Search

Background Andexanet alfa is approved (FDA “accelerated approval”; EMA “conditional approval”) as the first specific reversal agent for factor Xa (FXa) inhibitor-associated uncontrolled or life-threatening bleeding. Four-factor prothrombin complex concentrates (4F-PCC) are commonly used as an off-label, non-specific, factor replacement approach to manage FXa inhibitor-associated life-threatening bleeding. We evaluated the effectiveness and safety of andexanet alfa versus 4F-PCC for management of apixaban- or rivaroxaban-associated intracranial hemorrhage (ICH). Methods This two-cohort comparison study included andexanet alfa patients enrolled at US hospitals from 4/2015 to 3/2020 in the prospective, single-arm ANNEXA-4 study and a synthetic control arm of 4F-PCC patients admitted within a US healthcare system from 12/2016 to 8/2020. Adults with radiographically confirmed ICH who took their last dose of apixaban or rivaroxaban 60 mL, or planned surgery within 12 h were excluded. Outcomes were hemostatic effectiveness from index to repeat scan, mortality within 30 days, and thrombotic events within five days. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using propensity score-overlap weighted logistic regression. Results The study included 107 andexanet alfa (96.6% low dose) and 95 4F-PCC patients (79.3% receiving a 25 unit/kg dose). After propensity score-overlap weighting, mean age was 79 years, GCS was 14, time from initial scan to reversal initiation was 2.3 h, and time from reversal to repeat scan was 12.2 h in both arms. Atrial fibrillation was present in 86% of patients. Most ICHs were single compartment (78%), trauma-related (61%), and involved the intracerebral and/or intraventricular space(s) (53%). ICH size was ≥ 10 mL in volume (intracerebral and/or ventricular) or ≥ 10 mm in thickness (subdural or subarachnoid) in 22% of patients and infratentorial in 15%. Andexanet alfa was associated with greater odds of achieving hemostatic effectiveness (85.8% vs. 68.1%; OR 2.73; 95% CI 1.16–6.42) and decreased odds of mortality (7.9% vs. 19.6%; OR 0.36; 95% CI 0.13–0.98) versus 4F-PCC. Two thrombotic events occurred with andexanet alfa and none with 4F-PCC. Conclusions In this indirect comparison of patients with an apixaban- or rivaroxaban-associated ICH, andexanet alfa was associated with better hemostatic effectiveness and improved survival compared to 4F-PCC. Trial registration NCT02329327; registration date: December 31, 2014.

Increasingly, clinicians and researchers recognize that studies of interventions need to evaluate not only their therapeutic efficacy (i.e., the effect on an outcome in ideal, controlled settings) but also their real-world effectiveness in broad, unselected patient groups. Effectiveness trials inform clinical practice by comparing variations in therapeutic approaches that fall within the standard of care. In this article, we discuss the need for studies of comparative effectiveness in anesthesia and the limitations of individual patient randomized-controlled trials in determining comparative effectiveness. We introduce the concept of randomized cluster crossover trials as a means of answering questions of comparative effectiveness in anesthesia, using the design of the Benzodiazepine-Free Cardiac Anesthesia for Reduction in Postoperative Delirium (B-Free) trial (Clinicaltrials.gov identifier NCT03053869).

Different oral anticoagulants may be associated with gastrointestinal bleeding (GIB) from different locations or mucosal lesions. We aimed to test this hypothesis. Two blinded gastroenterologists independently analyzed source documents from the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial of dabigatran 150 mg BID (D150), dabigatran 110 mg BID (D110) versus warfarin in non-valvular atrial fibrillation (NVAF). Major GIB events (total n = 546) and life-threatening GIB events (n = 258) were more common with D150 versus warfarin (RR 1.57 [1.28–1.92] and RR 1.62 [1.20–2.18], respectively) and similar for D110 compared to warfarin (RR 1.11 [0.89–1.38] and RR 1.16 [0.84–1.61], respectively). Fatal bleeding was similarly rare across treatment groups. Lower GI major bleeding and life-threatening bleeding were more common with D150 compared to warfarin (RR 2.23 [1.47, 3.38] and RR 2.64 [1.36, 5.13], respectively) and with D110 compared to warfarin (RR 1.78 [1.16, 2.75] and RR 2.00 [1.00, 4.00], respectively). MGIB from colonic angiodysplasia was increased with dabigatran versus warfarin (P

Benzodiazepines are commonly administered during cardiac surgery because of their limited effect on hemodynamics and presumed role in preventing intraoperative awareness. Recent concerns about an increased risk of delirium with benzodiazepines have resulted in decreased usage in the intensive care unit and in geriatric perioperative practice. Little is known, however, about current benzodiazepine usage in the setting of adult cardiac surgery. We contacted all academic anesthesia departments in Canada to identify practicing attending cardiac anesthesiologists; this group constituted our sampling frame. Information regarding participant demographics, benzodiazepine usage, type, dose, and other administration details were obtained by electronic survey. Responses were analyzed descriptively. The survey was completed by 243/346 (70%) of cardiac anesthesiologists. Eleven percent of respondents do not administer benzodiazepines. Midazolam was the most commonly used benzodiazepine, with a mean (standard deviation) dose of 4.9 (3.8) mg given to an average patient. When respondents were asked the proportion of patients that they gave benzodiazepines, the response was bimodal. The most common considerations that influenced benzodiazepine use were patient age (73%), patient anxiety (63%), history of alcohol/drug/benzodiazepine use (60%), and the presence of risk factors for intraoperative awareness (44%). Benzodiazepine use is common among academic cardiac anesthesiologists in Canada. Nonetheless, heterogeneity exists between individual practices, suggesting clinical equipoise between restrictive and liberal administration of benzodiazepines for cardiac anesthesia. L’administration de benzodiazepines pendant la chirurgie cardiaque chez l’adulte: evaluation de la pratique actuelle des anesthesiologistes canadiens exercant en milieu universitaire

For an individual patient with both atrial fibrillation and heart failure, stroke risk is one of the most prominent mitigating factors for subsequent morbidity and mortality. Although the CHADS₂ stroke risk score is the most widely used score for risk stratification, it does not take into account the risk factors of vascular disease, female gender, or the age group 65-74 years, for which there is increasing evidence. There is also evidence that diastolic heart failure is as much a risk factor for stroke as systolic heart failure. The new oral anticoagulants dabigatran, rivaroxaban and apixaban appear to be appropriate agents in the heart failure population with atrial fibrillation and risk factors for stroke although there are dose-adjustments for renal insufficiency and these medications are contraindicated in advanced renal disease. As with the atrial fibrillation population as a whole, bleeding risk should be considered for every patient with heart failure prior to making recommendations regarding anticoagulation.

Carotid sinus syndrome (CSS) is an under recognized cause of recurrent unexplained syncope and potentially of recurrent falls in the elderly. The mechanisms that lead to syncope in patients with CSS remain debated. However, evidence for both peripheral and central alterations have been recently reported. The diagnosis of CSS is challenging and a high clinical suspicion is usually needed to make the diagnosis. Clinical presentation may be typical and characterized by a clear association between accidental manipulation of the carotid sinus and the presentation of syncope. On the other hand, recurrent unexplained syncope and unexplained falls may be the clinical presentation of patients with CSS without a specific trigger. Carotid sinus hypersensitivity documented by carotid sinus massage (CSM) may be the only finding indicating the possibility of CSS as the cause of syncope. In older patients with recurrent unexplained syncope and a negative diagnostic work-up, carotid sinus massage both in the supine and upright positions is recommended. CSS may present primarily as a cardioinhibitory response or a true vasodepressor response. Therapy should address any underlying pathology if present, and be directed to either prevent cardioinhibition, vasodepression or both alterations. A variety of medical therapies have been used with unclear effects. No appropriately designed controlled clinical trials have been performed comparing pacing with medical therapy. Nonetheless, available information indicates that pacing may have a strong beneficial effect and prevents recurrence of syncope in patients with CSS. The present paper critically reviews the latest insights in the pathophysiology, diagnosis and management of CSS.

There is an increased risk of stroke and other cardiovascular events in patients with atrial fibrillation (AF). Three meta-analyses of randomized clinical trials (RCTs) comparing oral anticoagulants (OAC) with aspirin (ASA) arrived at different conclusions regarding the relative efficacy of these agents to prevent ischemic stroke in AF patients. This article summarizes a recently published individual patient meta-analysis of all published RCTs comparing OAC and ASA in AF. In total, 4052 patients randomized to OAC or ASA were similar regarding important prognostic factors. Patients receiving OAC had a significantly lower risk of any stroke (hazard ratio [HR] 0.54 [95% CI 0.43-0.71]), ischemic stroke (HR 0.48 [0.37-0.63]), or cardiovascular events (HR 0.71 [0.59-0.85]). Patients receiving OAC were more likely to experience major bleeding (HR 1.71 [1.21-2.41]). The benefit of OAC was most prominent in patients at a high risk of stroke and other cardiovascular events, such as patients with hypertension, diabetes, or previous cerebrovascular events. Overall, OAC improves outcomes for cardiovascular events in AF patients but modestly increases the absolute risk of major bleeding. Since high-risk AF patients appear to benefit most from OAC, determining stroke risk in AF patients is very important.

Post-operative atrial fibrillation is very common. It is associated with increased length of ICU and hospital stay, and costs of post-operative care of patients after cardiac surgery. More then seventy trials on the pharmacological and non-pharmacological interventions were conducted since 1970's. Meta-analysis of these trials, together with detailed analysis of the largest of these trials suggested that conventional beta-blockers, sotalol, amiodarone and bi-atrial overdrive pacing are effective in prevention of post-operative atrial fibrillation. Amiodarone and bi-atrial pacing may decrease the length of hospital stay.

Clinical research into the management of atrial fibrillation—the most common serious arrhythmia—has mostly focused on arrhythmia prevention and the reduction of vascular events and death. In 2010, important advances have been made in stroke prevention with new anticoagulants and in atrial fibrillation rhythm management.

Patients with frequent vasovagal syncope are often resistant to medical therapy. Consensus statements from the United States and Great Britain [1,2] recommend dual chamber pacing for vasovagal syncope if patients have a positive tilt test ending in a relative bradycardia, and if pacing during a second tilt test prevents syncope. These recommendations were not tested until recently. There were concerns about how to select patients, that syncope detection algorithms are unproven, and that pacing might be unable to prevent symptoms due to vasodepression. Three recent nonrandomized studies [3–5] used pacemakers which sense initial drops in heart rate in order to activate early in the syncopal spell, and then pace at a relatively high rate. This acutely delivered relative tachycardia might provide for suf~cient cardiac output to overcome the effects of the vasodepression. One study used rate hysteresis and two used rate drop sensing. None of the studies required evidence that acute pacing during tilt testing prevented syncope. These studies showed a fairly uniform 75–90% reduction in the frequency of syncope. Given these promising results, we designed and are conducting the North American Vasovagal Pacemaker Study [6], a randomized clinical trial, to evaluate the effectiveness of dual chamber pacing with rate-drop sensing in patients at high risk of a recurrence of syncope.

Propafenone disposition kinetics were studied after intravenous and oral doses in patients with ventricular arrhythmias. Plasma concentration–time data were fit to a two-compartment model for all but one patient, whose data required fitting to a three-compartment model. The model-independent calculated values of clearance, steady-state volume of distribution, and terminal t½ were 11.2 ± 4.8 ml/min/kg, 3.6 ± 2.1 l/kg, and 5.0 ± 3.6 hr. After 5 days on oral propafenone, elimination t½ was 6.2 ± 3.3 hr. The longer t½s and the estimates of steady-state bioavailability above 100% suggests that clearance decreases during chronic oral dosing. Considerable intersubject variability was noted in all disposition parameters. Clinical Pharmacology and Therapeutics (1984) 36, 163–168; doi:10.1038/clpt.1984.157

Since N-acetylprocainamide was identified in the urine of patients receiving procainamide, this compound has been studied both as a metabolite of procainamide and as a separate antiarrhythmic agent. N-acetylprocainamide absorption following oral administration is more than 8-% complete. 59 to 89% of N-acetylprocainamide is excreted unchanged in the urine in subjects with normal renal function. Deacetylation of N-acetylprocainamide to procainamide is a minor route of N-acetylprocainamide elimination. The half-life of N-acetylprocainamide in patients with normal renal function has been reported to vary between 4.3 and 15.1 hours. Total body clearance (mean +/- SD) of N-acetylprocainamide in patients with normal renal function has been reported to range from 2.08 +/- 0.36 ml/min/kg to 3.28 +/- 0.52 ml/min/kg. There is a linear relationship between N-acetylprocainamide clearance and creatinine clearance. The half-life of N-acetylprocainamide in functionally anephric patients may be as long as 42 hours; however, it can be effectively cleared from plasma by haemodialysis. N-acetylprocainamide is 10% protein-bound. There is an age-related decline in N-acetylprocainamide clearance, mostly due to the decrease in creatinine clearance that occurs with ageing. In the neonate, the half-life of acetylprocainamide is prolonged. Several therapeutic trials carried out to assess the effectiveness of N-acetylprocainamide in suppressing chronic ventricular premature beats have now been reported. If there is a therapeutic response to N-acetylprocainamide it will probably occur at a plasma concentration between 15 and 25 micrograms/ml. A high degree of overlap has been reported between the concentration range associated with arrhythmic suppression and the range of concentrations where intolerable side effects begin to occur. No severe cardiac toxicity has been reported with oral therapy despite plasma concentrations as high as 40 micrograms/ml. However, hypotension has been reported in association with a rapid intravenous bolus of N-acetylprocainamide. A maximum intravenous infusion rate of 50 mg/min has been recommended. N-acetylprocainamide in patients receiving procainamide; however, N-acetylprocainamide concentrations remain below the therapeutic range in patients with normal renal function. In patients with renal failure receiving procainamide, N-acetylprocainamide concentrations rise dramatically. The dose of N-acetylprocainamide must be adjusted in patients with renal insufficiency, and it should be used more cautiously in the very old and very young. N-acetylprocainamide plasma concentration monitoring would be valuable clinically in patients with renal insufficiency receiving either N-acetylprocainamide or procainamide, and in the very young and the aged.