Rim Halaby

EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention

AIMS Among patients with ST-elevation myocardial infarction (STEMI), reperfusion injury contributes to additional myocardial damage. MTP-131 is a cell-permeable peptide that preserves the integrity of cardiolipin, enhances mitochondrial energetics, and improves myocyte survival during reperfusion. METHODS AND RESULTS EMBRACE STEMI is a multicentre, randomized, double-blind Phase 2a trial that evaluated the efficacy and safety of MTP-131 vs. placebo infused at a rate of 0.05 mg/kg/h for 1 h among first-time anterior STEMI subjects undergoing primary percutaneous coronary intervention (PCI) for a proximal or mid left anterior descending (LAD) artery occlusion. Administration of MTP-131 was not associated with a significant reduction in the primary endpoint, infarct size by creatine kinase-myocardial band (CK-MB) area under the curve (AUC) over 72 h (5785 ± 426 ng h/mL in placebo vs. 5570 ± 486 ng h/mL in MTP-131; ITALIC! P = NS). MTP-131 was not associated with an improvement in pre-specified magnetic resonance imaging, angiographic, electrocardiographic, or clinical outcomes. CONCLUSION Among subjects with first-time anterior STEMI due to a proximal or mid LAD lesion who undergo successful PCI, administration of MTP-131 was safe and well tolerated. Treatment with MTP-131 was not associated with a decrease in myocardial infarct size as assessed by AUC0-72 of CK-MB.

Extended-Duration Betrixaban Reduces the Risk of Stroke Versus Standard-Dose Enoxaparin Among Hospitalized Medically Ill Patients: An APEX Trial Substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban).

Background: Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Methods: Hospitalized acutely medically ill subjects (n=7513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35–42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10±4 days) for venous thromboprophylaxis. Stroke events were adjudicated by an independent, blinded event adjudication committee. Results: The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk [RR]=0.56; 95% confidence interval, 0.32–0.96; P=0.032; adjusted RR=0.43%; number needed to treat=233) and ischemic strokes (0.48% versus 0.91%; RR=0.53; 95% confidence interval, 0.30–0.94; P=0.026; adjusted RR=0.43%; number needed to treat=233) among patients treated with betrixaban versus enoxaparin through 77 days of follow-up. Among high-risk subjects, those with congestive heart failure or ischemic stroke as their index event, betrixaban reduced the risk of all-cause stroke (0.72% versus 1.48%; RR=0.49; 95% confidence interval, 0.26–0.90; P=0.019; adjusted RR=0.76%; number needed to treat=132) and ischemic stroke (0.63% versus 1.38%; RR=0.45; 95% confidence interval, 0.24–0.87; P=0.014; adjusted RR=0.75%; number needed to treat=134) compared with enoxaparin. Conclusions: Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01583218.

The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial

Background The APEX trial assessed the safety and efficacy of extended‐duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among hospitalized, acutely ill medical patients. The 80‐mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P‐glycoprotein inhibitor. Methods This analysis assessed the pharmacokinetics, efficacy, and safety of full‐ (80 mg) and reduced‐dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. Results The median concentration of betrixaban among subjects administered the 80‐mg dose was higher than that of the 40‐mg dose (19 ng/mL vs 11 ng/mL, P < .001). In the primary analysis cohort 1 (d‐dimer ≥2× upper limit of normal), the primary efficacy outcome (asymptomatic proximal deep vein thrombosis, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or venous thromboembolism–related death) was significantly reduced among subjects treated with 80 mg of extended‐duration betrixaban versus enoxaparin (6.27% [95/1516] vs 8.39% [130/1549], relative risk reduction = 0.26 [0.04‐0.42], P = .023), and similarly in the entire primary efficacy outcome population (4.87% [122/2506] vs 7.06% [181/2562], relative risk reduction = 0.30 [0.13‐0.44], P = .001). There was no difference in the primary outcome for subjects treated with 40 mg betrixaban vs enoxaparin across cohorts. In addition, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin. Conclusions The 80‐mg betrixaban dose achieves higher plasma concentrations than the 40‐mg dose and, in contrast to the 40‐mg dose, is associated with improved efficacy across all cohorts relative to standard‐dose enoxaparin without an excess risk of major bleeding in the management of medically ill subjects.

A Living Systematic Review of Nebulized Hypertonic Saline for Acute Bronchiolitis in Infants

Results | The LTL (expressed in the telomere repeat copy number to the single gene copy number ratio) remained unchanged during and after the OC intake. In contrast, the LTL doubled while taking PioFluMet and returned to baseline after the PioFluMet intake was stopped (Figure). The LTL changes across treatment groups during 18 months related inversely to fasting insulinemia, body fat fraction by dual energy x-ray absorptiometry, and visceral and hepatic adiposity by magnetic resonance imaging (all r values were between −0.53 and −0.57; all P values were between 0.002 and 0.007). The ratio of circulating neutrophils to lymphocytes was first similar in treatment groups and remained similar in and between groups across 24 months. Noteworthy adverse effects were not encountered in either treatment group.4

D-Dimer elevation and adverse outcomes.

Abstractd-Dimer is a biomarker of fibrin formation and degradation. While a d-dimer within normal limits is used to rule out the diagnosis of deep venous thrombosis and pulmonary embolism among patients with a low clinical probability of venous thromboembolism (VTE), the prognostic association of an elevated d-dimer with adverse outcomes has received far less emphasis. An elevated d-dimer is independently associated with an increased risk for incident VTE, recurrent VTE, and mortality. An elevated d-dimer is an independent correlate of increased mortality and subsequent VTE across a broad variety of disease states. Therefore, medically ill subjects in whom the d-dimer is elevated constitute a high risk subgroup in which the prospective evaluation of the efficacy and safety of antithrombotic therapy is warranted.

Extended-Duration Thromboprophylaxis Among Acute Medically Ill Patients: An Unmet Need.

Acute medical illnesses are associated with a prolonged elevation in inflammatory markers that predisposes patients to thrombosis beyond the duration of their hospital stay. In parallel, both observational and randomized data have demonstrated a rate of postdischarge venous thromboembolic events that often exceeds that observed in the hospital setting. Despite this significant residual risk of venous thromboembolic events following discharge among acute medically ill patients, no therapeutic strategies have been recommended to address this unmet need. Available randomized trials have demonstrated the efficacy of extending the duration of thromboprophylaxis with available anticoagulants; however, the efficacy is offset, at least in part, by an increase in bleeding events. Identification of the optimal therapeutic strategies, treatment duration, and risk assessment tools that reconcile both efficacy and safety of extended-duration thromboprophylaxis among acute medically ill patients is an area of ongoing investigation.

Renal Function Decline in Recipients and Donors of Kidney Grafts: Role of Aortic Stiffness

Background/Aims: Renal function decreases over time as a result of reduction in the number of functioning nephrons with age. In recipients and donors of kidney grafts, renal function decline may be linked differently to various parameters, namely arterial stiffness. Methods: We conducted a prospective cohort study including 101 recipients of kidney grafts and their donors aiming at determining the factors correlated to the renal function decline over time. Aortic stiffness was evaluated by the non-invasive measurement of aortic pulse wave velocity. The glomerular filtration rate was estimated using the Modification of Diet in Renal Disease (MDRD) equation and the annualized change was determined. Results: Decline in renal function was estimated at 1-year post-transplantation and annually thereafter (median follow-up 8 years, range 3.6-18.3), as the mean of the annualized decrease in the glomerular filtration rate. In recipients, filtration rate decreased by 4.8 ± 19.7 ml/min/1.73 m2 the first post-transplant year and at a yearly rate of 2.2 ± 3.8 ml/min/1.73 m2 thereafter. The first-year decline was related to smoking and acute rejection. Later decline was significantly associated with donor age and aortic stiffness. In living donors, renal function decline after the first year corresponded to 0.7 ml/min/1.73 m2, was significantly lower than that of recipients (p < 0.001), and was determined by donor age at nephrectomy. Conclusion: Recipients of kidney grafts show a glomerular filtration rate decline over time that is significantly associated with donor age and aortic stiffness after the first post-transplant year, while donors demonstrate a lower decline that is mostly determined by age at nephrectomy.

Association of D-dimer Levels with Clinical Event Rates and the Efficacy of Betrixaban versus Enoxaparin in the APEX Trial

Background  Elevated D-dimer concentrations are associated with an increased risk of venous thromboembolism (VTE). However, they may also provide prognostic value. The present analysis sought to study the association of D-dimer levels with VTE event rates and the efficacy of betrixaban versus enoxaparin in the APEX trial. Methods  Hospitalized acutely medically ill subjects ( n  = 7,513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35–42 days) or standard dose subcutaneous enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. D-dimer was assessed using a central core laboratory measurement. Results  For every 0.25 µg/mL increase in D-dimer concentration, there was a 2% increase in the relative risk of experiencing the primary efficacy endpoint (asymptomatic deep vein thrombosis [DVT], symptomatic DVT, nonfatal pulmonary embolism, or VTE-related death) in both the betrixaban ( p  < 0.001) and enoxaparin ( p  < 0.001) treatment arms. Among D-dimer-positive (≥ 2 × upper limit of normal; corresponding to ≥ 1.00 µg/mL) subjects, extended-duration betrixaban reduced the risk of experiencing the primary efficacy outcome (5.4% [ n  = 124] vs. 7.6% [ n  = 170]; odds ratio = 0.69; 95% confidence interval: 0.55–0.88; absolute risk reduction = 2.2%, number needed to treat = 46, p  = 0.003). There was no interaction between D-dimer and the treatment effect ( p int  = 0.53). Conclusion  Extended-duration betrixaban was superior to standard-duration enoxaparin, irrespective of D-dimer level at baseline. To prevent one VTE event, 46 D-dimer-positive patients would need to be treated with betrixaban.

Dual Pathway Therapy for Secondary Prevention Following Acute Coronary Syndrome

Although dual antiplatelet therapy has served as the standard of care following an acute coronary syndrome (ACS), a significant residual risk of ischemic events and cardiovascular mortality remains. Rather than further targeting the platelet with either a greater number of or more potent therapies, recent emphasis has shifted to treating an alternate pathway, namely thrombin generation, as part of a “dual-pathway” approach to secondary prevention of atherothrombotic events. While early studies combined the administration of antiplatelet agents and vitamin K antagonists and demonstrated a reduction in recurrent MI, there was an unacceptable increase in major bleeding. Combination of antiplatelet agents with novel oral anticoagulants may mitigate this bleeding risk and improve both net clinical outcomes as well as ease of use. The major challenge continues to be the identification of an optimal combination of antiplatelet and anticoagulant agents that strikes a balance between efficacy and bleeding risk. The aims of this article are to review the major clinical trials assessing the safety and efficacy of oral anticoagulants for secondary prevention of atherothrombotic events following ACS and to shed light on future directions in the development of dual-pathway therapy.

Triple Antiplatelet Therapy and Combinations with Oral Anticoagulants After Stent Implantation

Triple oral anticoagulation or triple antiplatelet therapies may be administered for various reasons. They reduce cardiac complications following percutaneous coronary intervention and stroke or other thromboembolic phenomenon in conditions such as atrial fibrillation. There is an elevated risk of severe bleeding, so it is necessary to balance risk and benefits. Newer oral anticoagulants and antiplatelet drugs may be considered; the number of options is increasing. This article examines triple therapies and the efficacy and safety of combinations of traditional anticoagulant and antiplatelet drugs, and reviews clinical trial data on novel agents. Guidelines to inform clinical decision-making are presented.