compared with homozygous individuals lacking the deletion (hazard ratio: 0.46; confidence interval [CI]: 0.21 to 0.99; p = 0.047; race × genotype interaction p = 0.053). In African Americans, the ADRB2 16R allele was associated with significantly increased mortality (hazard ratio for RG vs. GG: 2.10; CI: 1.14 to 3.86; RR vs. GG: 2.65; CI: 1.38 to 5.08; p = 0.013; race × genotype interaction p = 0.096).Adrenergic pathway polymorphisms are associated with mortality in ACS patients receiving BB in a race-specific manner. Understanding the mechanism by which different genes impact post-ACS mortality differently in Caucasians and African Americans might illuminate opportunities to improve BB therapy in these groups.Sharon Cresci, Gerald W. Dorn, Philip G. Jones, Amber L. Beitelshees, Allie Y. Li ... John Spertus ... et al

Insulin resistance is associated with significant clinical atherosclerosis in nondiabetic patients with acute myocardial infarction

The prevalence of insulin resistance (IR) is increasing worldwide because of increasing age, obesity, and physical inactivity. Emerging evidence supports a direct proatherogenic effect of IR on the coronary vasculature, but the relation between IR and angiographic atherosclerosis in a real-world clinical setting is uncertain. In this work, we assessed whether IR is independently associated with clinically significant angiographic atherosclerosis in nondiabetic individuals.We examined the association between IR and the extent of coronary atherosclerosis determined by angiography in 1073 nondiabetic patients surviving acute myocardial infarction. Patients were divided into quartiles on the basis of the homeostasis model assessment grading of IR, and associations between IR and multivessel coronary artery disease, defined as ≥ 2 arteries with ≥ 70% stenosis (or ≥ 50% left main stenosis), were analyzed in bivariate and multivariable modeling. Overall, the cohort had a median age of 56 years; 28.9% women and 21.8% nonwhite. The crude prevalence of multivessel coronary artery disease was 37.8%, 42.3%, 47.2%, and 48.0% for homeostasis model assessment grading of IR quartiles 1, 2, 3, and 4, respectively (P(trend) = 0.009). In multivariable modeling, compared with quartile 1, both quartile 3 (relative risk [95% confidence interval], 1.31 [1.07-1.60]) and quartile 4 (1.29 [1.03-1.60]) were independently associated with multivessel coronary artery disease. Covariates in the model included patient demographic and clinical characteristics and metabolic factors (low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglyceride, glycosylated hemoglobin, and high-sensitivity C-reactive protein).We demonstrate an independent association between IR and multivessel coronary artery disease in nondiabetic postmyocardial infarction patients. Our findings strengthen the experimental evidence for a direct atherogenic effect of IR independent of glucose control and other components of the metabolic syndrome.Wassef Karrowni, Yan Li, Philip G. Jones, Sharon Cresci, Mouin S. Abdallah ... John A. Spertus ... et al

Cause of Death in Patients With Acute Heart Failure: Insights From RELAX-AHF-2

Objectives: This study sought to better understand the discrepant results of 2 trials of serelaxin on acute heart failure (AHF) and short-term mortality after AHF by analyzing causes of death of patients in the RELAX-AHF-2 (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF-2) trial. Background: Patients with AHF continue to suffer significant short-term mortality, but limited systematic analyses of causes of death in this patient population are available. Methods: Adjudicated cause of death of patients in RELAX-AHF-2, a randomized, double-blind, placebo-controlled trial of serelaxin in patients with AHF across the spectrum of ejection fraction (EF), was analyzed. Results: By 180 days of follow-up, 11.5% of patients in RELAX-AHF-2 died, primarily due to heart failure (HF) (38% of all deaths). Unlike RELAX-AHF, there was no apparent effect of treatment with serelaxin on any category of cause of death. Older patients (≥75 years) had higher rates of mortality (14.2% vs. 8.8%) and noncardiovascular (CV) death (27% vs. 19%) compared to younger patients. Patients with preserved EF (≥50%) had lower rates of HF-related mortality (30% vs. 40%) but higher non-CV mortality (36% vs. 20%) compared to patients with reduced EF. Conclusions: Despite previous data suggesting benefit of serelaxin in AHF, treatment with serelaxin was not found to improve overall mortality or have an effect on any category of cause of death in RELAX-AHF-2. Careful adjudication of events in the serelaxin trials showed that older patients and those with preserved EF had fewer deaths from HF or sudden death and more deaths from other CV causes and from noncardiac causes. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778) © 2020 American College of Cardiology Foundatio

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 being 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 (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non-white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N-terminal pro-B-type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC-HF randomized patients representative of recent heart failure 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. © 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology

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.). Copyright © 2020 Massachusetts Medical Society