Weinreich, Michael

Abstract Background Upadacitinib (UPA), an oral selective and reversible JAK inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 induction trials. Aims Evaluate safety and efficacy of 52 weeks of UPA 15 mg QD (UPA15) and 30mg QD (UPA30) compared to placebo in patients achieving clinical response following UPA 45 mg treatment in the induction trials. Methods The primary analysis (n=451) evaluated efficacy and safety of UPA15 and UPA30 compared to PBO as maintenance therapy. The primary endpoint was clinical remission via adapted Mayo score at wk 52. Ranked secondary endpoints included endoscopic improvement, maintenance of clinical remission, corticosteroid-free clinical remission, maintenance of endoscopic improvement, endoscopic remission, maintenance of clinical response and Histologic-endoscopic mucosal improvement (HEMI). Results Baseline characteristics were similar between all treatment groups. Both UPA15 and UPA30 met the primary endpoint, and all secondary endpoints. Significantly greater percentages of patients receiving UPA15 and UPA30 vs. PBO achieved clinical remission (42.3% and 51.7%, vs. 12.1%), endoscopic improvement (48.7% and 61.6%, vs. 14.5%), maintenance of clinical remission (59.2% and 69.7%, vs. 22.2%), corticosteroid-free clinical remission (57.1% and 68.0%, vs. 22.2%), maintenance of endoscopic improvement (61.6% and 69.5%, vs. 18.9%), endoscopic remission, (24.2% and 25.9%, vs. 5.6%) and HEMI (34.8% and 49.3%, vs. 11.8%) (p<0.001 for all endpoints). UPA15 and UPA30 were both well-tolerated and no new safety signals were observed. Rates for serious adverse events (AEs) and AEs leading to treatment discontinuation were similar between UPA15 and UPA30 groups and lower compared to the PBO group. Most common AEs were nasopharyngitis and creatine phosphokinase elevation among UPA groups and UC exacerbation within the PBO group (30.2%). Herpes zoster was only reported in UPA groups (3.9%-4.1%). Similar rates of malignancy excluding NMSC were seen within all groups (0.7%-1.3%). MACE were only reported among patients receiving PBO (0.7%), while VTE were only found with UPA30 (1.3%). Conclusions In patients responding to UPA induction therapy, both UPA15 and UPA30 were safe and effective as maintenance treatment at 52 wk for all primary and secondary endpoints. Patients receiving UPA30 responded approximately 10% better for most endpoints compared to those receiving UPA15. Both doses were well-tolerated, with no new safety signals observed. Funding Agencies AbbVie

Abstract Background Upadacitinib (UPA) is a selective and reversible Janus kinase inhibitor.U-ACCOMPLISH is one of two phase 3 induction trials that evaluated the safety and efficacy of UPA 45 mg once daily (QD) in adults with ulcerative colitis (UC). Methods U-ACCOMPLISH was a multicentre, randomized, double-blind, placebo-controlled trial (NCT03653026) that enrolled patients with moderate-to-severe UC (defined as adapted Mayo score 5–9 with centrally read endoscopic score 2–3) who had inadequate response, loss of response, or intolerance to aminosalicylates, immunosuppressants, corticosteroids and/or biologics. Patients were randomized 2:1 to UPA 45 mg QD or placebo (PBO) for 8 weeks. At week 8, responders entered the maintenance phase and non-responders entered the extended treatment period to receive open-label UPA 45 mg QD for additional 8 weeks.The primary endpoint (clinical remission per adapted Mayo Score) and ranked secondary endpoints including symptomatic, endoscopic– histologic evaluations from the 8-week PBO-controlled period are reported here. Non-responder imputation incorporating multiple imputation for missing data due to COVID-19 are reported. Results 522 patients were randomized (UPA, n=345; PBO, n=177); the intent-to-treat population included 341 patients in UPA and 174 patients in PBO group. Baseline demographics and disease characteristics were similar between groups; 50.7% and 51.1% were biologic inadequate responders in UPA and PBO groups, respectively (Table 1). A significantly higher proportion of patients receiving UPA 45 mg QD (33.5%) versus PBO (4.1%) achieved the primary endpoint (adjusted treatment difference: 29.0% [23.2, 34.7]; P<0.001). A significantly higher proportion of patients receiving UPA versus PBO also achieved all ranked secondary endpoints (all P<0.001; Figure 1).Serious adverse events were reported by 3.2% and 4.5% of patients in UPA and PBO groups, respectively (Table 2). Similar rates of serious infection were observed in both groups (0.6%); 2 events each of herpes zoster and opportunistic infection were reported in UPA group. No active tuberculosis, malignancy, adjudicated major adverse cardiovascular events, or deaths were reported in the study. One patient with venous thromboembolism (deep vein thrombosis and pulmonary embolism) and 1 patient with gastrointestinal perforation were reported in the placebo group. Conclusion In U-ACCOMPLISH, 8-week UPA 45 mg QD induction treatment led to statistically significant improvements in clinical, endoscopic, and combined endoscopic-histologic endpoints. The treatment was well tolerated, and the safety profile and AE prevalence was comparable with previous studies of UPA with no new safety signals identified.

Background Bivalirudin may be an effective alternative anticoagulant to heparin for use in percutaneous peripheral interventions. We aimed to compare the safety and efficacy of bivalirudin versus heparin as the procedural anticoagulant agent in patients undergoing percutaneous peripheral intervention. Methods For this meta-analysis and systematic review, we conducted a search in PubMed, Medline, Embase, and Cochrane for all the clinical studies in which bivalirudin was compared to heparin as the procedural anticoagulant in percutaneous peripheral interventions. Outcomes studied included all-cause mortality, all-bleeding, major and minor bleeding, and access site complications. Results Eleven studies were included in the analysis, totaling 20,137 patients. There was a significant difference favoring bivalirudin over heparin for all-cause mortality (risk ratio 0.58, 95% CI 0.39–0.87), all-bleeding (risk ratio 0.62, 95% CI 0.50–0.78), major bleeding (risk ratio 0.61, 95% CI 0.39–0.96), minor bleeding (risk ratio 0.66, 95% CI 0.47–0.92), and access site complications (risk ratio 0.66, 95% CI 0.51–0.84). There was no significant difference in peri-procedural need for blood transfusions (risk ratio 0.79, 95% CI 0.57–1.08), myocardial infarction (risk ratio 0.87, 95% CI 0.59–1.28), stroke (risk ratio 0.77, 95% CI 0.59–1.01), intracranial bleeding (risk ratio 0.77, 95% CI 0.29–2.02), or amputations (OR 0.75, 95% CI 0.53–1.05). Conclusion Our meta-analysis suggests that bivalirudin use for percutaneous peripheral interventions is associated with lower all-cause mortality, bleeding, and access site complications as compared to heparin. Further large randomized trials are needed to confirm the current results.

Background Studies have shown that chronic total occlusion ( CTO ) in a noninfarct‐related artery in patients with ST‐segment–elevation myocardial infarction is linked to increased mortality. It remains unclear whether staged revascularization of a noninfarct‐related artery CTO in patients with ST‐segment–elevation myocardial infarction translates to improved outcomes. We performed a meta‐analysis to compare outcomes between patients presenting with ST‐segment–elevation myocardial infarction with concurrent CTO who underwent percutaneous coronary intervention of noninfarct‐related artery CTO versus those who did not. Method and Results We conducted an electronic database search of all published data. The primary end point was major adverse cardiovascular events. Secondary end points were all‐cause mortality, cardiovascular mortality, myocardial infarction, repeat revascularization with either percutaneous coronary intervention or coronary artery bypass grafting, stroke, and heart failure readmission. Odds ratios ( ORs ) and 95% confidence intervals ( CIs ) were computed. Random effects model was used and heterogeneity was considered if I 2 >25. Six studies (n=1253 patients) were included in the analysis. There was a significant difference in major adverse cardiovascular events ( OR , 0.54; 95% CI , 0.32–0.91), cardiovascular mortality ( OR , 0.43; 95% CI , 0.20–0.95), and heart failure readmissions ( OR , 0.57; 95% CI , 0.36–0.89), favoring the patients in the CTO percutaneous coronary intervention group. No significant differences were observed between the 2 groups for all‐cause mortality ( OR , 0.47; 95% CI , 0.22–1.00), myocardial infarction ( OR , 0.78; 95% CI , 0.41–1.46), repeat revascularization ( OR , 1.13; 95% CI , 0.56–2.27), and stroke ( OR , 0.51; 95% CI , 0.20–1.33). Conclusions In this meta‐analysis, CTO percutaneous coronary intervention of the noninfarct‐related artery in patients presenting with ST‐segment–elevation myocardial infarction was associated with a significant reduction in major adverse cardiovascular events, cardiovascular mortality, and heart failure readmissions.

BackgroundBivalirudin may be an effective anticoagulation alternative to heparin as anticoagulant agent in percutaneous transcatheter aortic valve interventions (PAVI). We aimed to compare safety and efficacy of bivalirudin versus heparin as the procedural anticoagulant agent in patients undergoing PAVI.MethodsWe conducted an electronic database search of all published data. The primary efficacy endpoints were all‐cause mortality, cardiovascular mortality, myocardial infarction, and stroke. Safety endpoints include major and life‐threatening bleed according to VARC and BARC bleeding, blood transfusion, vascular complications, and acute kidney injury. Odds ratios (OR) and 95% confidence intervals (CI) computed using the Mantel‐Haenszel method.ResultsThree studies (n = 1690 patients) were included, one randomized trial and two observational studies. There was a significant difference favoring bivalirudin over heparin for myocardial infarction (OR 0.41, 95%CI 0.20‐0.87). There was no significant difference in all‐cause mortality at 30 days (OR 0.97, 95%CI 0.62‐1.52), cardiovascular mortality (OR 1.03, 95%CI 0.52‐2.05), stroke (OR 1.23, 95%CI 0.62‐2.46), vascular complications (OR 0.96, 95%CI 0.70‐1.32), acute kidney injury (OR 1.03, 95%CI 0.53‐2.00), blood transfusion (OR 0.67, 95% CI 0.45‐1.01), major and life‐threatening bleed (OR 0.74, 95%CI 0.37‐1.49), and BARC bleeding (OR 0.52, 95%CI 0.23‐1.18).ConclusionsIn patient undergoing aortic valve interventions, no difference was seen between the use of bivalirudin and heparin as the procedural anticoagulant agent, except for a significant lower myocardial infarction events when bivalirudin was used. Further large randomized trials are needed to confirm current results.