A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Chronic oral study of myosin activation to increase contractility in heart failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial

Summary: Background: Impaired contractility is a fundamental abnormality in heart failure with reduced ejection fraction (HFrEF). We evaluated the pharmacokinetics of chronic therapy with the cardiac myosin activator omecamtiv mecarbil as well as its effect on cardiac function and structure in such patients. Methods: In this randomised, parallel-group, double-blind study, 448 patients from 87 sites in 13 countries with stable, symptomatic chronic heart failure and left ventricular ejection fraction ≤40% were randomly assigned (1:1:1) using an interactive web response system to oral omecamtiv mecarbil (25 mg twice daily; or 25 mg twice daily with pharmacokinetic-guided uptitration to 50 mg twice daily, PK-titration group) or placebo for 20 weeks. The primary endpoint was the maximal omecamtiv mecarbil plasma concentration (Cmax); secondary endpoints were changes from baseline in cardiac function and dimensions, heart rate and NT-proBNP at week 20. (ClinicalTrials.gov, NCT01786512) Findings: In patients enrolled from March 17, 2014 through March 5, 2015, Cmax (mean ± SD) at 12 weeks was 200±71 and 318±129 ng/mL in the 25 mg (n = 147) and PK-titration (n = 141) groups, respectively. Differences were seen in all secondary endpoints by 20 weeks in the PK titration group (n = 149) compared to placebo (n = 149): systolic ejection time [least square mean difference (95% CI); +25 (18, 32) msec, p<0·0001], stroke volume [+3·6 (0·5, 6·7) mL, p=0·0217], left ventricular end-systolic and end-diastolic dimensions [ 1·8 (-2·9, -0·6) mm, p=0·0027; 1·3 (-2·3, 0·3) mm, p=0·0128, respectively], heart rate [ 3·0 (-5·1, -0·8) bpm, p=0·0070] and NT-proBNP [ 970 (-1672, -268) pg/mL, p=0·0069). The maximum changes from baseline in plasma troponin-I concentrations were greater in patients assigned to omecamtiv mecarbil [PK titration: 0·020 ng/mL, (0·005, 0·038); median (Q1, Q3), p<0·0001] than placebo [0·010 ng/mL (0·000, 0·020)]. No important differences in adverse clinical events were observed. Interpretation: In patients with chronic HFrEF, pharmacokinetic-guided dosing of omecamtiv mecarbil achieved plasma concentrations associated with improvements in cardiac performance and ventricular dimensions

One-Year Outcomes after PCI Strategies in Cardiogenic Shock.

BACKGROUND Among patients with acute myocardial infarction, cardiogenic shock, and multivessel coronary artery disease, the risk of a composite of death from any cause or severe renal failure leading to renal-replacement therapy at 30 days was found to be lower with percutaneous coronary intervention (PCI) of the culprit lesion only than with immediate multivessel PCI. We evaluated clinical outcomes at 1 year. METHODS We randomly assigned 706 patients to either culprit-lesion-only PCI or immediate multivessel PCI. The results for the primary end point of death or renal-replacement therapy at 30 days have been reported previously. Prespecified secondary end points at 1 year included death from any cause, recurrent myocardial infarction, repeat revascularization, rehospitalization for congestive heart failure, the composite of death or recurrent infarction, and the composite of death, recurrent infarction, or rehospitalization for heart failure. RESULTS As reported previously, at 30 days, the primary end point had occurred in 45.9% of the patients in the culprit-lesion-only PCI group and in 55.4% in the multivessel PCI group (P=0.01). At 1 year, death had occurred in 172 of 344 patients (50.0%) in the culprit-lesion-only PCI group and in 194 of 341 patients (56.9%) in the multivessel PCI group (relative risk, 0.88; 95% confidence interval [CI], 0.76 to 1.01). The rate of recurrent infarction was 1.7% with culprit-lesion-only PCI and 2.1% with multivessel PCI (relative risk, 0.85; 95% CI, 0.29 to 2.50), and the rate of a composite of death or recurrent infarction was 50.9% and 58.4%, respectively (relative risk, 0.87; 95% CI, 0.76 to 1.00). Repeat revascularization occurred more frequently with culprit-lesion-only PCI than with multivessel PCI (in 32.3% of the patients vs. 9.4%; relative risk, 3.44; 95% CI, 2.39 to 4.95), as did rehospitalization for heart failure (5.2% vs. 1.2%; relative risk, 4.46; 95% CI, 1.53 to 13.04). CONCLUSIONS Among patients with acute myocardial infarction and cardiogenic shock, the risk of death or renal-replacement therapy at 30 days was lower with culprit-lesion-only PCI than with immediate multivessel PCI, and mortality did not differ significantly between the two groups at 1 year of follow-up. (Funded by the European Union Seventh Framework Program and others; CULPRIT-SHOCK ClinicalTrials.gov number, NCT01927549 .)

Clinical Outcomes According to ECG Presentations in Infarct-Related Cardiogenic Shock in the Culprit Lesion Only PCI vs Multivessel PCI in Cardiogenic Shock Trial.

BACKGROUND The impact of ECG presentations of acute myocardial infarction (AMI) in cardiogenic shock is unknown. RESEARCH QUESTION In myocardial infarction with cardiogenic shock, is there a difference in the outcomes and effect of revascularization strategies between non-ST-segment elevation myocardial infarction (NSTEMI) and left bundle branch block myocardial infarction (LBBBMI) vs ST-segment elevation myocardial infarction (STEMI)? STUDY DESIGN AND METHODS Cardiogenic shock patients from the CULPRIT-SHOCK trial with NSTEMI or LBBBMI were compared with STEMI patients for 30-day and 1-year all-cause mortality. The interaction between ECG presentation and the effect of revascularization strategies on outcomes was evaluated. RESULTS Of 665 cardiogenic shock patients analyzed, 55.9% demonstrated STEMI, 29.3% demonstrated NSTEMI, and 14.7% demonstrated LBBBMI. Patients differed in mean age (68.0 years in STEMI patients, 71.0 years in NSTEMI patients, and 73.5 years in LBBBMI patients; P = .015), cardiovascular risk factors, and angiographic severity. No difference was found in the 30-day risk of death between NSTEMI and STEMI patients (48.7% vs 43.0%; adjusted OR [aOR], 1.05; 95% CI, 0.66-1.67; P = .85), nor between LBBBMI and STEMI patients (59.2% vs 43.0%; aOR, 1.31; 95% CI, 0.73-2.34; P = .36). Although the univariate risk of death by 1 year was higher in NSTEMI and LBBBMI patients compared with STEMI patients, ECG presentation was not an independent risk factor of mortality after adjustment (NSTEMI vs STEMI: 56.4% vs 46.8%; aOR, 1.21; 95% CI, 0.76-1.92; P = .42; LBBBMI vs STEMI: 69.4% vs 46.8%; aOR, 1.59; 95% CI, 0.89-2.84; P = .12). ECG presentation did not modify the effect of the revascularization strategy on 30-day and 1-year mortality (P = .91 and P = .97 for interaction). INTERPRETATION In patients with cardiogenic shock, NSTEMI and LBBBMI presentations reflect higher-risk profiles than STEMI presentations, but are not independent risk factors of mortality. ECG presentations did not modify the treatment effect, supporting culprit-lesion-only percutaneous coronary intervention as the preferred strategy across the AMI spectrum