Permutation criteria to evaluate multiple clinical endpoints in a proof-of-concept study: lessons from Pre-RELAX-AHF

Clinically relevant endpoints cannot be routinely targeted with reasonable power in a small study. Hence, proof-of-concept studies are often powered to a primary surrogate endpoint. However, in acute heart failure (AHF) effects on surrogates have not translated into clinical benefit in confirmatory studies. Although observing an effect on one of many endpoints due to chance is likely, observing concurrent positive trends across several outcomes by chance is usually unlikely. Pre-RELAX-AHF, which compared 4 relaxin doses with placebo in AHF, has shown favourable trends versus placebo (one-sided P <0.10) on six of nine clinical endpoints in the 30 mu g/kg/day group. To illustrate evaluation of multiple, correlated clinical endpoints for evidence of efficacy and for dose selection, a permutation method was applied retrospectively. By randomly re-assigning the treatment group to the actual data for each of the 229 subjects, 20,000 permutation samples were constructed. The permutation P value for at least six favourable trends among nine endpoints in any dose groups was 0.0073 (99.9% CI 0.0053-0.0093). This is higher than would be expected if the endpoints were uncorrelated (0.00026), but much lower than the probability of observing one of nine comparisons significant at the traditional two-sided P <0.05 (0.74). Thus, the result was unlikely due to correlated endpoints or to chance. Examining consistency of effect across multiple clinical endpoints in a proof-of-concept study may identify efficacious therapies and enable dose selection for confirmatory trials. The merit of the approach described requires confirmation through prospective application in designing future studies

Successful management of Influenza A associated fulminant myocarditis: mobile circulatory support in intensive care unit: a case report

A 26-year-old woman was referred to an Emergency Department because of common flu-like syndrome with hemodynamic collapse. In Intensive Care Unit (ICU), she was diagnosed as a probable septic shock. But despite treatment her condition rapidly deteriorated during the subsequent hours. Diagnosis of cardiogenic shock was established. Mechanical circulatory support was inserted into the patient. She was transferred in a Cardio-Vascular Surgical ICU where at the 5th day of mechanical circulatory support, echocardiography showed heart recovery which allowed weaning of mechanical circulatory support and progressive withdrawal of inotropic support. She was discharged at the 26th day. During her hospitalization, presence of Influenza A RNA was shown in myocardial biopsy

A novel approach to improve cardiac performance: cardiac myosin activators

Decreased systolic function is a central factor in the pathogenesis of heart failure, yet there are no safe medical therapies to improve cardiac function in patients. Currently available inotropes, such as dobutamine and milrinone, increase cardiac contractility at the expense of increased intracellular concentrations of calcium and cAMP, contributing to increased heart rate, hypotension, arrhythmias, and mortality. These adverse effects are inextricably linked to their inotropic mechanism of action. A new class of pharmacologic agents, cardiac myosin activators, directly targets the kinetics of the myosin head. In vitro studies have demonstrated that these agents increase the rate of effective myosin cross-bridge formation, increasing the duration and amount of myocyte contraction, and inhibit non-productive consumption of ATP, potentially improving myocyte energy utilization, with no effect on intracellular calcium or cAMP. Animal models have shown that this novel mechanism increases the systolic ejection time, resulting in improved stroke volume, fractional shortening, and hemodynamics with no effect on myocardial oxygen demand, culminating in significant increases in cardiac efficiency. A first-in-human study in healthy volunteers with the lead cardiac myosin activator, CK-1827452, as well as preliminary results from a study in patients with stable chronic heart failure, have extended these findings to humans, demonstrating significant increases in systolic ejection time, fractional shortening, stroke volume, and cardiac output. These studies suggest that cardiac myosin activators offer the promise of a safe and effective treatment for heart failure. A program of clinical studies are being planned to test whether CK-1827452 will fulfill that promise

Short term effects of milrinone on biomarkers of necrosis, apoptosis, and inflammation in patients with severe heart failure

<p>Abstract</p> <p>Introduction</p> <p>Inotropes are associated with adverse outcomes in heart failure (HF), raising concern they may accelerate myocardial injury. Whether biomarkers of myocardial necrosis, inflammation and apoptosis change in response to acute milrinone administration is not well established.</p> <p>Methods</p> <p>Ten patients with severe HF and reduced cardiac output who were to receive milrinone were studied. Blood samples were taken just before initiation of milrinone and after 24 hours of infusion. Dosing was at the discretion of the patient's attending physician (range 0.25–0.5 mcg/kg/min). Plasma measurements of troponin, myoglobin, N-terminal-pro-BNP, interleukin-6, tumor necrosis factor-α, soluble Fas, and soluble Fas-ligand were performed at both time points.</p> <p>Results</p> <p>Troponin was elevated at baseline in all patients (mean 0.1259 ± 0.17 ng/ml), but there was no significant change after 24 hours of milrinone (mean 0.1345 ± 0.16 ng/ml, p = 0.44). There were significant improvements in interleukin-6, tumor necrosis factor-α, soluble Fas, and soluble Fas-ligand (all p < 0.05) indicative of reduced inflammatory and apoptotic signaling compared to baseline.</p> <p>Conclusion</p> <p>In conclusion, among patients with severe HF and low cardiac output, ongoing myocardial injury is common, and initiation of milrinone did not result in exacerbation of myocardial injury but instead was associated with salutary effects on other biomarkers.</p

A High Red Blood Cell Distribution Width Predicts Failure of Arteriovenous Fistula

In hemodialysis patients, a native arteriovenous fistula (AVF) is the preferred form of permanent vascular access. Despite recent improvements, vascular access dysfunction remains an important cause of morbidity in these patients. In this prospective observational cohort study, we evaluated potential risk factors for native AVF dysfunction. We included 68 patients with chronic renal disease stage 5 eligible for AVF construction at the Department of General and Vascular Surgery, Central Clinical Hospital Ministry of Internal Affairs, Warsaw, Poland. Patient characteristics and biochemical parameters associated with increased risk for AVF failure were identified using Cox proportional hazards models. Vessel biopsies were analyzed for inflammatory cells and potential associations with biochemical parameters. In multivariable analysis, independent predictors of AVF dysfunction were the number of white blood cells (hazard ratio [HR] 1.67; 95% confidence interval [CI] 1.24 to 2.25; p<0.001), monocyte number (HR 0.02; 95% CI 0.00 to 0.21; p = 0.001), and red blood cell distribution width (RDW) (HR 1.44; 95% CI 1.17 to 1.78; p<0.001). RDW was the only significant factor in receiver operating characteristic curve analysis (area under the curve 0.644; CI 0.51 to 0.76; p = 0.046). RDW>16.2% was associated with a significantly reduced AVF patency frequency 24 months after surgery. Immunohistochemical analysis revealed CD45-positive cells in the artery/vein of 39% of patients and CD68-positive cells in 37%. Patients with CD68-positive cells in the vessels had significantly higher white blood cell count. We conclude that RDW, a readily available laboratory value, is a novel prognostic marker for AVF failure. Further studies are warranted to establish the mechanistic link between high RDW and AVF failure

Hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Community-acquired (CAP) and nosocomial pneumonias contribute substantially to morbidity and hospital resource utilization. Hyponatremia, occurring in >1/4 of patients with CAP, is associated with greater disease severity and worsened outcomes.</p> <p>Methods</p> <p>To explore how hyponatremia is associated with outcomes in hospitalized patients with pneumonia, we analyzed a large administrative database with laboratory component from January 2004 to December 2005. Hyponatremia was defined as at least two [Na⁺] < 135 mEq/L within 24 hours of admission value.</p> <p>Results</p> <p>Of 7,965 patients with pneumonia, 649 (8.1%) with hyponatremia were older (72.4 ± 15.7 vs. 68.0 ± 22.0, p < 0.01), had a higher mean Deyo-Charlson Comorbidity Index Score (1.7 ± 1.7 vs. 1.6 ± 1.6, p = 0.02), and higher rates of ICU (10.0% vs. 6.3%, p < 0.001) and MV (3.9% vs. 2.3%, p = 0.01) in the first 48 hours of hospitalization than patients with normal sodium. Hyponatremia was associated with an increased ICU (6.3 ± 5.6 vs. 5.3 ± 5.1 days, p = 0.07) and hospital lengths of stay (LOS, 7.6 ± 5.3 vs. 7.0 ± 5.2 days, p < 0.001) and a trend toward increased hospital mortality (5.4% vs. 4.0%, p = 0.1). After adjusting for confounders, hyponatremia was associated with an increased risk of ICU (OR 1.58, 95% CI 1.20–2.08), MV (OR 1.75 95% CI 1.13–2.69), and hospital death (OR 1.3, 95% CI 0.90–1.87) and with increases of 0.8 day to ICU and 0.3 day to hospital LOS, and over $1,300 to total hospital costs.</p> <p>Conclusion</p> <p>Hyponatremia is common among hospitalized patients with pneumonia and is associated with worsened clinical and economic outcomes. Studies in this large population are needed to explore whether prompt correction of [Na⁺] may impact these outcomes.</p

Delphi-Consensus Weights for Ischemic and Bleeding Events to Be Included in a Composite Outcome for RCTs in Thrombosis Prevention

To weight ischemic and bleeding events according to their severity to be used in a composite outcome in RCTs in the field of thrombosis prevention.Using a Delphi consensus method, a panel of anaesthesiology and cardiology experts rated the severity of thrombotic and bleeding clinical events. The ratings were expressed on a 10-point scale. The median and quartiles of the ratings of each item were returned to the experts. Then, the panel members evaluated the events a second time with knowledge of the group responses from the first round. Cronbach's a was used as a measure of homogeneity for the ratings. The final rating for each event corresponded to the median rating obtained at the last Delphi round.Of 70 experts invited, 32 (46%) accepted to participate. Consensus was reached at the second round as indicated by Cronbach's a value (0.99 (95% CI 0.98-1.00)) so the Delphi was stopped. Severity ranged from under-popliteal venous thrombosis (median = 3, Q1 = 2; Q3 = 3) to ischemic stroke or intracerebral hemorrhage with severe disability at 7 days and massive pulmonary embolism (median = 9, Q1 = 9; Q3 = 9). Ratings did not differ according to the medical specialty of experts.These ratings could be used to weight ischemic and bleeding events of various severity comprising a composite outcome in the field of thrombosis prevention