BACKGROUND: Stress ulcers are acute superficial inflammatory lesions of the gastric mucosa induced when an individual is subjected to unusually high physiologic demands. In recent years, use of acid suppression therapy (AST) for stress ulcer prophylaxis (SUP) in inpatient settings other than intensive care has become increasingly common, leading to increased drug cost and an avoidable increased risk of adverse events such as hospitalacquired pneumonia.
Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiologic features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and critically-ill patients with COVID-19. This manuscript provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.
Background Coronavirus disease 2019 (COVID‐19) is associated with macro‐ and micro‐thromboses, which are triggered by endothelial cell activation, coagulopathy, and uncontrolled inflammatory response. Conventional antithrombotic agents are under assessment in dozens of randomized controlled trials (RCTs) in patients with COVID‐19, with preliminary results not demonstrating benefit in several studies. Objectives Given the possibility that more novel agents with antithrombotic effects may have a potential utility for management of patients with COVID‐19, we assessed ongoing RCTs including these agents with their potential mechanism of action in this population. Methods We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to identify RCTs of novel antithrombotic agents in patients with COVID‐19. Results Based on a systematic literature search, 27 RCTs with 10 novel antithrombotic agents (including nafamostat, dociparstat, rNAPc2, and defibrotide) were identified. The results from these trials have not been disseminated yet. The studied drugs in the ongoing or completed RCTs include agents affecting the coagulation cascade, drugs affecting endothelial activation, and mixed acting agents. Their postulated antithrombotic mechanisms of action and their potential impact on patient management are summarized. Conclusion Some novel antithrombotic agents have pleiotropic anti‐inflammatory and antiviral effects, which may help reduce the viral load or fibrosis, and improve oxygenation. Results from ongoing RCTs will elucidate their actual role in the management of patients with COVID‐19.
IMPORTANCE Dose-reduced regimens of direct oral anticoagulants (DOACs) may be used for 2 main purposes: dose-adjusted treatment intended as full-intensity anticoagulation (eg, for stroke prevention in atrial fibrillation [AF] in patients requiring dose reduction) or low-intensity treatment (eg, extended-duration treatment of venous thromboembolism [VTE]). We reviewed randomized clinical trials (RCTs) to understand the scenarios in which dose-adjusted or low-intensity DOACs were tested and reviewed the labeled indications by regulatory authorities, using data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs. OBSERVATIONS Among 4191 screened publications, 35 RCTs that used dose-adjusted DOACs were identified for dabigatran, apixaban, rivaroxaban, and edoxaban. Of these 35 RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs. To our knowledge, dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment. Low-intensity DOACs were identified in 37 RCTs. Low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban), primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban), primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or (postdischarge) high-risk medical patients (rivaroxaban), in stable atherosclerotic vascular disease, or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban). Minor variations exist between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs. Data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities.CONCLUSIONS AND RELEVANCE Dose adjustment and low-intensity treatment are 2 different forms of dose-reduced DOACs. Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications. Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.
Background Atrioventricular block (AVB) is an important complication following valvular surgery. Several factors including inflammation‐mediated injury might trigger AVB. Methods Patients with advanced postoperative AVB were randomly assigned to receive either dexamethasone (0.4 mg/kg, maximum 30 mg/day) intravenously for 3 days or conservative care only. Primary endpoint was recovery rate in Day 5 since randomization. Secondary endpoints were recovery rate in Day 7 and Day 10, cumulative AVB time, permanent pacemaker (PPM) implantation rate, length of stay in critical care units, and postoperative major adverse events (MAE). Results We enrolled 139 subjects (48.9% male) with mean age of 59.9 years randomly allocated to intervention group (n = 69) and control group (n = 70). Dexamethasone led to higher recovery rates at Day 5 (82.6% vs. 62.9%, p = .009) and Day 7 (88.4% vs. 61.4%, p < .0001) respectively. This benefit ceased at Day 10 (83.05% vs. 78.6%, p = .547). Median cumulative AVB time was shorter in dexamethasone group compared with control group (41 h vs. 64 h, p = .044). PPM implantation rates were similar between the dexamethasone and control groups (15.9% vs. 17.1%, respectively, p = .849). Median length of stay in intensive care unit (ICU) (10 days vs. 12 days, p = .03) and MAE (17.4% vs. 25.7%, p = .133) tended to be lower with dexamethasone. Conclusion Dexamethasone may serve as a safe and effective medication to help hasten recovery of advanced AVB after valvular surgery.
Background: Preoperative anemia is an independent risk factor for higher rates of blood transfusion in cardiac surgery. This study aimed to evaluate the effects of intravenous iron sucrose and erythropoietin on transfusion requirements in patients with preoperative iron deficiency anemia (IDA) undergoing on-pump coronary artery bypass graft (CABG) surgery. Methods: In this open-label, randomized clinical trial, patients with preoperative IDA who were candidates for on-pump CABG were randomized into intervention (iron plus erythropoietin) or control groups. Iron sucrose was administered as a 200 mg intravenous dose and erythropoietin as a 100 IU/kg bolus 1 to 2 days before surgery. The primary outcome was the amount of blood transfusion during the first 4 postoperative days. Results: The study population consisted of 114 patients. The mean age was 64.11±8.18 years in the intervention group and 63.35±8.70 years in the control group. Twenty-seven patients (47.4%) in the intervention group and 25 (43.9%) in the control group were males. The number of red blood cell units transfused per patient exhibited a significant fall in the intervention group compared with the control group (P˂0.001). The ferritin level showed a significant rise in the intervention group on postoperative day 7 (P=0.027). The length of stay in the intensive care unit and the hospital was significantly lower in the intervention arm (P=0.041 and P=0.006, respectively). No adverse events were reported in both groups. Conclusion: The use of erythropoietin and iron sucrose 1 to 2 days before surgery significantly decreased the need for blood transfusion in patients with IDA undergoing CABG without any significant adverse events.
Primary percutaneous coronary intervention (PPCI) is the gold standard of treatment in patients with acute ST-elevation myocardial infarction (STEMI). The no-reflow phenomenon (NRP) is a detrimental consequence of STEMI. Colchicine is an antiinflammatory drug that may help prevent the NRP and improve patient outcomes. In a randomized, double-blind, placebo-controlled clinical trial, 451 patients with acute STEMI who were candidates for PPCI and eligible for enrollment were randomized into the colchicine group (n = 229) and the control group (n = 222). About 321 patients were eligible to participate; 161 patients were assigned to the colchicine group, whereas 160 patients were assigned to the control group. Colchicine was administered 1 mg before PCI and 0.5 mg daily after the procedure until discharge. NRP, measured by angiographic findings including the thrombolysis in myocardial infarction flow grade and the thrombolysis in myocardial infarction myocardial perfusion grade, was reported as the primary outcome. Secondary end points included ST resolution 90 minutes after the procedure, P-selectin, high-sensitivity C-reactive protein, and troponin levels postprocedurally, predischarge ejection fraction, and major adverse cardiac events (MACE) at 1 month and 1 year after PPCI. NRP rates did not show a significant difference between the 2 groups (P = 0.98). Moreover, the levels of P-selectin, high-sensitivity C-reactive protein, and troponin were not significantly different. MACE and predischarge ejection fraction were also not significantly different between the groups. In patients with STEMI treated by PPCI, colchicine administered before PPCI was not associated with a signif-icant reduction in the NRP and MACE prevention (trial registration: IRCT20120111008698N23).
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