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Context Diabetes mellitus is a risk factor for nephrolithiasis. A recent observational study found that in patients with type 2 diabetes (T2D), SGLT2 inhibitor use was associated with a 49% lower risk of nephrolithiasis compared with GLP-1 receptor agonists. Objective We examined the association between nephrolithiasis and the SGLT2 inhibitor empagliflozin, using existing data from randomized clinical trials. Methods We pooled data from 15 081 T2D patients randomized to empagliflozin (n = 10 177) or placebo (n = 4904) from 20 phase I-IV trials, including the large cardiovascular outcome trial, EMPA-REG OUTCOME. Incident urinary tract stone events were captured using a predefined collection of MedRA terms. A sensitivity analysis using a narrower definition was also performed. Incidence rate ratios (IRR) and 95% CIs were calculated using the relative risk estimate, stratified by study. Results The median exposures to study drug were 543 days (placebo) and 549 days (empagliflozin); 183 patients experienced an incident urolithiasis during follow-up (placebo, 79; empagliflozin, 104), yielding annual incidence rates of 1.01 vs 0.63 events/100 patient-years in the 2 respective groups. The IRR was 0.64 (95% CI, 0.48-0.86), in favor of empagliflozin. In the sensitivity analysis, the results were similar (IRR, 0.62 [95% CI, 0.45-0.85]). Conclusion Compared with placebo, empagliflozin therapy was associated with an approximate 40% reduced risk of urinary tract stone events in T2D patients. The underlying mechanisms are unknown but may involve altered lithogenic profile of the urine. Dedicated randomized prospective clinical trials are warranted to confirm these initial observations in patients with and without T2D.

Aims Nephrolithiasis is a common disease, estimated to affect 10% of the US population. In addition to pain, often severe, it can lead to urinary tract infections and acute kidney injury, while contributing to health care costs from emergency room visits and follow-up interventions necessary to relieve stone burden. Type 2 diabetes (T2D) is a well-known risk factor for nephrolithiasis. Recently in an observational study of patients with T2D, use of sodium-glucose transport protein 2 (SGLT2) inhibitors as glucose lowering agents was associated with a 49% lower risk of nephrolithiasis when compared with use of glucagon like peptide 1 (GLP-1) receptor agonists. We examined, prospectively, the association between renal stone disease and the use of the SGLT2 inhibitor empagliflozin, using existing data from randomized clinical trials. Methods Pooled data from 15,081 patients with T2D treated with empagliflozin (10,177) or placebo (4,904) from 20 phase I-IV randomized, placebo-controlled trials including the large cardiovascular outcome trial, EMPA-REG OUTCOME, were included in this analysis. Incident urinary tract stone events were captured using a pre-defined collection of MedDRA terms: nephrolithiasis, renal colic, ureterolithiasis, calculus bladder, calculus urinary, calculus urethral, and nephrocalcinosis (MedDRA version 22.1). A sensitivity analysis used a narrower definition by excluding the terms renal colic and nephrocalcinosis. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were calculated using the relative risk estimate stratified by study. Results The median exposure to study drug was 543 (placebo) and 549 (empagliflozin 10 or 25 mg) days We found that a total of 183 patients experienced an incident urolithiasis during follow-up (79 in placebo, 104 in pooled empagliflozin) yielding annual incidence rates of 1.01 versus 0.63 events per 100 patient years in placebo and empagliflozin, respectively. All but one event occurred in patients with no prior history of urinary tract stones. The IRR was 0.64 (95% CI 0.48, 0.86), in favor of empagliflozin. In the sensitivity analysis, now restricted to nephrolithiasis, ureterolithiasis, calculus bladder, calculus urinary, and calculus urethral, the results were similar (IRR, empagliflozin vs. placebo, 0.62 [95% CI 0.45, 0.85]). Conclusion As compared to placebo, use of empagliflozin was associated with an approximate 40% reduction in the risk of urolithiasis in patients with T2D. Alterations in lithogenic profile of the urine (including dilutional effects) of potential stone formers after SGLT2 inhibition may explain this finding. Based on these initial observations, mechanistic studies to elucidate the mediator(s) of this seemingly protective effect and dedicated randomized prospective clinical trials appear warranted in patients with renal stone disease. As with follow-up SGLT2 inhibitor investigations conducted in patients with heart failure and chronic kidney disease, such trials should include individuals who do not have T2D. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:12 p.m. - 1:17 p.m.

Background: GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic t...

Objective To further examine anticoagulation reversal and clinical outcomes in dabigatran treated patients requiring urgent surgery or procedural interventions. Background Idarucizumab, a humanized monoclonal antibody fragment, reverses dabigatran anticoagulation. Methods Data from surgical and procedural patients in RE-VERSE AD, a multicenter, open-label, single-arm, prospective cohort of dabigatran reversal were evaluated. A total of 202 patients in this group received 5 g of idarucizumab before surgery or procedures. Results The interventions included 49 abdominal, 45 orthopedic, 34 vascular, 8 neurologic, and 4 genitourinary surgical procedures, or 29 catheter-based cases, 20 cases for drainage, and 8 diagnostic procedures. Five patients did not undergo their intended intervention after receiving idarucizumab. Complete reversal of the dabigatran anticoagulant effect occurred within minutes in almost all patients, with normal hemostasis in more than 91% of patients. The median time from the first vial of idarucizumab to surgery or procedures was less than 2 hours in all groups except neurosurgery, where it was 3.3 hours. Fresh frozen plasma and packed red cells were the most frequently transfused blood products. Postreversal thromboembolic events occurred in 10 (5%) patients at 30 days, 5 of whom had restarted anticoagulation before the event. Overall 30-day mortality was 12.6%. There were no serious adverse safety signals due to idarucizumab dosing. Conclusions Idarucizumab facilitates management of patients requiring urgent procedures by providing rapid dabigatran reversal, and is the only agent of its class studied in surgical patients.

Background Dabigatran and idarucizumab, its reversal agent, are renally cleared. Objectives The purpose of this study was to determine the extent of reversal and outcomes according to baseline renal function in dabigatran-treated nondialysis patients receiving idarucizumab. Methods In 503 patients in RE-VERSE AD (Reversal of Effects of Idarucizumab in Patients on Active Dabigatran), the extent of dabigatran reversal and clinical outcomes were compared according to baseline renal function (creatinine clearance: normal ≥80, mild 50 to Results Compared with patients with normal renal function, those with impaired renal function were older, were more often women, and had lower body mass indexes, more comorbidities, higher CHADS2 scores, and higher dabigatran plasma levels despite more frequent use of lower-dose dabigatran regimens. Regardless of renal function, median reversal measured by dilute thrombin time was 100% within 4 h of idarucizumab administration, and over 98% of patients achieved this with corresponding undetectable levels of unbound dabigatran. By 12 or 24 h, 56% of patients with severe, 29.1% with moderate, and 9.2% with mild renal impairment had dabigatran levels >20 ng/ml compared with 8.3% of patients with normal renal function at baseline. Time to cessation of bleeding and the proportion with normal hemostasis with procedures were similar regardless of renal function, but patients with severe renal impairment had higher 30- and 90-day mortality rates. Conclusions Idarucizumab completely reverses dabigatran in >98% of patients regardless of renal function. Although re-elevation of dabigatran levels within 12 to 24 h is more common with renal impairment, the time to bleeding cessation and the extent of hemostasis during procedures are similar. (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab; NCT02104947 )

Background: Although dabigatran has a favorable risk-benefit profile compared with vitamin K antagonist therapy for venous thromboembolism and nonvalvular atrial fibrillation, major bleeding events, including gastrointestinal (GI) bleeding, may occur. Therefore, our aim was to provide insights into the efficacy and safety of idarucizumab for urgent dabigatran reversal in patients with major GI bleeding. Methods: Patients with uncontrollable GI bleeding requiring reversal were enrolled from June 2014 through July 2016 in the RE-VERSE AD study (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab), a prospective, multicenter, open-label study of idarucizumab, and were followed up for 90 days for primary and secondary outcomes. Patients were to receive a 5-g dose of intravenous idarucizumab, administered as 2 bolus infusions of 2.5 g no more than 15 minutes apart. The primary end point was the maximum reversal of dabigatran anticoagulation within 4 hours after administration of idarucizumab as measured by the dabigatran-specific assays diluted thrombin time and ecarin clotting time. Further end points included investigator-reported bleeding cessation within the first 24 hours and incidence of rebleeding, thromboembolic events, or mortality. Results: GI bleeding occurred in 137 patients enrolled in RE-VERSE AD, of which 84% was adjudicated as major or life-threatening, 48 (35.0%) was upper GI tract in origin, 43 (31.4%) was lower GI in origin, and 46 (33.6%) was either both or unknown. Complete reversal of dabigatran was observed in 118 of 121 patients (97.5%) with an elevated diluted thrombin time at presentation and 95 of 131 patients (72.5%) with an elevated ecarin clotting time and was similar for upper and lower GI bleeding. Bleeding cessation within 24 hours was reported in 92 of 134 evaluable patients (68.7%) after a median duration of 2.4 hours (interquartile range, 2.0–3.9 hours). During the 90-day follow-up, 6 patients (4.4%) had a postreversal thromboembolic event, and 20 patients (14.6%) died. Conclusions: Idarucizumab showed a rapid and complete reversal of dabigatran activity in nearly all patients presenting with GI bleeding, facilitating emergency patient care without the additional presence of anticoagulation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02104947.

Introduction Although guideline-adherent antithrombotic therapy (ATT) for stroke prevention in atrial fibrillation (AF) is associated with lower mortality and thromboembolism, ATT uptake shows geographic variation worldwide. We aimed to assess thromboembolic risk and baseline ATT by geographic region and identify factors associated with prescription of ATT in a large, truly global registry of patients with recently diagnosed AF. Methods and Results Our analysis comprises 15,092 patients newly diagnosed with non-valvular AF at risk for stroke, enrolled in Phase II of Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF). Global oral anticoagulation (OAC) use was 79.9%, being highest in Europe (90.1%), followed by Africa/Middle East (87.4%) and Latin America (85.3%), North America (78.3%) and Asia (55.2%). Among OAC users, vitamin K antagonists (VKAs) have been replaced by non-VKA OACs (NOACs) as the more prevalent OAC option in all regions, with highest use in North America (66.5%) and lowest in Asia (50.2%). In Asia, OAC was 80.4% in community hospitals but only 49.8% in university hospitals and 42.6% in specialist offices, and varied from 21.0% in China to 89.7% in Japan (NOACs at 5.8% in China and 83.3% in Japan). Globally, 76.5% of low-risk patients were prescribed ATT (46.1% OAC), whereas 17.7% high-risk patients were not anticoagulated (Europe 8.8%; North America 18.9%; Asia 42.4%). Conclusion Substantial inter- and intra-regional differences in ATT for stroke prevention in AF are evident in this global registry. While guideline-adherent ATT can be further improved, NOACs are the main contributor to high OAC use worldwide.

GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non-vitamin K antagonist oral anticoagulant (NOAC), became available.This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1.During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients' baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics.Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHAThe baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701).

Introduction: Given their substantial risk of recurrent stroke, patients with atrial fibrillation (AF) and prior stroke are at highest risk. Such patients should be pre-scribed oral anticoagulants (OAC), either a Vitamin K Antagonist (VKA) or Non-VKA OAC (NOAC). Methods: Using an inception cohort design, GLORIA-AF collected data on choice of antithrombotic therapy for patients with newly identified AF at risk of stroke (CHA2DS2VASc scores ≥ 1) in the course of routine care. We examined the use of an-tithrombotic therapy in those with prior stroke. Results: From 15,092 patients in Phase II of GLORIA-AF enrolled in 5 geographical regions worldwide (Europe, North America, Asia, Latin America and Africa/Middle East), 1,582 patients (median age 75 years, 54.9% male) had previous stroke, with a median CHA2DS2-VASc score of 5, compared with a score of 3 in those without previ-ous stroke (n=13,500). For 10 patients previos stroke status was unknown. In those with previous stroke, VKA alone was prescribed in 25.2%, VKA plus an-tiplatelet therapy (AP) in 5.8%, NOAC alone in 42.9%, NOAC plus AP in 7.7%, and AP alone in 12.1%; 6.3% received no antithrombotic therapy. Proportions were broadly similar in males and females. In comparison, among patients without prior stroke the proportions on AP only or no therapy were a little higher (20.2 versus 18.3%). Among those with prior stroke, proportions on AP alone in Asia, Europe, and North America were 24.2, 9.9 and 5.6% respectively, while proportions on no antithrombotic therapy in these regions were 16.3, 3.2 and 4.5%. Conclusion: In this prospective registry, AF patients with prior stroke and a median CHA2DS2-VASc score of 5, approximately 18% were treated with AP alone or no an-tithrombotic therapy, and the treatment gap was greater in Asia than in Europe or North America.

Purpose/Background : Oral anticoagulation is recommended for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) and stroke risk factors, but discontinuation rates are high among those treated with vitamin K antagonists (VKA). After the first year of treatment, about half of patients permanently stop taking VKA therapy. We examined persistence to therapy with dabigatran etexilate (DE) in patients enrolled in the global, prospective GLORIA-AF Registry Program. Methods: GLORIA-AF collects data in three phases from routine clinical practice in 44 countries worldwide. Enrollment in Phase II was initiated following approval of DE, the first non-VKA oral anticoagulant (NOAC) available. During this phase, all patients with newly diagnosed NVAF at risk for stroke starting DE are followed for 2 years. This analysis is based on a pre-specified interim analysis once follow-up of the first 3000 DE patients was completed. Patients were recruited between November 2011 and December 2013 at nearly 1,000 sites worldwide, by cardiologists, neurologists and general practitioners. To reduce selection bias, patients were recruited consecutively, irrespective of antithrombotic therapy. Persistence was defined as time from initiation to discontinuation of therapy for >30 days or substitution of initial treatment by another oral anticoagulant. Persistence rates were analyzed on the basis of a time-to-event analysis using the Kaplan Meier method. Results: Among eligible patients, 2,937 were prescribed DE; 823 (27.4%) in North America, 1,503 (50.1%) in Europe, 194 (6.5%) in Latin America, 54 (1.8%) in Africa/Middle East and 363 (12.1%) in Asia. Overall, 55.3% were male, the median age was 71.0 (range 23-98) years; 36.7% were ≥75 years old. The CHA2DS2VASc score was ≥2 in 88.2%, 78.9% had hypertension, 22.7% diabetes mellitus, 10.1% prior stoke and 24.9% heart failure. All but 5 eligible patients took at least one dose of DE. The probability of remaining on DE treatment was 76.6% at 1 year and 69.2% at 2 years (based on Kaplan-Meier method). At the 2 years visit, half of the permanently discontinued patients (418 out of 828) had switched to another oral anticoagulant. Characteristics of patients discontinuing vs. sustaining therapy and relationships to stroke risk and geographical region will be presented. Conclusions: In this global, prospective, cohort of patients newly diagnosed with NVAF and treated with DE, persistence on therapy was high through 2 years of treatment, with an estimated probability of remaining on treatment of about 77% after 1 year and 70% after 2 years. The detailed results will provide a global perspective on the factors that influence treatment persistence in patients prescribed a NOAC for stroke prophylaxis. Disclosures Teutsch: Boehringer Ingelheim: Employment. Huisman:Boehringer Ingelheim Pharma GmbH & Co.KG: Other: Grant support; GlaxoSmithKline: Other: Grant support; Bayer HealthCare: Other: Grant support; Pfizer: Other: Grant support; Actelion: Other: Grant support. Lip:Bayer, BMS/Pfizer, Boehringer Ingelheim and Sanofi Aventis: Speakers Bureau; Bayer, Astellas, Merck, Sanofi, Bristol-Myers Squibb (BMS)/Pfizer, Daiichi-Sankyo, Biotronik, Portola and Boehringer Ingelheim: Consultancy. Diener:AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Novartis, Sanofi Aventis, Syngis and Talecris: Research Funding; Abbott, Allergan, AstraZeneca, Bayer Vital, BMS, Boehringer Ingelheim, CoAxia, Corimmun, Covidien, Daiichi-Sankyo, D-Pharm, Fresenius, GlaxoSmithKline, Janssen-Cilag, Johnson & Johnson, Knoll, Lilly, Medtronic, MindFrame, MSD, Neurobiological Technologies: Honoraria; The Department of Neurology at the University Duisburg-Essen received research grants from the German Research Council (DFG), German Ministry of Education and Research (BMBF), European Union, National Institutes of Health, Bertelsmann Foundation and Heinz: Research Funding. Dubner:steering committee member for Boehringer Ingelheim: Consultancy; St Jude Medical: Research Funding. Changsheng:steering committee member for Boehringer Ingelheim: Consultancy. Rothman:RTI Health Solutions: Employment. Zint:Boehringer Ingelheim: Employment. Elsaesser:Boehringer Ingelheim: Employment. Paquette:Boehringer Ingelheim: Employment. Bartels:Boehringer Ingelheim: Employment. Halperin:Bayer HealthCare: Consultancy; Boehringer Ingelheim: Consultancy.

Introduction The complete Fontan circulation is the definite palliation for many complex congenital cardiac lesions. After bi-directional Glenn anastomosis (BDG), two well-established techniques – intracardiac tunneling and extracardiac prosthesis – are available for completion, although the choice of technique is still a matter of debate. Material and methods We retrospectively reviewed the surgical and clinical records of patients with single ventricle physiology, who underwent intracardiac (group I) or extracardiac (group II) Fontan palliation after BDG. Results Complete data were available in 72 patients. Thirty-eight patients received intracardiac (median weight: 12.6 kg) and 34 patients extracardiac repair (median weight: 15.6 kg). Patients with intracardiac tunneling had longer cardiopulmonary bypass (CBP) time (170 min vs. 104 min; p < 0.001), longer ventilatory (39 h vs. 21 h; p = 0.009) and longer inotropic support (48 h vs. 10 h; p < 0.001). Ventilatory and inotropic support were dependent on CPB (r = 0.69 and r = 0.637) and on aortic cross-clamping (r = 0.785 and r = 0.705 only group I), but not dependent on age, weight or pulmonary artery pressure (PAP). Conclusions Both techniques are feasible without perioperative mortality. Normally developed children with good hemodynamics after BDG received an elective extracardiac procedure without fenestration later. Patients with developmental retardation, severe progressive cyanosis, myocardial dysfunction, or moderate to severe atrio-ventricular valve insufficiency are scheduled for an earlier intracardiac baffle repair with routine fenestration, as they are at higher risk. Prolonged CPB and aortic cross-clamping times adversely impact the early postoperative course. Further strategies must be developed to avoid these effects, particularly in the patient group at higher imminent risk.

Background The Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) was designed to provide prospectively collected information on patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke, with the aim of addressing treatment patterns and questions of effectiveness and safety. Methods and Results In this predefined analysis from GLORIA-AF, the baseline characteristics and initial antithrombotic management of the first 10,000 patients in Phase II of this large Registry Program are presented. Overall, 32.3% of patients received vitamin K antagonists (VKAs) and 47.7% received non-VKA oral anticoagulants (NOACs), while 12.3% received antiplatelet treatment and 7.6% did not receive any antithrombotic treatment. Among patients with CHA 2 DS 2 -VASc score ≥2, 6.7% received no antithrombotic treatment and 10.0% received aspirin. In Europe, treatment with dabigatran was as common as treatment with VKAs (38.8% and 37.8%, respectively). More than half of the patients were treated with NOACs (52.4%), while antiplatelet treatment was given to 5.7%, and 4.1% did not receive any antithrombotic treatment. In North America, treatment with dabigatran (25.0%) was as common as with VKAs (26.1%), but overall NOAC use was more common (52.1%) than with VKAs (26.1%); however, 14.1% received antiplatelet treatment, while 7.6% received no antithrombotic treatment. In Asia, treatment with VKAs (31.9%) was more prevalent than NOACs (25.5%), but antiplatelet treatment was given to 25.8%, and 16.9% did not receive any antithrombotic treatment. In Asia, only 60.7% of patients with high stroke risk received oral anticoagulants (OACs). Paroxysmal atrial fibrillation and minimally symptomatic (or asymptomatic) patients were often undertreated with OACs. Conclusion In this analysis, OAC use was high in Europe and North America, with overall NOAC use higher than VKA use. A considerable percentage of high-risk patients in North America still received antiplatelet treatment or were untreated, while Asian patients had a high proportion of aspirin use and nontreatment.

Vitamin K antagonists (VKAs) or the newer non-VKA oral anticoagulants (NOACs) are recommended for prevention of stroke in patients with atrial fibrillation (AF) and additional stroke risk factors. To assess changing patterns of antithrombotic therapy, GLORIA-AF Phase II collected data on patients

Introduction Cyclic alveolar recruitment/derecruitment (R/D) is an important mechanism of ventilator-associated lung injury. In experimental models this process can be measured with high temporal resolution by detection of respiratory-dependent oscillations of the paO2 (ΔpaO2). A previous study showed that end-expiratory collapse can be prevented by an increased respiratory rate in saline-lavaged rabbits. The current study compares the effects of increased positive end-expiratory pressure (PEEP) versus an individually titrated respiratory rate (RRind) on intra-tidal amplitude of Δ paO2 and on average paO2 in saline-lavaged pigs. Methods Acute lung injury was induced by bronchoalveolar lavage in 16 anaesthetized pigs. R/D was induced and measured by a fast-responding intra-aortic probe measuring paO2. Ventilatory interventions (RRind (n = 8) versus extrinsic PEEP (n = 8)) were applied for 30 minutes to reduce Δ paO2. Haemodynamics, spirometry and Δ paO2 were monitored and the Ventilation/Perfusion distributions were assessed by multiple inert gas elimination. The main endpoints average and Δ paO2 following the interventions were analysed by Mann-Whitney-U-Test and Bonferroni's correction. The secondary parameters were tested in an explorative manner. Results Both interventions reduced Δ paO2. In the RRind group, ΔpaO2 was significantly smaller (P < 0.001). The average paO2 continuously decreased following RRind and was significantly higher in the PEEP group (P < 0.001). A sustained difference of the ventilation/perfusion distribution and shunt fractions confirms these findings. The RRind application required less vasopressor administration. Conclusions Different recruitment kinetics were found compared to previous small animal models and these differences were primarily determined by kinetics of end-expiratory collapse. In this porcine model, respiratory rate and increased PEEP were both effective in reducing the amplitude of paO2 oscillations. In contrast to a recent study in a small animal model, however, increased respiratory rate did not maintain end-expiratory recruitment and ultimately resulted in reduced average paO2 and increased shunt fraction.