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6/30/23, 2:17 AM TOMAHAWK Pathway Feedback Search Clinical Topics Home Studies TOMAHAWK TOMAHAWK Disease Cardiac arrest Trial question Is immediate angiography superior to delayed angiography in patients with resuscitated out-of- hospital cardiac arrest without ST-segment elevation? Study design Multi-center Open label RCT Population Characteristics of study participants 30.0% female N = 530 70.0% male 530 patients (161 female, 369 male) Inclusion criteria: adults with successfully resuscitated out-of-hospital cardiac arrest of possible cardiac origin Key exclusion criteria: ST-segment elevation or new LBBB; no ROSC upon hospital admission; the need for immediate coronary angiography/intervention; obvious extra-cardiac etiology or in- hospital cardiac arrest Interventions N=265 immediate-angiography (immediate coronary angiography) N=265 delayed-angiography (initial intensive care assessment with delayed or selective angiography) https://web.pathway.md/studies/recwz8D7ysqvzMGdX 1/2 6/30/23, 2:17 AM TOMAHAWK Pathway Primary outcome Death from any cause at day 30 54.0 % 54 46 40.5 % 27.0 % 13.5 % Borderline significant increase 0.0 % Immediate-angiography Delayed-angiography Borderline significant increase in death from any cause at day 30 (54% vs. 46%; HR 1.28, 95% CI 1 to 1.63) Secondary outcomes Borderline significant increase in death or severe neurologic deficit at day 30 (64.3% vs. 55.6%; RR 1.16, 95% CI 1 to 1.34) No significant difference in severe neurologic deficit (18.8% vs. 12.7%; RR 1.48, 95% CI 0.82 to 2.67) Safety outcomes No significant differences in moderate or severe bleeding, stroke, acute kidney failure leading to renal-replacement therapy. Conclusion In adults with successfully resuscitated out-of-hospital cardiac arrest of possible cardiac origin, immediate-angiography was inferior to delayed-angiography with respect to death from any cause at day 30. Reference Steffen Desch, Anne Freund, Ibrahim Akin et al. Angiography after Out-of-Hospital Cardiac Arrest without ST-Segment Elevation. N Engl J Med. 2021 Dec 30;385(27):2544-2553. Open reference URL https://web.pathway.md/studies/recwz8D7ysqvzMGdX 2/2

6/30/23, 2:17 AM TOPAZ-1 Pathway Feedback Search Clinical Topics Home Studies TOPAZ 1 TOPAZ 1 Disease Disease Cholangiocarcinoma Gallbladder cancer Trial question What is the role of durvalumab plus chemotherapy in patients with advanced biliary tract cancer? Study design Multi-center Double blinded RCT Population Characteristics of study participants 50.0% female N = 685 50.0% male 685 patients (340 female, 345 male) Inclusion criteria: patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease Key exclusion criteria: ampullary carcinoma; active or prior documented autoimmune or inflammatory disorders; known allergy or hypersensitivity to any study treatment Interventions N=341 durvalumab (1500 mg durvalumab plus gemcitabine and cisplatin) N=344 placebo (matching placebo plus gemcitabine and cisplatin) Primary outcome Overall survival https://web.pathway.md/studies/rec3OAXMDoELlr2at 1/2 6/30/23, 2:17 AM TOPAZ-1 Pathway 41.9 % 41.9 34.3 31.4 % 20.9 % Significant increase 10.5 % NNT = 13 0.0 % Durvalumab Placebo Significant increase in overall survival (41.9% vs. 34.3%; HR 1.22, 95% CI 1.03 to 1.52) Secondary outcomes Significant increase in progression-free survival (7.2 months vs. 5.7 months; HR 1.33, 95% CI 1.12 to 1.59) Borderline significant increase in objective response rate (26.7% vs. 18.7%; OR 1.6, 95% CI 1.11 to 2.31) Safety outcomes No significant difference in grade 3 or 4 adverse events. Conclusion In patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease, durvalumab was superior to placebo with respect to overall survival. Reference Do-Youn Oh, M.D., Ph.D. et al. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evid. 2022;1(8). Open reference URL https://web.pathway.md/studies/rec3OAXMDoELlr2at 2/2

6/30/23, 2:19 AM TOPCAT Pathway Feedback Search Clinical Topics Home Studies TOPCAT TOPCAT Disease Heart failure Trial question What is the effect of spironolactone in patients with HF and a preserved LVEF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 52.0% female N = 3445 48.0% male 3445 patients (1775 female, 1670 male) Inclusion criteria: patients with HF and a preserved LVEF Key exclusion criteria: severe systemic illness with a life expectancy of < 3 years, severe renal dysfunction, and specific coexisting conditions, medications, or acute events Interventions N=1722 spironolactone (15 to 45 mg daily) N=1723 placebo (matching placebo) Primary outcome Death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure 20.4 https://web.pathway.md/studies/reccOqPEnjny7ynTe 1/2 6/30/23, 2:19 AM TOPCAT Pathway 0 20.4 % 18.6 15.3 % 10.2 % 5.1 % No significant difference 0.0 % Spironolactone Placebo No significant difference in death from cardiovascular causes, aborted cardiac arrest, or hospitalization for HF (18.6% vs. 20.4%; HR 0.89, 95% CI 0.77 to 1.04) Secondary outcomes Significant decrease in hospitalization for HF (12% vs. 14.2%; HR 0.83, 95% CI 0.69 to 0.99) No significant difference in cardiovascular death (9.3% vs. 10.2%; HR 0.9, 95% CI 0.73 to 1.12) No significant difference in aborted cardiac arrest (0.2% vs. 0.3%; HR 0.6, 95% CI 0.14 to 2.5) Safety outcomes No significant differences in serious adverse events, serum creatinine level 3.0 mmg/dL, or dialysis. Significant difference in hyperkalemia (18.7% vs. 9.1%) and hypokalemia (16.2% vs. 22.9%). Conclusion In patients with HF and a preserved LVEF, spironolactone was not superior to placebo with respect to death from cardiovascular causes, aborted cardiac arrest, or hospitalization for HF. Reference Pitt B, Pfeffer MA, Assmann SF et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Apr 10;370(15):1383-92. Open reference URL https://web.pathway.md/studies/reccOqPEnjny7ynTe 2/2

6/30/23, 2:19 AM TRAAP Pathway Feedback Search Clinical Topics Home Studies TRAAP TRAAP Disease Postpartum hemorrhage Trial question What is the role of prophylactic administration of tranexamic acid in addition to prophylactic oxytocin in the incidence of postpartum hemorrhage in women with vaginal delivery? Study design Multi-center Double blinded RCT Population 3891 female patients Inclusion criteria: women in labor who had a planned vaginal delivery of a singleton live fetus at 35 weeks of gestation and were receiving prophylactic oxytocin after delivery Key exclusion criteria: increased risk of venous or arterial thrombosis or bleeding, a history of epilepsy or seizure, or poor comprehension of oral French Interventions N=1921 tranexamic acid (1 g dose IV over a period of 30-60 seconds during the 2 minutes after delivery) N=1918 placebo (normal saline) Primary outcome Postpartum hemorrhage of at least 500 ml 9.8 % 9.8 8.1 7.4 % 4.9 % 2.5 % https://web.pathway.md/studies/recKdpVxNr55njlGG 1/2 6/30/23, 2:19 AM TRAAP Pathway No significant difference 0.0 % Tranexamic acid Placebo No significant difference in postpartum hemorrhage of at least 500 ml (8.1% vs. 9.8%; RR 0.83, 95% CI 0.68 to 1.01) Secondary outcomes Significant decrease in provider-assessed clinically significant postpartum hemorrhage (7.8% vs. 10.4%; RR 0.74, 95% CI 0.61 to 0.91) Significant decrease in the use of additional uterogenic agents (7.2% vs. 9.7%; RR 0.75, 95% CI 0.61 to 0.92) Significant decrease in blood loss > 500 mL in the collector bag (6.6% vs. 8.8%; RR 0.75, 95% CI 0.6 to 0.94) Safety outcomes No significant difference in adverse events at 3 months. Significant difference in non-severe frequency of vomiting or nausea in the delivery room (7.0% vs. 3.2%). Conclusion In women in labor who had a planned vaginal delivery of a singleton live fetus at 35 weeks of gestation and were receiving prophylactic oxytocin after delivery, tranexamic acid was not superior to placebo with respect to postpartum hemorrhage of at least 500 ml. Reference Sentilhes L, Winer N, Azria E et al. Tranexamic Acid for the Prevention of Blood Loss after Vaginal Delivery. N Engl J Med. 2018 Aug 23;379(8):731-742. Open reference URL https://web.pathway.md/studies/recKdpVxNr55njlGG 2/2

6/30/23, 2:19 AM TRAAP2 Pathway Feedback Search Clinical Topics Home Studies TRAAP2 TRAAP2 Disease Cesarean delivery Trial question What is the role of tranexamic acid in women undergoing Cesarean delivery? Study design Multi-center Double blinded RCT Population 4431 female patients Inclusion criteria: women undergoing Cesarean delivery at 34 gestational weeks Key exclusion criteria: previous episode of deep vein thrombosis or PE; increased risk of venous or arterial thrombosis or bleeding; history of epilepsy or seizure; prenatal Hgb level 9 g/dL in the week before delivery; autoimmune disease Interventions N=2222 tranexamic acid (intravenous administration of prophylactic uterotonic agent and 1 g tranexamic acid) N=2209 placebo (intravenous administration of prophylactic uterotonic agent and matching placebo) Primary outcome Postpartum hemorrhage 31.6 % 31.6 26.7 23.7 % 15.8 % Significant decrease 7.9 % https://web.pathway.md/studies/recJXzqro2SbR7uMq 1/2 6/30/23, 2:19 AM TRAAP2 Pathway NNT = 20 0.0 % Tranexamic acid Placebo Significant decrease in postpartum hemorrhage (26.7% vs. 31.6%; RR 0.84, 95% CI 0.75 to 0.94) Secondary outcomes No significant difference in gravimetrically estimated blood loss (689 mL vs. 719 mL; ARD -30.6, 95% CI -90.2 to 29) No significant difference in clinically significant postpartum hemorrhage according to health care provider (13.6% vs. 14.8%; RR 0.92, 95% CI 0.79 to 1.08) No significant difference in use of additional uterotonic agents for excessive bleeding (5.9% vs. 7.2%; RR 0.81, 95% CI 0.64 to 1.03) Safety outcomes No significant difference in thromboembolic events. Significant difference in vomiting or nausea in the operating room (43.0% vs. 36.3%). Conclusion In women undergoing Cesarean delivery at 34 gestational weeks, tranexamic acid was superior to placebo with respect to postpartum hemorrhage. Reference Lo c Sentilhes, Marie V S nat, Ma la Le Lous et al. Tranexamic Acid for the Prevention of Blood Loss after Cesarean Delivery. N Engl J Med. 2021 Apr 29;384(17):1623-1634. Open reference URL https://web.pathway.md/studies/recJXzqro2SbR7uMq 2/2

6/30/23, 2:19 AM TRACS Pathway Feedback Search Clinical Topics Home Studies TRACS TRACS Disease Disease Disease Aortic regurgitation Aortic stenosis Mitral regu Trial question Is restrictive perioperative transfusion strategy noninferior to liberal transfusion strategy in patients undergoing cardiac surgery? Study design Single center Single blinded RCT Population Characteristics of study participants 38.0% female N = 502 62.0% male 502 patients (192 female, 310 male) Inclusion criteria: adult patients undergoing elective cardiac surgery with cardiopulmonary bypass Key exclusion criteria: emergency procedure; LV aneurysm resection; inability to receive blood products; chronic anemia; low platelet count; hepatic dysfunction; end-stage renal disease Interventions N=249 a restrictive strategy (blood transfusion when hematocrit < 24%) N=253 a liberal strategy (blood transfusion when hematocrit < 30%) Primary outcome Death from all causes and severe morbidity during hospital stay https://web.pathway.md/studies/reccOHItnzERyzgCZ 1/2 6/30/23, 2:19 AM TRACS Pathway 11.0 % 11 10 8.3 % 5.5 % Difference not exceeding nonferiority margin 2.8 % 0.0 % A restrictive strategy A liberal strategy Difference not exceeding nonferiority margin in death from all causes and severe morbidity during the hospital stay (11% vs. 10%; AD 1%, 95% CI -6 to 4) Secondary outcomes No significant difference in death at day 30 (6% vs. 5%; AD 1%, 95% CI -19.45 to 21.45) No significant difference in cardiac complications (24% vs. 21%; AD 3%, 95% CI -2.3 to 8.3) Conclusion In adult patients undergoing elective cardiac surgery with cardiopulmonary bypass, a restrictive strategy was noninferior to a liberal strategy with respect to death from all causes and severe morbidity during the hospital stay. Reference Ludhmila A Hajjar, Jean-Louis Vincent, Filomena R B G Galas et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010 Oct 13;304(14):1559-67. Open reference URL https://web.pathway.md/studies/reccOHItnzERyzgCZ 2/2

6/30/23, 2:19 AM TRACT Pathway Feedback Search Clinical Topics Home Studies TRACT TRACT Disease Iron deficiency anemia Trial question What is the role of immediate transfusion in children with uncomplicated severe anemia? Study design Multi-center Open label RCT Population Characteristics of study participants 44.0% female N = 1565 56.0% male 1565 patients (683 female, 882 male) Inclusion criteria: children 2 months to 12 years of age with uncomplicated severe anemia Key exclusion criteria: known chronic disease including kidney or liver failure, malignant conditions, or congenital heart disease; burns; trauma; surgery; previous transfusions during the same hospitalization; or exclusively breastfed children Interventions N=778 immediate transfusion (20 mL or 30 mL of whole-blood equivalent per kilogram of body weight) N=787 control (no immediate transfusion; transfusion with 20 mL of whole-blood equivalent per kilogram triggered by new signs of clinical severity or a drop in Hgb to < 4 g/dL) https://web.pathway.md/studies/recupSZUYCwjqjdD9 1/2 6/30/23, 2:19 AM TRACT Pathway Primary outcome Rate of death by day 28 1.7 % 1.7 1.3 % 0.9 0.8 % 0.4 % No significant difference 0.0 % Immediate transfusion Control No significant difference in the rate of death by day 28 (0.9% vs. 1.7%; HR 0.54, 95% CI 0.22 to 1.36) Secondary outcomes Borderline significant increase in length of hospital stay (3 days vs. 4 days; HR 1.62, 95% CI 1.46 to 1.8) No significant difference in readmission to hospital at 180 days (15.8% vs. 14.4%; HR 1.09, 95% CI 0.84 to 1.4) Borderline significant decrease in development of severe anemia after discharge (13.6% vs. 18%; HR 0.73, 95% CI 0.56 to 0.94) Safety outcomes No significant difference in serious adverse events. Significant differences in development of new profound anemia during primary hospitalization (1.4% vs. 39.3%), correction of anemia (51.3% vs. 5.5%). Conclusion In children 2 months to 12 years of age with uncomplicated severe anemia, immediate transfusion was not superior to control with respect to the rate of death by day 28. Reference Kathryn Maitland, Sarah Kiguli, Peter Olupot-Olupot et al. Immediate Transfusion in African Children with Uncomplicated Severe Anemia. N Engl J Med. 2019 Aug 1;381(5):407-419. Open reference URL https://web.pathway.md/studies/recupSZUYCwjqjdD9 2/2

6/30/23, 2:19 AM TRANSCEND Pathway Feedback Search Clinical Topics Home Studies TRANSCEND TRANSCEND Disease Disease Disease Acute ischemic stroke Coronary artery disease Diabetes m Trial question What is the role of telmisartan in patients intolerant to ACEIs with CVD or diabetes? Study design Multi-center Double blinded RCT Population Characteristics of study participants 43.0% female N = 5926 57.0% male 5926 patients (2547 female, 3379 male) Inclusion criteria: patients intolerant to ACEIs with CVD or diabetes with end-organ damage Key exclusion criteria: symptomatic congestive HF; uncontrolled hypertension on treatment; renal artery stenosis; hepatic dysfunction; proteinuria Interventions N=2954 telmisartan (at a dose of 80 mg/day) N=2972 placebo (matching placebo) Primary outcome Composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure 17 17 0 % https://web.pathway.md/studies/recR3LSw0iZHk9lhL 1/2 6/30/23, 2:19 AM 17.0 % TRANSCEND Pathway 15.7 12.8 % 8.5 % 4.3 % No significant difference 0.0 % Telmisartan Placebo No significant difference in composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for HF (15.7% vs. 17%; HR 0.92, 95% CI 0.81 to 1.05) Secondary outcomes Significant decrease in composite of cardiovascular death, myocardial infarction, or stroke (13% vs. 14.8%; HR 0.87, 95% CI 0.76 to 1) Significant decrease in hospitalization for cardiovascular cause (30.3% vs. 33%; RR 0.92, 95% CI 0.85 to 0.99) No significant difference in revascularization procedures (11.8% vs. 13.1%; HR 0.9, 95% CI 0.77 to 1.03) Safety outcomes Significant difference in discontinuation of study drug due to hypotensive symptoms (0.98% vs. 0.54%). Conclusion In patients intolerant to ACEIs with CVD or diabetes with end-organ damage, telmisartan was not superior to placebo with respect to the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for HF. Reference Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, S Yusuf, K Teo et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008 Sep 27;372(9644):1174-83. Open reference URL https://web.pathway.md/studies/recR3LSw0iZHk9lhL 2/2

6/30/23, 2:19 AM TRANSFORM-HF Pathway Feedback Search Clinical Topics Home Studies TRANSFORM HF TRANSFORM HF Disease Heart failure Trial question Is torsemide superior to furosemide in patients hospitalized with HF? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 2859 63.0% male 2859 patients (1058 female, 1801 male) Inclusion criteria: in-hospital patients with new or worsening HF Key exclusion criteria: RRT; heart transplant; implant anticipated in < 3 months; life expectancy < 12 months; known hypersensitivity to study drugs Interventions N=1431 torsemide (oral dose left to the treating physician) N=1428 furosemide (oral dose between 2:1 and 4:1 of torsemide's) Primary outcome Death from all causes 26.2 % 26.1 26.2 https://web.pathway.md/studies/recz1VZ1NGjr1OXy9 1/2 6/30/23, 2:19 AM TRANSFORM-HF Pathway 6 6 19.6 % 13.1 % 6.5 % No significant difference 0.0 % Torsemide Furosemide No significant difference in death from all causes (26.1% vs. 26.2%; HR 1.02, 95% CI 0.89 to 1.18) Secondary outcomes No significant difference in death from all causes or hospitalization at 12 months (47.3% vs. 49.3%; HR 0.92, 95% CI 0.83 to 1.02) No significant difference in total hospitalizations at 12 months (37.5% vs. 40.4%; RR 0.94, 95% CI 0.84 to 1.07) Conclusion In in-hospital patients with new or worsening HF, torsemide was not superior to furosemide with respect to death from all causes. Reference Frederik H Verbrugge, Venu Menon. Torsemide comparison with furosemide for management of heart failure (TRANSFORM-HF) trial. Eur Heart J Acute Cardiovasc Care. 2022 Dec 27;11(12):931- 932. Open reference URL https://web.pathway.md/studies/recz1VZ1NGjr1OXy9 2/2

6/30/23, 2:23 AM Transfusion strategies for acute upper GI bleeding Pathway Feedback Search Clinical Topics Home Studies Transfusion strategies for acute upper GI bleeding Transfusion strategies for acute upper GI bleeding Disease Non-variceal upper gastrointesti Trial question What is the role of restrictive transfusion strategy in patients with severe acute upper gastrointestinal bleeding? Study design Single center Open label RCT Population Characteristics of study participants 32.0% female N = 921 68.0% male 921 patients (284 female, 605 male) Inclusion criteria: patients with severe acute upper gastrointestinal bleeding Key exclusion criteria: massive exsanguinating bleeding; an acute coronary syndrome, symptomatic peripheral vasculopathy, stroke, TIA, or transfusion within the previous 90 days; a recent history of trauma or surgery; or lower gastrointestinal bleeding Interventions N=461 restrictive blood transfusion therapy (transfusion when the Hgb level fell below 7 g/dL) N=460 liberal blood transfusion therapy (transfusion when the Hgb fell < 9 g/dL) Primary outcome https://web.pathway.md/studies/recCLx4ijXGIpAdIn 1/2 6/30/23, 2:23 AM Transfusion strategies for acute upper GI bleeding Pathway Death at 45 days 9.0 % 9 6.8 % 5 4.5 % Significant decrease 2.3 % NNT = 25 0.0 % Restrictive blood transfusion therapy Liberal blood transfusion therapy Significant decrease in death at 45 days (5% vs. 9%; HR 0.55, 95% CI 0.33 to 0.92) Secondary outcomes Significant decrease in further bleeding (10% vs. 16%; HR 0.62, 95% CI 0.43 to 0.91) No significant difference in death, in patients with bleeding from peptic ulcer (3% vs. 5%; HR 0.7, 95% CI -0.51 to 1.91) Significant decrease in death, in patients with cirrhosis and Child-Pugh class A or B (4% vs. 12%; HR 0.3, 95% CI 0.11 to 0.85) Safety outcomes Significant differences in adverse events (40% vs. 48%, p = 0.02). Conclusion In patients with severe acute upper gastrointestinal bleeding, restrictive blood transfusion therapy was superior to liberal blood transfusion therapy with respect to death at 45 days. Reference Villanueva C, Colomo A, Bosch A et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013 Jan 3;368(1):11-21. Open reference URL https://web.pathway.md/studies/recCLx4ijXGIpAdIn 2/2

6/30/23, 2:20 AM TRAP-LRTI Pathway Feedback Search Clinical Topics Home Studies TRAP LRTI TRAP LRTI Disease Acute bronchitis Trial question Is placebo noninferior to azithromycin in adults with lower respiratory tract infection associated with low procalcitonin concentration? Study design Multi-center Double blinded RCT Population 499 patients Inclusion criteria: adults with clinically suspected non-pneumonia lower respiratory tract infection and symptom duration from 24 hours to 28 days Key exclusion criteria: long-term invasive mechanical ventilation for any indication, cystic fibrosis or chronic bronchiectasis, infection at any other anatomic site requiring antibacterial therapy, immunosuppression Interventions N=250 placebo (matching placebo for 5 days) N=249 azithromycin (an oral dose of 250 mg; 2 capsules on day 1 followed by one capsule daily for 4 days) Primary outcome Clinical improvement at day 5 69.0 % 69 63 51.8 % 34.5 % https://web.pathway.md/studies/recGpKvldvqEZ6Myj 1/2 6/30/23, 2:20 AM TRAP-LRTI Pathway 17.3 % Difference exceeding nonferiority margin 0.0 % Placebo Azithromycin Difference exceeding nonferiority margin in clinical improvement at day 5 (63% vs. 69%; ARD -6, 95% CI -15 to 2) Secondary outcomes No significant difference in abdominal pain at day 5 (16% vs. 23%; ARD -7, 95% CI -14.47 to 0.47) Conclusion In adults with clinically suspected non-pneumonia lower respiratory tract infection and symptom duration from 24 hours to 28 days, placebo was not noninferior to azithromycin with respect to clinical improvement at day 5. Reference Ephraim L Tsalik, Nadine G Rouphael, Ruxana T Sadikot et al. Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trial. Lancet Infect Dis. 2023 Apr;23(4):484-495. Open reference URL https://web.pathway.md/studies/recGpKvldvqEZ6Myj 2/2

6/30/23, 2:20 AM TRAPS Pathway Feedback Search Clinical Topics Home Studies TRAPS TRAPS Disease Antiphospholipid syndrome Trial question Is rivaroxaban noninferior to warfarin in high-risk patients with thrombotic antiphospholipid syndrome? Study design Multi-center Open label RCT Population Characteristics of study participants 64.0% female N = 120 36.0% male 120 patients (77 female, 43 male) Inclusion criteria: high-risk patients with thrombotic antiphospholipid syndrome Key exclusion criteria: severe hypersensitivity to rivaroxaban, pregnancy or breast feeding, concomitant treatment with other anticoagulants, major surgical procedure or trauma within 30 days, gastrointestinal bleeding within 6 months of randomization, chronic hemorrhagic disorder, intracranial neoplasm, AVM or aneurysm Interventions N=59 rivaroxaban (20 mg once daily; 15 mg once daily based on kidney function) N=61 warfarin (INR target 2.5) https://web.pathway.md/studies/recmv6xb2KgXegXby 1/2 6/30/23, 2:20 AM TRAPS Pathway Primary outcome Vascular death, thromboembolic events, or major bleeding 19.0 % 19 14.3 % 9.5 % Difference exceeding nonferiority margin 4.8 % 3 0.0 % Rivaroxaban Warfarin Difference exceeding nonferiority margin in vascular death, thromboembolic events, or major bleeding (19% vs. 3%; HR 6.7, 95% CI 1.5 to 30.5) Secondary outcomes No significant difference in major bleeding (7% vs. 3%; HR 2.5, 95% CI 0.5 to 13.6) Conclusion In high-risk patients with thrombotic antiphospholipid syndrome, rivaroxaban was not noninferior to warfarin with respect to vascular death, thromboembolic events, or major bleeding. Reference Pengo V, Denas G, Zoppellaro G et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Open reference URL https://web.pathway.md/studies/recmv6xb2KgXegXby 2/2

6/30/23, 2:20 AM TRAVERSE Pathway Feedback Search Clinical Topics Home Studies TRAVERSE TRAVERSE Disease Male hypogonadism Trial question Is testosterone-replacement therapy noninferior to placebo in men with hypogonadism and preexisting or a high risk of CVD? Study design Multi-center Double blinded RCT Population 5204 male patients Inclusion criteria: men, aged 45-80 years, who had preexisting or a high risk of CVD and who reported symptoms of hypogonadism and had 2 fasting testosterone levels < 300 ng/dL Key exclusion criteria: congenital or acquired severe hypogonadism; history of prostate cancer or prostate nodules; elevated screening PSA level; thrombophilia; uncontrolled HF Interventions N=2601 testosterone (daily transdermal 1.62% gel, dose adjusted to maintain testosterone levels between 350-750 ng/dL) N=2603 placebo (matching placebo gel daily) Primary outcome First occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke 7.3 % 7.3 7 5.5 % 3.6 % 1.8 % https://web.pathway.md/studies/recAIrRuZ5jCOpbXM 1/2 6/30/23, 2:20 AM TRAVERSE Pathway Difference not exceeding nonferiority margin 0.0 % Testosterone Placebo Difference not exceeding nonferiority margin in first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (7% vs. 7.3%; HR 0.96, 96% CI 0.78 to 1.17) Secondary outcomes No significant difference in first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization (10.4% vs. 10.1%; HR 1.02, 95% CI 0.86 to 1.21) No significant difference in death from cardiovascular causes (3.4% vs. 4%; HR 0.84, 95% CI 0.63 to 1.12) No significant difference in nonfatal myocardial infarction (2.6% vs. 2.4%; HR 1.1, 95% CI 0.78 to 1.56) Safety outcomes No significant differences in adverse and serious adverse event, prostate cancer. Significant differences in nonfatal arrhythmias warranting intervention (5.2% vs. 3.3%), AF (3.5% vs. 2.4%), AKI (2.3% vs. 1.5%). Conclusion In men, aged 45-80 years, who had preexisting or a high risk of CVD and who reported symptoms of hypogonadism and had 2 fasting testosterone levels < 300 ng/dL, testosterone was noninferior to placebo with respect to first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Reference A Michael Lincoff, Shalender Bhasin, Panagiotis Flevaris et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023 Jun 16. Open reference URL https://web.pathway.md/studies/recAIrRuZ5jCOpbXM 2/2

6/30/23, 2:23 AM Treadmill balance training in older adults Pathway Feedback Search Clinical Topics Home Studies Treadmill balance training in older adults Treadmill balance training in older adults Disease Falls in the elderly Trial question What is the effect of treadmill perturbation-based balance training in community-dwelling older adults? Study design Single center Open label RCT Population Characteristics of study participants 56.0% female N = 140 44.0% male 140 patients (79 female, 61 male) Inclusion criteria: community-dwelling adults 65 years of age and were able to walk without a walking aid Key exclusion criteria: orthopedic surgery within the past 12 months; osteoporosis or osteoporosis-related fractures; progressive neurological disease; an unstable medical condition preventing safe participation; severe cognitive impairment Interventions N=70 perturbation-based balance training (four 20-minute perturbation-based balance training sessions, with postural disturbances induced by sudden treadmill accelerations) https://web.pathway.md/studies/recvqSF3uO3lbvVkf 1/2 6/30/23, 2:23 AM Treadmill balance training in older adults Pathway N=70 treadmill walking training (four 20-minute regular treadmill walking sessions at the participant's preferred walking speed) Primary outcome Daily-life fall rates in past 12 months 1.1 1.14 0.9 0.9 0.6 0.3 No significant difference 0.0 Perturbation-based balance training Treadmill walking training No significant difference in daily-life fall rates in the past 12 months (0.9 vs. 1.14; RR 0.78, 95% CI 0.48 to 1.27) Secondary outcomes No significant difference in participants with at least 1 fall (49% vs. 57%; RR 0.87, 95% CI 0.63 to 1.2) No significant difference in median time to first fall (94 days vs. 123 days; HR 0.7, 95% CI 0.43 to 1.14) No significant difference in participants with at least 1 fall-related injury (24% vs. 34%; RR 0.74, 95% CI 0.43 to 1.25) Conclusion In community-dwelling adults 65 years of age and were able to walk without a walking aid, perturbation-based balance training was not superior to treadmill walking training with respect to a daily-life fall rates in the past 12 months. Reference Jens Eg N rgaard, Stig Andersen, Jesper Ryg et al. Effect of Treadmill Perturbation-Based Balance Training on Fall Rates in Community-Dwelling Older Adults: A Randomized Clinical Trial. JAMA Netw Open. 2023 Apr 3;6(4):e238422. Open reference URL https://web.pathway.md/studies/recvqSF3uO3lbvVkf 2/2

6/30/23, 2:20 AM TREAT Pathway Feedback Search Clinical Topics Home Studies TREAT TREAT Disease Disease Disease Anemia of chronic kidney disease Chronic kidney disease Diabetes m Trial question What is the role of darbepoetin alfa in patients with T2DM and CKD, and anemia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 57.0% female N = 4038 43.0% male 4038 patients (2312 female, 1726 male) Inclusion criteria: patients with diabetes, CKD, and moderate anemia (Hgb level < 9.0 g/dL) who were not undergoing dialysis Key exclusion criteria: uncontrolled hypertension; previous kidney transplantation or scheduled receipt of a kidney transplant from a living related donor; current use of intravenous antibiotics, chemotherapy, or radiation therapy; diagnosed human immunodeficiency virus infection; active bleeding; a hematologic disease; or pregnancy Interventions N=2012 darbepoetin alfa (Aranesp, Amgen, to target Hgb level of approximately 13 g/dL) N=2026 placebo (matching placebo) https://web.pathway.md/studies/recu4mYJGtHCeHrD4 1/2 6/30/23, 2:20 AM TREAT Pathway Primary outcome Death or a cardiovascular event 31.4 % 31.4 29.7 23.5 % 15.7 % 7.8 % No significant difference 0.0 % Darbepoetin alfa Placebo No significant difference in death or a cardiovascular event (31.4% vs. 29.7%; HR 1.05, 95% CI 0.94 to 1.17) Secondary outcomes No significant difference in death or end-stage renal disease (32.4% vs. 30.5%; HR 1.06, 95% CI 0.95 to 1.19) Significant increase in fatal or nonfatal stroke (5% vs. 2.6%; HR 1.92, 95% CI 1.38 to 2.68) Significant decrease in cardiac revascularization (4.2% vs. 5.8%; HR 0.71, 95% CI 0.54 to 0.94) Safety outcomes Significant difference in change in patient-reported fatigue (54.7% vs. 49.5%,p = 0.002). Conclusion In patients with diabetes, CKD, and moderate anemia (Hgb level < 9.0 g/dL) who were not undergoing dialysis, darbepoetin alfa was not superior to placebo with respect to death or a cardiovascular event. Reference Pfeffer MA, Burdmann EA, Chen CY et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009 Nov 19;361(21):2019-32. Open reference URL https://web.pathway.md/studies/recu4mYJGtHCeHrD4 2/2

6/30/23, 2:20 AM TREATY Pathway Feedback Search Clinical Topics Home Studies TREATY TREATY Disease Obesity Trial question Is a regimen of time-restricted with calorie restriction superior to calorie restriction only in patients with obesity? Study design Single center Open label RCT Population Characteristics of study participants 49.0% female N = 139 51.0% male 139 patients (68 female, 71 male) Inclusion criteria: adult patients with obesity Key exclusion criteria: acute or chronic viral hepatitis; malignant tumors; serious cardiovascular or cerebrovascular disease; type 1 and T2DM; serious liver dysfunction; CKD Interventions N=69 time-restricted eating (eating only between 8:00 am and 4:00 pm with calorie restriction) N=70 daily calorie restriction (continuous energy restriction without a restriction of feeding time) Primary outcome Reduction in body weight at 1 year https://web.pathway.md/studies/recwlXbPMJWWUEf85 1/2 6/30/23, 2:20 AM TREATY Pathway 8.0 kg 8 6.3 6.0 kg 4.0 kg 2.0 kg No significant difference 0.0 kg Time-restricted eating Daily calorie restriction No significant difference in reduction in body weight at 1 year (8 kg vs. 6.3 kg; AD 1.8 kg, 95% CI -0.4 to 4) Secondary outcomes No significant difference in reduction in BMI at 1 year (2.9 vs. 2.3; AD 0.7, 95% CI -0.1 to 1.5) No significant difference in reduction in waist circumference at 1 year (8.8 cm vs. 7 cm; AD 1.8 cm, 95% CI -0.5 to 4) No significant difference in reduction in body fat mass at 1 year (5.9 kg vs. 4.5 kg; AD 1.5 kg, 95% CI -0.2 to 3.1) Safety outcomes No significant difference in adverse events. Conclusion In adult patients with obesity, time-restricted eating was not superior to daily calorie restriction with respect to reduction in body weight at 1 year. Reference Deying Liu, Yan Huang, Chensihan Huang et al. Calorie Restriction with or without Time-Restricted Eating in Weight Loss. N Engl J Med. 2022 Apr 21;386(16):1495-1504. Open reference URL https://web.pathway.md/studies/recwlXbPMJWWUEf85 2/2

6/30/23, 2:20 AM TRICC Pathway Feedback Search Clinical Topics Home Studies TRICC TRICC Disease Transfusion strategies in critical Trial question Is restrictive strategy of transfusion superior to liberal strategy in critically ill patients with euvolemia who had Hgb concentrations < 9.0 g/dL within 72 hours after admission to ICU? Study design Multi-center Single blinded RCT Population Characteristics of study participants 37.0% female N = 838 63.0% male 838 patients (314 female, 524 male) Inclusion criteria: critically ill patients with euvolemia who had Hgb concentrations < 9.0 g/dL within 72 hours after admission to ICU Key exclusion criteria: age < 16 years; inability to receive blood products; active blood loss at the time of enrollment ,chronic anemia; pregnancy; brain death or imminent death Interventions N=418 restrictive blood transfusion therapy (transfusion when Hgb concentration < 7.0 g/dL, Hgb concentrations maintained at 7.0-9.0 g/dL) N=420 liberal blood transfusion therapy (transfusion when Hgb concentration < 10.0 g/dL, Hgb concentration maintained at 10.0-12.0 g/dL) https://web.pathway.md/studies/recUBPNL3FHnamUfN 1/2 6/30/23, 2:20 AM TRICC Pathway Primary outcome Death at 30 days 23.3 % 23.3 18.7 17.5 % 11.7 % 5.8 % No significant difference 0.0 % Restrictive blood transfusion therapy Liberal blood transfusion therapy No significant difference in death at 30 days (18.7% vs. 23.3%; AD 4.7%, 95% CI -0.84 to 10.2) Secondary outcomes Significant decrease in death at 30 days among patients with APACHE II score 20 (8.7% vs. 16.1%; RR 0.54, 95% CI 1 to 13.6) No significant difference in death in the hospital (22.3% vs. 28.1%; AD 5.8%, 95% CI -0.3 to 11.7) No significant difference in length of stay in the hospital (34.8 days vs. 35.5 days; AD 0.7 days, 95% CI -1.9 to 3.4) Safety outcomes No significant differences in rates of cardiac events, infectious complications, multiorgan failure. Significant differences in pulmonary edema (5.3% vs. 10.7%), myocardial infarction (0.7% vs. 2.9%). Conclusion In critically ill patients with euvolemia who had Hgb concentrations < 9.0 g/dL within 72 hours after admission to ICU, restrictive blood transfusion therapy was not superior to liberal blood transfusion therapy with respect to death at 30 days. Reference Hebert PC, Wells G, Blajchman MA et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999 Feb 11;340(6):409-17. Open reference URL https://web.pathway.md/studies/recUBPNL3FHnamUfN 2/2

6/30/23, 2:20 AM TRICS III 6 month follow up Pathway Feedback Search Clinical Topics Home Studies TRICS III 6 month follow up TRICS III 6 month follow up Disease Transfusion strategies in critical Trial question Is the restrictive strategy for red-cell transfusion noninferior to a liberal strategy among patients undergoing cardiac surgery who were at moderate-to-high risk for death? Study design Multi-center Open label RCT Population Characteristics of study participants 35.5% female N = 5243 64.5% male 5243 patients (1721 female, 3139 male) Inclusion criteria: adult patients undergoing cardiac surgery with cardiopulmonary bypass who were at moderate-to-high predicted risk for death Key exclusion criteria: unable to receive or refusal of blood products, involvement in a preoperative autologous pre-donation program, undergoing heart transplant or surgery solely for insertion of a ventricular assist device Interventions N=2430 a restrictive transfusion strategy (red cell transfusion if the Hgb concentration < 7.5 g/dL intraoperatively or postoperatively) https://web.pathway.md/studies/recdiG8d9bwdfAE0S 1/2 6/30/23, 2:20 AM TRICS III 6 month follow up Pathway N=2430 a liberal transfusion strategy (transfusion if the Hgb concentration < 9.5 g/dL in the ICU or < 8.5 g/dL in the non-ICU ward) Primary outcome Rate of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis occurring within 6 months after the initial surgery 17.4 % 17.4 17.1 13.0 % 8.7 % Difference not exceeding nonferiority margin 4.3 % 0.0 % A restrictive transfusion strategy A liberal transfusion strategy Difference not exceeding nonferiority margin in the rate of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis occurring within 6 months after the initial surgery (17.4% vs. 17.1%; OR 1.02, 95% CI 0.87 to 1.18) Secondary outcomes No significant difference in death at 6 months (6.2% vs. 6.4%; OR 0.95, 95% CI 0.75 to 1.21) No significant difference in the rate of death from any cause, myocardial infarction, stroke, or new- onset renal failure with dialysis, emergency department visit, hospital readmission, or coronary revascularization occurring within 6 months after the initial surgery (43.8% vs. 42.8%; OR 1.04, 95% CI 0.93 to 1.17) No significant difference in myocardial infarction at 6 months (7.3% vs. 7.3%; OR 0.99, 99% CI 0.79 to 1.24) Safety outcomes No significant differences in stroke, new-onset renal failure with dialysis, coronary revascularization. Conclusion In adult patients undergoing cardiac surgery with cardiopulmonary bypass who were at moderate- to-high predicted risk for death, a restrictive transfusion strategy was noninferior to a liberal transfusion strategy with respect to the rate of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis occurring within 6 months after the initial surgery. Reference C David Mazer, Richard P Whitlock, Dean A Fergusson et al. Six-Month Outcomes after Restrictive or Liberal Transfusion for Cardiac Surgery. N Engl J Med. 2018 Sep 27;379(13):1224-1233. Open reference URL https://web.pathway.md/studies/recdiG8d9bwdfAE0S 2/2

6/30/23, 2:20 AM TRICS III Pathway Feedback Search Clinical Topics Home Studies TRICS III TRICS III Disease Transfusion strategies in critical Trial question Is a restrictive RBC transfusion strategy noninferior to a liberal strategy in patients undergoing cardiac surgery? Study design Multi-center Open label RCT Population Characteristics of study participants 35.5% female N = 5243 64.5% male 5243 patients (1721 female, 3139 male) Inclusion criteria: adult patients undergoing cardiac surgery with cardiopulmonary bypass who had a moderate-to-high predicted risk of death, according to the European System for Cardiac Operative Risk Evaluation Key exclusion criteria: unable to receive blood products, declined blood products, involved in a preoperative autologous donation program, undergoing heart transplantation, having surgery solely for the insertion of a ventricular assist device, pregnant or lactating Interventions N=2430 restrictive blood transfusion therapy (transfuse if Hgb level was < 7.5 g/dL, starting from induction of anesthesia) https://web.pathway.md/studies/rectGGvRP0VoAhSKL 1/2 6/30/23, 2:20 AM TRICS III Pathway N=2430 liberal blood transfusion therapy (transfuse if Hgb level was < 9.5 g/dL in the operating room or ICU or was < 8.5 g/dL in the non-ICU ward) Primary outcome Death, myocardial infarction, stroke, or new-onset renal failure requiring dialysis at 28 days 12.5 % 12.5 11.4 9.4 % 6.3 % Difference not exceeding nonferiority margin 3.1 % 0.0 % Restrictive blood transfusion therapy Liberal blood transfusion therapy Difference not exceeding nonferiority margin in death, myocardial infarction, stroke, or new-onset renal failure requiring dialysis at 28 days (11.4% vs. 12.5%; OR 0.9, 95% CI 0.76 to 1.07) Secondary outcomes No significant difference in death (3% vs. 3.6%; OR 0.85, 95% CI 0.62 to 1.16) Conclusion In adult patients undergoing cardiac surgery with cardiopulmonary bypass who had a moderate-to- high predicted risk of death, according to the European System for Cardiac Operative Risk Evaluation, restrictive blood transfusion therapy was noninferior to liberal blood transfusion therapy with respect to death, myocardial infarction, stroke, or new-onset renal failure requiring dialysis at 28 days. Reference Mazer CD, Whitlock RP, Fergusson DA et al. Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery. N Engl J Med. 2017 Nov 30;377(22):2133-2144. Open reference URL https://web.pathway.md/studies/rectGGvRP0VoAhSKL 2/2

6/30/23, 2:20 AM TRISS Pathway Feedback Search Clinical Topics Home Studies TRISS TRISS Disease Disease Sepsis and septic shock Transfusion strategies in critical Trial question What is the effect of lower Hgb threshold for transfusion in patients with septic shock? Study design Multi-center Open label RCT Population Characteristics of study participants 47.0% female N = 998 53.0% male 998 patients (467 female, 531 male) Inclusion criteria: patients in the ICU who had septic shock and a Hgb concentration 9 g/dL Key exclusion criteria: declined transfusion, previous adverse reaction to transfusion, received blood transfusion in ICU, acute coronary syndrome, life-threatening bleeding, and acute burn injury Interventions N=502 restrictive blood transfusion therapy (1 unit of leukoreduced red cells when Hgb level 7 g/dL) N=496 liberal blood transfusion therapy (1 unit of leukoreduced red cells when Hgb level 9/dL) Primary outcome https://web.pathway.md/studies/recMe9UDfEHKIv9sO 1/2 6/30/23, 2:20 AM TRISS Pathway Death at 90 days 45.0 % 45 43 33.8 % 22.5 % 11.3 % No significant difference 0.0 % Restrictive blood transfusion therapy Liberal blood transfusion therapy No significant difference in death at 90 days (43% vs. 45%; RR 0.94, 95% CI 0.78 to 1.09) Secondary outcomes No significant difference in use of life support at day 28 (16.1% vs. 19.9%; RR 0.77, 95% CI 0.54 to 1.09) No significant difference in ischemic events in the ICU (7.2% vs. 8%; RR 0.9, 95% CI 0.58 to 1.39) Safety outcomes No significant differences in severe adverse reaction (0% vs. 0.2%, p=1.00). Conclusion In patients in the ICU who had septic shock and a Hgb concentration 9 g/dL, restrictive blood transfusion therapy was not superior to liberal blood transfusion therapy with respect to death at 90 days. Reference Holst LB, Haase N, Wetterslev J et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014 Oct 9;371(15):1381-91. Open reference URL https://web.pathway.md/studies/recMe9UDfEHKIv9sO 2/2

6/30/23, 2:21 AM TRIST Pathway Feedback Search Clinical Topics Home Studies TRIST TRIST Disease Disease Disease Acute leukemia Acute myeloid leukemia Acute pro Trial question Is restrictive RBC transfusion strategy noninferior to liberal RBC transfusion strategy in patients undergoing hematopoietic cell transplantation? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 299 64.0% male 299 patients (108 female, 191 male) Inclusion criteria: patients with hematologic malignancies requiring hematopoietic cell transplantation Key exclusion criteria: pregnancy or lactation; receipt of RBC transfusion after hematopoietic cell transplantation before enrollment; or receipt of hematopoietic cell transplantation for nonmalignant diseases Interventions N=149 restrictive strategy (Hgb threshold < 70 g/L) N=150 liberal strategy (Hgb threshold < 90 g/L) https://web.pathway.md/studies/reckaRepbbQjupsg6 1/2 6/30/23, 2:21 AM TRIST Pathway Primary outcome Health-related quality of life measured by Functional Assessment of Cancer Therapy-Bone Marrow Transplantation score at day 100 112.8 112.8 107.5 84.6 56.4 Difference not exceeding nonferiority margin 28.2 0.0 Restrictive strategy Liberal strategy Difference not exceeding nonferiority margin in health-related quality of life measured by Functional Assessment of Cancer Therapy-BMT score at day 100 (112.8 vs. 107.5; AD 1.6, 95% CI -2.5 to 5.6) Secondary outcomes No significant difference in transplantation-related deaths at day 100 (1.34% vs. 2.67%; RR 0.5, 95% CI 0.09 to 2.71) No significant difference in sinusoidal obstruction syndrome (5.71% vs. 5.56%; RR 1.03, 95% CI 0.27 to 3.95) No significant difference in acute graft versus host disease (31.75% vs. 39.71%; RR 0.8, 95% CI 0.5 to 1.27) Safety outcomes No significant difference in transfusion-related adverse events. Significant difference in RBC unit transfusions (2.73 units vs. 5.02 units). Conclusion In patients with hematologic malignancies requiring hematopoietic cell transplantation, restrictive strategy was noninferior to liberal strategy with respect to a health-related quality of life measured by Functional Assessment of Cancer Therapy-BMT score at day 100. Reference Jason Tay, David S Allan, Elizabeth Chatelain et al. Liberal Versus Restrictive Red Blood Cell Transfusion Thresholds in Hematopoietic Cell Transplantation: A Randomized, Open Label, Phase III, Noninferiority Trial. J Clin Oncol. 2020 May 1;38(13):1463-1473. Open reference URL https://web.pathway.md/studies/reckaRepbbQjupsg6 2/2

6/30/23, 2:21 AM TRITON-TIMI 38 Pathway Feedback Search Clinical Topics Home Studies TRITON TIMI 38 TRITON TIMI 38 Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the role of prasugrel in patients with moderate-to-high-risk acute coronary syndromes with scheduled PCI? Study design Multi-center Quadruple blinded RCT Population Characteristics of study participants 26.0% female N = 13608 74.0% male 13608 patients (3538 female, 10070 male) Inclusion criteria: patients with moderate-to-high-risk acute coronary syndromes with scheduled PCI Key exclusion criteria: an increased risk of bleeding, anemia, thrombocytopenia, a history of pathologic intracranial findings, or the use of any thienopyridine within 5 days before enrollment Interventions N=6813 prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose for 6-15 months) N=6795 clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose for 6 to 15 months) https://web.pathway.md/studies/recVXfQlItCUPtqBr 1/2 6/30/23, 2:21 AM TRITON-TIMI 38 Pathway Primary outcome Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke 12.1 % 12.1 9.9 9.1 % 6.0 % Significant decrease 3.0 % NNT = 45 0.0 % Prasugrel Clopidogrel Significant decrease in death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (9.9% vs. 12.1%; HR 0.81, 95% CI 0.73 to 0.9) Secondary outcomes Significant decrease in nonfatal myocardial infarction (7.3% vs. 9.5%; HR 0.76, 95% CI 0.67 to 0.85) Safety outcomes No significant differences in nonfatal bleeding (1.1% vs. 0.9%, p=0.23). Significant differences in major bleeding (2.4% vs. 1.8%, p = 0.03; HR 1.32, 95% CI 1.03-1.68), life-threatening bleeding (1.4% vs. 0.9%, p = 0.01), including fatal bleeding (0.4% vs. 0.1%, p = 0.002). Conclusion In patients with moderate-to-high-risk acute coronary syndromes with scheduled PCI, prasugrel was superior to clopidogrel with respect to death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Reference Wiviott SD, Braunwald E, McCabe CH et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. Open reference URL https://web.pathway.md/studies/recVXfQlItCUPtqBr 2/2

6/30/23, 2:21 AM TRIUMPH Pathway Feedback Search Clinical Topics Home Studies TRIUMPH TRIUMPH Trial question What is the effect of eculizumab in patients with paroxysmal nocturnal Hgburia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 60.0% female N = 87 40.0% male 87 patients (52 female, 35 male) Inclusion criteria: patients with paroxysmal nocturnal Hgburia Key exclusion criteria: complement deficiency, an active bacterial infection, or a history of meningococcal disease and receipt of BMT Interventions N=43 eculizumab (IV at a dose of 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26) N=44 placebo (matching placebo) Primary outcome Significant increase in stabilization of Hgb levels in the absence of transfusions (ARD 49, 95% CI 19.93 to 78.07) Secondary outcomes Significant decrease in units of packed red cells transfusion (MD -10, 95% CI -15.93 to -4.07) Significant increase in change in the quality of life during treatment , global health status scale (10.9 vs. -8.5; MD 19.4, 95% CI 7.89 to 30.91) https://web.pathway.md/studies/recQFOqolL7vWjhyu 1/2 6/30/23, 2:21 AM TRIUMPH Pathway Safety outcomes Significant difference in serious adverse events (9% vs. 20%). Conclusion In patients with paroxysmal nocturnal Hgburia, eculizumab was superior to placebo with respect to stabilization of Hgb levels in the absence of transfusions. Reference Hillmen P, Young NS, Schubert J et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006 Sep 21;355(12):1233-43. Open reference URL https://web.pathway.md/studies/recQFOqolL7vWjhyu 2/2

6/30/23, 2:21 AM TRuE-V1 Pathway Feedback Search Clinical Topics Home Studies TRuE V1 TRuE V1 Disease Vitiligo Trial question What is the role of ruxolitinib cream in patients with vitiligo? Study design Multi-center Double blinded RCT Population Characteristics of study participants 56.0% female N = 330 44.0% male 330 patients (186 female, 144 male) Inclusion criteria: patients 12 years of age who had non-segmental vitiligo with depigmentation covering 10% of total body-surface area Key exclusion criteria: complete leukotrichia within any facial lesions; any biologic or experimental therapy within 12 weeks; phototherapy within 8 weeks; immunomodulating treatments within 4 weeks, or topical treatments within 1 week Interventions N=221 ruxolitinib (application of ruxolitinib 1.5% cream BID for 24 weeks with treatment extension through week 52) N=109 placebo (vehicle cream applied BID for 24 weeks with treatment extension and use of 1.5% ruxolitinib cream through week 52) https://web.pathway.md/studies/recXFPJkVedhQpMS4 1/2 6/30/23, 2:21 AM TRuE-V1 Pathway Primary outcome Percentage of patients achieving depigmentation of 75% in facial vitiligo area scoring index at week 24 29.8 % 29.8 22.4 % 14.9 % Significant increase 7.5 % 7.4 NNT = 4 0.0 % Ruxolitinib Placebo Significant increase in the percentage of patients achieving depigmentation of 75% in the facial vitiligo area scoring index at week 24 (29.8% vs. 7.4%; RR 4, 95% CI 1.9 to 8.4) Secondary outcomes Significant increase in the percentage of patients achieving depigmentation of 50% in the facial vitiligo area scoring index at week 24 (51.2% vs. 16.9%; RR 3, 95% CI 1.9 to 4.8) Significant increase in the percentage of patients achieving depigmentation of 90% in the facial vitiligo area scoring index at week 24 (15.3% vs. 2.2%; RR 7.3, 95% CI 1.8 to 29.5) Significant increase in the percentage of patients achieving depigmentation of 50% in the total body vitiligo area scoring index at week 24 (20.6% vs. 5.1%; RR 4.1, 95% CI 1.6 to 10.5) Safety outcomes No significant difference in any adverse event. Conclusion In patients 12 years of age who had non-segmental vitiligo with depigmentation covering 10% of total body-surface area, ruxolitinib was superior to placebo with respect to the percentage of patients achieving depigmentation of 75% in the facial vitiligo area scoring index at week 24. Reference David Rosmarin, Thierry Passeron, Amit G Pandya et al. Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo. N Engl J Med. 2022 Oct 20;387(16):1445-1455. Open reference URL https://web.pathway.md/studies/recXFPJkVedhQpMS4 2/2

6/30/23, 2:21 AM TRuE-V2 Pathway Feedback Search Clinical Topics Home Studies TRuE V2 TRuE V2 Disease Vitiligo Trial question What is the role of ruxolitinib cream in patients with vitiligo? Study design Multi-center Double blinded RCT Population Characteristics of study participants 50.0% female N = 343 50.0% male 343 patients (172 female, 171 male) Inclusion criteria: patients 12 years of age who had non-segmental vitiligo with depigmentation covering 10% of total body-surface area Key exclusion criteria: complete leukotrichia within any facial lesions; any biologic or experimental therapy within 12 weeks; phototherapy within 8 weeks; immunomodulating treatments within 4 weeks, or topical treatments within 1 week Interventions N=228 ruxolitinib (application of ruxolitinib 1.5% cream BID for 24 weeks with treatment extension through week 52) N=115 placebo (vehicle cream applied BID for 24 weeks with treatment extension and use of 1.5% ruxolitinib cream through week 52) https://web.pathway.md/studies/rec7HrzUPeShWdr1V 1/2 6/30/23, 2:21 AM TRuE-V2 Pathway Primary outcome Percentage of patients achieving depigmentation of 75% in facial vitiligo area scoring index at week 24 30.9 % 30.9 23.2 % 15.4 % Significant increase 11.4 7.7 % NNT = 5 0.0 % Ruxolitinib Placebo Significant increase in the percentage of patients achieving depigmentation of 75% in the facial vitiligo area scoring index at week 24 (30.9% vs. 11.4%; RR 2.7, 95% CI 1.5 to 4.9) Secondary outcomes Significant increase in the percentage of patients achieving depigmentation of 50% in the facial vitiligo area scoring index at week 24 (51.4% vs. 20.9%; RR 2.5, 95% CI 1.6 to 3.7) Significant increase in the percentage of patients achieving depigmentation of 90% in the facial vitiligo area scoring index at week 24 (16.3% vs. 1.3%; RR 13.1, 95% CI 1.9 to 90.2) Significant increase in the percentage of patients achieving depigmentation of 50% in the total body vitiligo area scoring index at week 24 (23.9% vs. 6.8%; RR 3.5, 95% CI 1.7 to 7.5) Safety outcomes No significant difference in any adverse event. Conclusion In patients 12 years of age who had non-segmental vitiligo with depigmentation covering 10% of total body-surface area, ruxolitinib was superior to placebo with respect to the percentage of patients achieving depigmentation of 75% in the facial vitiligo area scoring index at week 24. Reference David Rosmarin, Thierry Passeron, Amit G Pandya et al. Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo. N Engl J Med. 2022 Oct 20;387(16):1445-1455. Open reference URL https://web.pathway.md/studies/rec7HrzUPeShWdr1V 2/2

6/30/23, 2:21 AM TRUST Pathway Feedback Search Clinical Topics Home Studies TRUST TRUST Disease Disease Hypothyroidism Subclinical hypothyroidism Trial question What is the effect of levothyroxine in older patients with subclinical hypothyroidism? Study design Multi-center Double blinded RCT Population Characteristics of study participants 54.0% female N = 737 46.0% male 737 patients (396 female, 341 male) Inclusion criteria: adult patients 65 years of age who had persisting subclinical hypothyroidism, with thyrotropin level of 4.60-19.99 mlU/L and free thyroxine level within reference range Key exclusion criteria: current prescription for levothyroxine, antithyroid drugs, amiodarone, or lithium, thyroid surgery or receipt of radioactive iodine within the previous 12 months, dementia, hospitalization for a major illness or an elective surgery within the previous 4 weeks, acute coronary syndrome within the previous 4 weeks, and terminal illness Interventions N=368 levothyroxine (starting dose of 50 g daily or 25 g if the body weight was < 50 kg or patient had coronary heart disease, with dose adjustment according to thyrotropin level) N=369 placebo (mock dose adjustment) https://web.pathway.md/studies/recktT7ePkYSxNhYA 1/2 6/30/23, 2:21 AM TRUST Pathway Primary outcome Change in Tiredness score at 12 months 3.8 3.8 3.2 2.8 1.9 0.9 No significant difference 0.0 Levothyroxine Placebo No significant difference in change in Tiredness score at 12 months (3.8 vs. 3.2; AD 0.4, 95% CI -2.1 to 2.9) Safety outcomes No significant differences in incidence of serious adverse events of special interest (AF, HF, fracture, or new diagnosis of osteoporosis). Conclusion In adult patients 65 years of age who had persisting subclinical hypothyroidism, with thyrotropin level of 4.60-19.99 mlU/L and free thyroxine level within reference range, levothyroxine was not superior to placebo with respect to change in Tiredness score at 12 months. Reference Stott DJ, Rodondi N, Kearney PM et al. Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism. N Engl J Med. 2017 Jun 29;376(26):2534-2544. Open reference URL https://web.pathway.md/studies/recktT7ePkYSxNhYA 2/2

6/30/23, 2:22 AM TTH48 Pathway Feedback Search Clinical Topics Home Studies TTH48 TTH48 Disease Cardiac arrest Trial question What is the role of prolonged targeted temperature management in survivors of out-of-hospital cardiac arrest? Study design Multi-center Open label RCT Population Characteristics of study participants 10.0% female N = 79 90.0% male 79 patients (8 female, 71 male) Inclusion criteria: out-of-hospital cardiac arrest survivors with perceived good cognitive outcome Key exclusion criteria: out-of-hospital cardiac arrest of suspected origin other than cardiac, in- hospital cardiac arrest, terminal disease, coagulation disorders, unwitnessed asystolia Interventions N=43 TTM48 (prolonged target temperature management for 48 hours) N=36 TTM24 (standard targeted temperature management for 24 hours) Primary outcome Cognitive impairment at 6 months https://web.pathway.md/studies/recL5DTR2NnIoMzmZ 1/2 6/30/23, 2:22 AM TTH48 Pathway 33.0 % 33 24.8 % 16.5 % Significant increase 12 8.3 % NNH = 5 0.0 % TTM48 TTM24 Significant increase in cognitive impairment at 6 months (12% vs. 33%; RR 2.9, 95% CI 1.1 to 7.4) Safety outcomes No significant differences in attention, executive function. Conclusion In out-of-hospital cardiac arrest survivors with perceived good cognitive outcome, TTM48 was superior to TTM24 with respect to cognitive impairment at 6 months. Reference Lars Evald, Kolbj rn Br nnick, Christophe Henri Valdemar Duez et al. Prolonged targeted temperature management reduces memory retrieval deficits six months post-cardiac arrest: A randomised controlled trial. Resuscitation. 2019 Jan;134:1-9. Open reference URL https://web.pathway.md/studies/recL5DTR2NnIoMzmZ 2/2

6/30/23, 2:22 AM TTM Pathway Feedback Search Clinical Topics Home Studies TTM TTM Disease Cardiac arrest Trial question What is the role of targeted temperature at 33 degree C in unconscious adults after out-of-hospital cardiac arrest? Study design Multi-center Single blinded RCT Population Characteristics of study participants 19.2% female N = 950 80.8% male 950 patients (178 female, 761 male) Inclusion criteria: unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause Key exclusion criteria: interval from the ROSC to screening > 240 minutes, unwitnessed arrest with asystole as the initial rhythm, acute intracranial hemorrhage or stroke, and a body temperature < 30 degree C Interventions N=473 cooling to 33 degree C (target body temperature of 33 degree C) N=466 cooling to 36 degree C (target body temperature of 36 degree C) https://web.pathway.md/studies/recg1Lxcak1p1uubB 1/2 6/30/23, 2:22 AM TTM Pathway Primary outcome All-cause death 50.0 % 50 48 37.5 % 25.0 % 12.5 % No significant difference 0.0 % Cooling to 33 degree C Cooling to 36 degree C No significant difference in all-cause death (50% vs. 48%; HR 1.06, 95% CI 0.89 to 1.28) Secondary outcomes No significant difference in poor neurologic function (CPC scale) or death at 6 months (54% vs. 52%; HR 1.02, 95% CI 0.88 to 1.16) No significant difference in poor neurologic function by mRS or death at 6 months (52% vs. 52%; HR 1.01, 95% CI 0.89 to 1.14) Conclusion In unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause, cooling to 33 degree C was not superior to cooling to 36 degree C with respect to a all-cause death. Reference Nielsen N, Wetterslev J, Cronberg T et al. Targeted temperature management at 33 C versus 36 C after cardiac arrest. N Engl J Med. 2013 Dec 5;369(23):2197-206. Open reference URL https://web.pathway.md/studies/recg1Lxcak1p1uubB 2/2

6/30/23, 2:22 AM TTM2 Pathway Feedback Search Clinical Topics Home Studies TTM2 TTM2 Disease Cardiac arrest Trial question Is hypothermia superior to normothermia in patients with coma after out-of-hospital cardiac arrest? Study design Multi-center Open label RCT Population Characteristics of study participants 21.0% female N = 1861 79.0% male 1861 patients (384 female, 1477 male) Inclusion criteria: adults with coma who had an out-of-hospital cardiac arrest Key exclusion criteria: Interval from ROSC to screening of > 180 minutes; unwitnessed cardiac arrest with asystole as the initial rhythm; limitations in care Interventions N=930 hypothermia (targeted temperature of 33 Celsius) N=931 normothermia (targeted temperature 37.5 Celsius with early treatment of fever) Primary outcome Death from any cause at 6 months 50 50 0 % 48 https://web.pathway.md/studies/recYTqEBxnKU1tM6r 1/2 6/30/23, 2:22 AM 50.0 % TTM2 Pathway 50 48 37.5 % 25.0 % 12.5 % No significant difference 0.0 % Hypothermia Normothermia No significant difference in death from any cause at 6 months (50% vs. 48%; RR 1.04, 95% CI 0.94 to 1.14) Secondary outcomes No significant difference in the percentage of patients with moderately severe disability or worse at 6 months (55% vs. 55%; RR 1, 95% CI 0.92 to 1.09) No significant difference in the percentage of patients with poor functional outcome at 6 months (54% vs. 54%; RR 1, 95% CI 0.91 to 1.08) No significant difference in health-related quality of life in participants who survived to 6 months (74 vs. 75; MD -0.8, 95% CI -3.6 to 2) Safety outcomes No significant differences in bleeding, pneumonia, sepsis. Significant difference in arrhythmias resulting in hemodynamic compromise (24% vs. 17%). Conclusion In adults with coma who had an out-of-hospital cardiac arrest, hypothermia was not superior to normothermia with respect to death from any cause at 6 months. Reference Josef Dankiewicz, Tobias Cronberg, Gisela Lilja et al. Hypothermia versus Normothermia after Out- of-Hospital Cardiac Arrest. N Engl J Med. 2021 Jun 17;384(24):2283-2294. Open reference URL https://web.pathway.md/studies/recYTqEBxnKU1tM6r 2/2

6/30/23, 2:24 AM Twice-daily RT for SCLC Pathway Feedback Search Clinical Topics Home Studies Twice-daily RT for SCLC Twice-daily RT for SCLC Disease Small cell lung cancer Trial question Is twice-daily thoracic radiotherapy superior to once daily thoracic radiotherapy in patients with limited small cell lung cancer receiving cisplatin plus etoposide? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 417 59.0% male 417 patients (173 female, 244 male) Inclusion criteria: patients with limited small cell lung cancer receiving four 21-day cycles of cisplatin plus etoposide Key exclusion criteria: pleural effusion on chest films, contralateral hilar or supraclavicular adenopathy, symptomatic cardiac disease, myocardial infarction within the previous six months, prior cancer or prior treatment with either chemotherapy or radiotherapy Interventions N=211 twice-daily thoracic radiotherapy (total of 45 Gy of concurrent thoracic radiotherapy given twice-daily over a three-week period) https://web.pathway.md/studies/recZ62VhVUcFp1HP5 1/2 6/30/23, 2:24 AM Twice-daily RT for SCLC Pathway N=206 once daily thoracic radiotherapy (total of 45 Gy of concurrent thoracic radiotherapy given once daily over a period of five weeks) Primary outcome Median survival at a follow-up of 8 years 23.0 months 23 19 17.3 months 11.5 months 5.8 months Significant increase 0.0 months Twice-daily thoracic radiotherapy Once daily thoracic radiotherapy Significant increase in median survival at a follow-up of 8 years (23 months vs. 19 months; HR 1.2, 95% CI 1 to 1.6) Secondary outcomes No significant difference in failure-free survival at 2 years (29% vs. 24%; AD 5%, 95% CI -0.96 to 10.96) No significant difference in complete response rate (56% vs. 49%; AD 7%, 95% CI -4.38 to 18.38) Significant decrease in simultaneous local and distal treatment failure (6% vs. 23%; ARD -17, 95% CI -29.94 to -4.06) Safety outcomes No significant difference in hospitalization of the patient or perforation of the esophagus. Significant difference in grade 3 esophagitis (27% vs. 11% patients). Conclusion In patients with limited small cell lung cancer receiving four 21-day cycles of cisplatin plus etoposide, twice-daily thoracic radiotherapy was superior to once daily thoracic radiotherapy with respect to median survival at a follow-up of 8 years. Reference Turrisi AT rd, Kim K, Blum R et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med. 1999 Jan 28;340(4):265-71. Open reference URL https://web.pathway.md/studies/recZ62VhVUcFp1HP5 2/2

6/30/23, 12:05 AM UKPDS 33 Pathway Feedback Search Clinical Topics Home Studies UKPDS 33 UKPDS 33 Disease Diabetes mellitus type 2 Trial question Is intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin superior to conventional policy with diet? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 3867 61.0% male 3867 patients (1508 female, 2359 male) Inclusion criteria: patients with T2DM, median age 54 years, who after 3 months' diet treatment had a mean of two fasting plasma glucose concentrations of 6.1-15.0 mmol/L Key exclusion criteria: ketonuria > 3 mmol/L; serum creatinine > 175 mol/L; myocardial infarction in the previous year; current angina or HF; > 1 major vascular event; retinopathy requiring laser treatment; malignant hypertension; or uncorrected endocrine disorder Interventions N=2729 intensive blood-glucose treatment (with sulphonylurea, chlorpropamide, glibenclamide, or glipizide; or insulin, target FPG < 6 mmol/L) N=1138 conventional treatment (aim to best achieve FPG with diet alone) Primary outcome Incidence of diabetes-related events https://web.pathway.md/studies/recJrWQ5MbDj9SfEn 1/2 6/30/23, 12:05 AM UKPDS 33 Pathway 46.0/1000 py 46 40.9 34.5/1000 py 23.0/1000 py 11.5/1000 py Significant decrease 0.0/1000 py Intensive blood-glucose treatment Conventional treatment Significant decrease in the incidence of diabetes-related events (40.9 /1000 py vs. 46 /1000 py; RR 0.88, 95% CI 0.79 to 0.99) Secondary outcomes No significant difference in the incidence of diabetes-related death (10.4 /1000 py vs. 11.5 /1000 py; RR 0.9, 95% CI 0.73 to 1.11) No significant difference in the incidence of death from any cause (17.9 /1000 py vs. 18.9 /1000 py; RR 0.94, 95% CI 0.8 to 1.1) Safety outcomes Significant differences in hypoglycemic episodes (p < 0.0001) and weight gain (mean 2.9 kg, p < 0.001). Conclusion In patients with T2DM, median age 54 years, who after 3 months' diet treatment had a mean of two fasting plasma glucose concentrations of 6.1-15.0 mmol/L, intensive blood-glucose treatment was superior to conventional treatment with respect to the incidence of diabetes- related events. Reference UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53. Open reference URL https://web.pathway.md/studies/recJrWQ5MbDj9SfEn 2/2

6/30/23, 12:06 AM UKPDS 34 Pathway Feedback Search Clinical Topics Home Studies UKPDS 34 UKPDS 34 Disease Diabetes mellitus type 2 Reference UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):854-65. Open reference URL https://web.pathway.md/studies/recWn5ibJWWegtkFl 1/1

6/30/23, 12:06 AM ULTRA Pathway Feedback Search Clinical Topics Home Studies ULTRA ULTRA Disease Subarachnoid hemorrhage Trial question What is the role of ultra-early, short-term treatment with tranexamic acid in patients with subarachnoid hemorrhage? Study design Multi-center Open label RCT Population Characteristics of study participants 67.0% female N = 955 33.0% male 955 patients (644 female, 311 male) Inclusion criteria: adult patients with spontaneous CT-proven subarachnoid hemorrhage Key exclusion criteria: no loss of consciousness after the hemorrhage, traumatic subarachnoid hemorrhage pattern on CT, treatment for deep vein thrombosis or PE, history of hypercoagulability disorder, history of severe renal failure, imminent death within 24 hours Interventions N=480 tranexamic acid (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first plus standard care) N=475 control (standard care alone) Primary outcome Good clinical outcome at 6 months, modified Rankin Scale score of 0-3 https://web.pathway.md/studies/recR2vLPhQHipEQ6R 1/2 6/30/23, 12:06 AM ULTRA Pathway 64.0 % 64 60 48.0 % 32.0 % 16.0 % No significant difference 0.0 % Tranexamic acid Control No significant difference in good clinical outcome at 6 months, mRS score of 0-3 (60% vs. 64%; aOR 0.86, 95% CI 0.66 to 1.12) Secondary outcomes Borderline significant decrease in excellent clinical outcome, mRS score of 0-2 (48% vs. 56%; OR 0.74, 95% CI 0.57 to 0.96) No significant difference in death from all causes at 30 days (22% vs. 22%; OR 0.98, 95% CI 0.72 to 1.33) No significant difference in death from all causes at 6 months (27% vs. 24%; OR 1.15, 95% CI 0.86 to 1.54) Safety outcomes No significant difference in any serious adverse events. Significant difference in all rebleeding before aneurysm treatment (10% vs. 14%). Conclusion In adult patients with spontaneous CT-proven subarachnoid hemorrhage, tranexamic acid was not superior to control with respect to good clinical outcome at 6 months, mRS score of 0-3. Reference Ren Post, Menno R Germans, Maud A Tjerkstra et al. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial. Lancet. 2021 Jan 9;397(10269):112-118. Open reference URL https://web.pathway.md/studies/recR2vLPhQHipEQ6R 2/2

6/30/23, 12:06 AM UNITI-1 (fixed-dose ustekinumab) Pathway Feedback Search Clinical Topics Home Studies UNITI 1 (fixed-dose ustekinumab) UNITI 1 (fixed-dose ustekinumab) Disease Crohn's disease Trial question What is the role of fixed-dose ustekinumab in patients with moderately to severely active Crohn's disease? Study design Multi-center Double blinded RCT Population Characteristics of study participants 56.0% female N = 492 44.0% male 492 patients (276 female, 216 male) Inclusion criteria: patients with active moderate to severe Crohn's disease who didn't respond to to TNF antagonists or had unacceptable side effects Key exclusion criteria: patients with gastrointestinal conditions that might require surgery or might preclude the use of Crohn's disease activity index; infections including active tuberculosis; history of cancer Interventions N=245 ustekinumab (an induction dose of 130 mg IV) N=247 placebo (matching placebo) Primary outcome 100-point clinical response at week 6 34.3 % 34.3 https://web.pathway.md/studies/rec4A9QkXtoKvjzpp 1/2 6/30/23, 12:06 AM UNITI-1 (fixed-dose ustekinumab) Pathway 25.7 % 21.5 17.1 % Significant increase 8.6 % NNT = 8 0.0 % Ustekinumab Placebo Significant increase in 100-point clinical response at week 6 (34.3% vs. 21.5%; AD 12.8%, 95% CI 5 to 20.7) Secondary outcomes Significant increase in clinical remission at week 8 (15.9% vs. 7.3%; AD 8.6%, 95% CI 3 to 14.2) Significant increase in 100-point clinical response at week 8 (33.5% vs. 20.2%; AD 13.2%, 95% CI 5.5 to 21) Significant increase in 70-point clinical response at week 6 (46.1% vs. 30.4%; AD 15.8%, 95% CI 7.3 to 24.2) Safety outcomes No significant difference in adverse events. Conclusion In patients with active moderate to severe Crohn's disease who didn't respond to to TNF antagonists or had unacceptable side effects, ustekinumab was superior to placebo with respect to a 100-point clinical response at week 6. Reference Brian G Feagan, William J Sandborn, Christopher Gasink et al. Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med. 2016 Nov 17;375(20):1946-1960. Open reference URL https://web.pathway.md/studies/rec4A9QkXtoKvjzpp 2/2

6/30/23, 12:06 AM UNITI-1 (weight-based dose of ustekinumab) Pathway Feedback Search Clinical Topics Home Studies UNITI 1 (weight-based dose of ustekinumab) UNITI 1 (weight-based dose of ustekinumab) Disease Crohn's disease Trial question What is the role of weight-based dose ustekinumab in patients with moderately to severely active Crohn's disease? Study design Multi-center Double blinded RCT Population Characteristics of study participants 56.0% female N = 496 44.0% male 496 patients (277 female, 219 male) Inclusion criteria: patients with active moderate to severe Crohn's disease who didn't respond to to TNF antagonists or had unacceptable side effects Key exclusion criteria: patients with gastrointestinal conditions that might require surgery or might preclude the use of Crohn's disease activity index; infections including active tuberculosis; history of cancer Interventions N=249 ustekinumab (an induction dose of approximately 6 mg/kg of body weight) N=247 placebo (matching placebo) Primary outcome 100-point clinical response at week 6 33.7 % 33.7 https://web.pathway.md/studies/rec4sVhwR0CgPicws 1/2 6/30/23, 12:06 AM UNITI-1 (weight-based dose of ustekinumab) Pathway 25.3 % 21.5 16.9 % Significant increase 8.4 % NNT = 8 0.0 % Ustekinumab Placebo Significant increase in 100-point clinical response at week 6 (33.7% vs. 21.5%; AD 12.3%, 95% CI 4.5 to 20.1) Secondary outcomes Significant increase in clinical remission at week 8 (20.9% vs. 7.3%; AD 13.6%, 95% CI 7.6 to 19.6) Significant increase in 100-point clinical response at week 8 (37.8% vs. 20.2%; AD 17.5%, 95% CI 9.7 to 25.3) Significant increase in 70-point clinical response at week 6 (43.8% vs. 30.4%; AD 13.4%, 95% CI 3.2 to 23.6) Safety outcomes No significant difference in adverse events. Conclusion In patients with active moderate to severe Crohn's disease who didn't respond to to TNF antagonists or had unacceptable side effects, ustekinumab was superior to placebo with respect to a 100-point clinical response at week 6. Reference Brian G Feagan, William J Sandborn, Christopher Gasink et al. Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med. 2016 Nov 17;375(20):1946-1960. Open reference URL https://web.pathway.md/studies/rec4sVhwR0CgPicws 2/2

6/30/23, 12:07 AM UPLIFT Pathway Feedback Search Clinical Topics Home Studies UPLIFT UPLIFT Disease Chronic obstructive pulmonary Trial question What is the role of tiotropium in patients with COPD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 25.0% female N = 5993 75.0% male 5993 patients (1519 female, 4473 male) Inclusion criteria: patients with moderate-to-very-severe COPD Key exclusion criteria: a history of asthma, a COPD exacerbation or respiratory infection within 4 weeks before screening, a history of pulmonary resection, use of supplemental oxygen for > 12 hours/day, and the presence of a coexisting illness that could preclude participation in the study Interventions N=2987 tiotropium (80 g of ipratropium, four inhalations, followed 60 minutes later by 400 g of albuterol, four inhalations) N=3006 placebo (matching placebo) Primary outcome Incidence of decline in post-bronchodilator forced expiratory volume in 1 second 42 42 0 mL/year 40 https://web.pathway.md/studies/rectburr9SmEJPNMC 1/2 6/30/23, 12:07 AM UPLIFT Pathway 42.0 mL/year 40 31.5 mL/year 21.0 mL/year 10.5 mL/year No significant difference 0.0 mL/year Tiotropium Placebo No significant difference in the incidence of decline in post-bronchodilator FEV in 1 second (40 mL/year vs. 42 mL/year; MD -2, 95% CI -6 to 2) Secondary outcomes Significant increase in improvement of 4 units in the St. George's Respiratory Questionnaire scores at 4 years (45% vs. 36%; AD 11%, 95% CI 4.47 to 17.53) Significant decrease in median time to first exacerbation (16.7 months vs. 12.5 months; HR 0.86, 95% CI 0.81 to 0.91) No significant difference in the rate of death after 4 years (14.9% vs. 16.5%; HR 0.89, 95% CI 0.79 to 1.02) Safety outcomes No significant difference in adverse events and serious adverse events. Significant difference in fatal events (12.8% vs. 13.7%). Conclusion In patients with moderate-to-very-severe COPD, tiotropium was not superior to placebo with respect to the incidence of decline in post-bronchodilator FEV in 1 second. Reference Tashkin DP, Celli B, Senn S et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008 Oct 9;359(15):1543-54. Open reference URL https://web.pathway.md/studies/rectburr9SmEJPNMC 2/2

6/30/23, 12:09 AM V-HeFT II Pathway Feedback Search Clinical Topics Home Studies V HeFT II V HeFT II Disease Heart failure Trial question What is the role of enalapril in male patients with HF and LV dilation or a LVEF < 45%? Study design Multi-center Double blinded RCT Population 804 male patients Inclusion criteria: male patients with HF and LV dilation or an LVEF < 45% Key exclusion criteria: myocardial infarction or cardiac surgery within the previous three months, angina pectoris limiting exercise or requiring long-term medical therapy, serious obstructive valvular disease, or obstructive lung disease Interventions N=403 enalapril (20 mg daily) N=401 hydralazine-isosorbide dinitrate arm (300 mg hydralazine plus 160 mg isosorbide dinitrate daily) Primary outcome Death at 2 years 25.0 % 25 18.8 % 18 12.5 % Significant decrease 6.3 % NNT = 14 0.0 % Enalapril Hydralazine-isosorbide dinitrate arm https://web.pathway.md/studies/recm6DNOnJLMGIrEq 1/2 6/30/23, 12:09 AM V-HeFT II Pathway Significant decrease in death at 2 years (18% vs. 25%; RR 0.72, 95% CI 0.13 to 1.31) Secondary outcomes No significant difference in death in presence of coronary artery disease (14.1% vs. 14.3%; RR 0.87, 95% CI 0.64 to 1.19) Conclusion In male patients with HF and LV dilation or an LVEF < 45%, enalapril was superior to hydralazine-isosorbide dinitrate arm with respect to death at 2 years. Reference Cohn JN, Johnson G, Ziesche S et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991 Aug 1;325(5):303-10. Open reference URL https://web.pathway.md/studies/recm6DNOnJLMGIrEq 2/2

6/30/23, 12:09 AM V-HeFT Pathway Feedback Search Clinical Topics Home Studies V HeFT V HeFT Disease Heart failure Reference Cohn JN, Archibald DG, Ziesche S et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1986 Jun 12;314(24):1547-52. Open reference URL https://web.pathway.md/studies/reckhfCwi1fUQxKqs 1/1

6/30/23, 12:09 AM VA Cooperative Study Pathway Feedback Search Clinical Topics Home Studies VA Cooperative Study VA Cooperative Study Trial question What is the role of aspirin in male patients with unstable angina? Study design Multi-center Double blinded RCT Population 1266 male patients Inclusion criteria: male patients with unstable angina Key exclusion criteria: congestive HF NYHA IV, tachyarrhythmia, anemia, contraindications to aspirin, bleeding tendency, myocardial infarction within 6 weeks, or other illness that might limit 1 year survival Interventions N=625 aspirin (324 mg in buffered solution daily for 12 weeks) N=641 placebo (matching placebo daily for 24 weeks) Primary outcome Death or acute MI 10.1 % 10.1 7.6 % 5.0 % 5 Significant decrease 2.5 % NNT = 20 0.0 % Aspirin Placebo Significant decrease in death or acute MI (5% vs. 10.1%; RR 0.49, 95% CI 0.22 to 0.76) Secondary outcomes Significant decrease in nonfatal myocardial infarction (3.4% vs. 6.9%; RR 0.49, 95% CI 0.15 to 0.83) Borderline significant decrease in death (1.6% vs. 3.3%; RR 0.48, 95% CI -0.01 to 0.97) Safety outcomes https://web.pathway.md/studies/recEiax7hRPyuWyZb 1/2 6/30/23, 12:09 AM VA Cooperative Study Pathway y No significant difference in gastrointestinal symptoms or evidence of blood loss. Conclusion In male patients with unstable angina, aspirin was superior to placebo with respect to death or acute MI. Reference Lewis HD Jr, Davis JW, Archibald DG et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1983 Aug 18;309(7):396-403. Open reference URL https://web.pathway.md/studies/recEiax7hRPyuWyZb 2/2

6/30/23, 12:10 AM VA-NEPHRON D Pathway Feedback Search Clinical Topics Home Studies VA NEPHRON D VA NEPHRON D Disease Disease Diabetes mellitus type 2 Diabetic nephropathy Trial question What is the role of combined therapy with ACEIs and angiotensin-receptor blockers in patients with T2DM who have diabetic nephropathy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 1.1% female N = 1648 98.9% male 1648 patients (12 female, 1436 male) Inclusion criteria: patients with T2DM, a urinary albumin-to-creatinine ratio of at least 300, and an eGFR of 30.0 to 89.9 mL/min/1.73 m of body-surface area Key exclusion criteria: known nondiabetic kidney disease, a serum potassium level > 5.5 mmol/L, treatment with sodium polystyrene sulfonate, or an inability to stop prescribed medications that increase the risk of hyperkalemia Interventions N=724 combined angiotensin inhibition (losartan at a dose of 100 mg/day plus lisinopril at a dose of 10 to 40 mg/day) N=724 monotherapy (losartan at a dose of 100 mg/day plus placebo) Primary outcome https://web.pathway.md/studies/rec4o5msKPuuICw4l 1/2 6/30/23, 12:10 AM VA-NEPHRON D Pathway Decline in eGFR (by 30 mL/min if eGFR 60-90 at baseline, or by 50% eGFR 30-60 at baseline), ESRD, or death 21.0 % 21 18.2 15.8 % 10.5 % 5.3 % No significant difference 0.0 % Combined angiotensin inhibition Monotherapy No significant difference in decline in eGFR (by 30 mL/min if eGFR 60-90 at baseline, or by 50% eGFR 30-60 at baseline), ESRD, or death (18.2% vs. 21%; HR 0.88, 95% CI 0.7 to 1.12) Secondary outcomes No significant difference in decline in eGFR or end-stage renal disease (10.6% vs. 14%; HR 0.78, 95% CI 0.58 to 1.05) No significant difference in death (8.7% vs. 8.3%; HR 1.04, 95% CI 0.73 to 1.49) No significant difference in cardiovascular events (18.5% vs. 18.8%; HR 0.97, 95% CI 0.76 to 1.23) Safety outcomes Significant differences in serious adverse events (57.5% vs. 52.5%, p = 0.06), including hyperkalemia (9.9% vs. 4.4%, p < 0.001) and AKI (18.0% vs. 11.0%, p < 0.001). Conclusion In patients with T2DM, a urinary albumin-to-creatinine ratio of at least 300, and an eGFR of 30.0 to 89.9 mL/min/1.73 m of body-surface area, combined angiotensin inhibition was not superior to monotherapy with respect to decline in eGFR (by 30 mL/min if eGFR 60-90 at baseline, or by 50% eGFR 30-60 at baseline), ESRD, or death. Reference Fried LF, Emanuele N, Zhang JH et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013 Nov 14;369(20):1892-903. Open reference URL https://web.pathway.md/studies/rec4o5msKPuuICw4l 2/2

6/30/23, 12:10 AM VADT Pathway Feedback Search Clinical Topics Home Studies VADT VADT Disease Diabetes mellitus type 2 Trial question What is the role of intensive glucose control in patients with poorly controlled T2DM? Study design Multi-center Open label RCT Population Characteristics of study participants 3.0% female N = 1791 97.0% male 1791 patients (52 female, 1739 male) Inclusion criteria: military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for T2DM Key exclusion criteria: glycated Hgb level < 7.5%, occurrence of a cardiovascular event during the previous 6 months, advanced congestive HF, severe angina, a life expectancy < 7 years, or body-mass index > 40 Interventions N=892 intensive therapy (target to achieve a glycated Hgb level of < 6%) N=899 standard therapy (target to achieve a glycated Hgb level of < 9%) Primary outcome Cardiovascular events 264.0 264 235 198 0 https://web.pathway.md/studies/recU1I04ktsJG1b6v 1/2 6/30/23, 12:10 AM 198.0 VADT Pathway 132.0 66.0 No significant difference 0.0 Intensive therapy Standard therapy No significant difference in cardiovascular events (235 vs. 264; HR 0.88, 95% CI 0.74 to 1.05) Secondary outcomes No significant difference in death from any cause (102 vs. 95; HR 1.07, 95% CI 0.81 to 1.42) Safety outcomes Significant differences in serious adverse events (24.1% vs. 17.6%, p = 0.05), including dyspnea (p = 0.006). Conclusion In military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for T2DM, intensive therapy was not superior to standard therapy with respect to cardiovascular events. Reference Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129-39. Open reference URL https://web.pathway.md/studies/recU1I04ktsJG1b6v 2/2

6/30/23, 12:38 AM Val-HeFT Pathway Feedback Search Clinical Topics Home Studies Val-HeFT Val-HeFT Disease Heart failure Trial question What is the role of valsartan in patients with HF of NYHA class II, III, or IV on a stable background of standard therapy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 20.0% female N = 5010 80.0% male 5010 patients (1005 female, 4005 male) Inclusion criteria: patients with HF of NYHA class II, III, or IV on a stable background of standard therapy Key exclusion criteria: pregnancy; postpartum cardiomyopathy; right HF caused by pulmonary disease; rapidly deteriorating HF; hypertrophic cardiomyopathy; clinically important renal, hepatic, or hematological disorders Interventions N=2511 valsartan (160 mg BID) N=2499 placebo (matching placebo BID) Primary outcome Death, cardiac arrest, hospitalization for heart failure, or receipt of intravenous inotropic or vasodilator therapy for heart failure https://web.pathway.md/studies/rec71Z5dZTO75jgKt 1/2 6/30/23, 12:38 AM Val-HeFT Pathway 32.1 % 32.1 28.8 24.1 % 16.1 % Significant decrease 8.0 % NNT = 30 0.0 % Valsartan Placebo Significant decrease in death, cardiac arrest, hospitalization for HF, or receipt of intravenous inotropic or vasodilator therapy for HF (28.8% vs. 32.1%; RR 0.87, 97.5% CI 0.77 to 0.97) Secondary outcomes Significant decrease in hospitalizations for HF (13.8% vs. 18.2%; RR 0.76, 95% CI 0.31 to 1.21) Safety outcomes Significant differences in adverse events leading to discontinuation of drug (9.9% vs. 7.2%, p < 0.001). Conclusion In patients with HF of NYHA class II, III, or IV on a stable background of standard therapy, valsartan was superior to placebo with respect to death, cardiac arrest, hospitalization for HF, or receipt of intravenous inotropic or vasodilator therapy for HF. Reference Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001 Dec 6;345(23):1667-75. Open reference URL https://web.pathway.md/studies/rec71Z5dZTO75jgKt 2/2

6/30/23, 12:10 AM VAM-IHCA Pathway Feedback Search Clinical Topics Home Studies VAM IHCA VAM IHCA Disease Cardiac arrest Trial question What is the effect of vasopressin and methylprednisolone in patients with in-hospital cardiac arrest? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 501 64.0% male 501 patients (179 female, 322 male) Inclusion criteria: adult patients with in-hospital cardiac arrest who received at least 1 dose of epinephrine during cardiac arrest Key exclusion criteria: do-not-resuscitate order, prior enrollment in the trial, invasive mechanical circulatory support, pregnancy Interventions N=237 vasopressin and methylprednisolone (20 units of vasopressin with 40 mg methylprednisolone) N=264 placebo (sodium chloride solution) Primary outcome Return of spontaneous circulation 42.0 % 42 https://web.pathway.md/studies/recvTiNn7q3ESOfdJ 1/2 6/30/23, 12:10 AM VAM-IHCA Pathway 33 31.5 % 21.0 % Significant increase 10.5 % NNH = 11 0.0 % Vasopressin and methylprednisolone Placebo Significant increase in ROSC (42% vs. 33%; RR 1.3, 95% CI 1.03 to 1.63) Secondary outcomes No significant difference in survival at day 30 (9.7% vs. 12%; RR 0.83, 95% CI 0.5 to 1.37) No significant difference in favorable neurologic outcome at day 30 (7.6% vs. 7.6%; RR 1, 95% CI 0.55 to 1.83) No significant difference in survival at day 90 (8.4% vs. 9.1%; RR 0.93, 95% CI 0.53 to 1.62) Safety outcomes No significant differences in hyperglycemia, hypernatremia. Conclusion In adult patients with in-hospital cardiac arrest who received at least 1 dose of epinephrine during cardiac arrest, vasopressin and methylprednisolone were superior to placebo with respect to ROSC. Reference Lars W Andersen, Dan Isbye, Jesper Kj rgaard et al. Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In- Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2021 Oct 26;326(16):1586-1594. Open reference URL https://web.pathway.md/studies/recvTiNn7q3ESOfdJ 2/2

6/30/23, 12:39 AM Vancomycin vs. metronidazole for C. difficile colitis Pathway Feedback Search Clinical Topics Home Studies Vancomycin vs. metronidazole for C. difficile colitis Vancomycin vs. metronidazole for C. difficile colitis Disease Clostridioides difficile infection Trial question What is the effect of vancomycin in patients with C. difficile-associated diarrhea? Study design Single center Double blinded RCT Population Characteristics of study participants 45.5% female N = 172 54.5% male 172 patients (68 female, 82 male) Inclusion criteria: patients with C. difficile-associated diarrhea were stratified according to whether they had mild or severe disease based on clinical criteria Key exclusion criteria: perforated viscus or bowel obstruction; prior failure of C. difficile- associated diarrhea to respond to either study drug; pregnancy; history of allergy to either study drug; or treatment with oral vancomycin or parenteral or oral metronidazole during the previous 14 days Interventions N=71 vancomycin (125 mg QID PO for 10 days) N=79 metronidazole (250 mg QID PO for 10 days) Primary outcome Cure 97.0 % 97 https://web.pathway.md/studies/recEMrhrCChPON0S2 1/2 6/30/23, 12:39 AM Vancomycin vs. metronidazole for C. difficile colitis Pathway 84 72.8 % 48.5 % Significant increase 24.3 % NNH = 8 0.0 % Vancomycin Metronidazole Significant increase in cure (97% vs. 84%; RR 1.15, 95% CI 0.33 to 1.97) Secondary outcomes No significant difference in cure, in patients with mild disease (98% vs. 90%; RR 1.09, 95% CI -1.22 to 3.4) Significant increase in cure rate, in patients with severe disease (97% vs. 76%; RR 1.28, 95% CI 0.2 to 2.36) Conclusion In patients with C. difficile-associated diarrhea were stratified according to whether they had mild or severe disease based on clinical criteria, vancomycin was superior to metronidazole with respect to cure. Reference Zar FA, Bakkanagari SR, Moorthi KM et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007 Aug 1;45(3):302-7. Open reference URL https://web.pathway.md/studies/recEMrhrCChPON0S2 2/2

6/30/23, 12:10 AM VANCS Pathway Feedback Search Clinical Topics Home Studies VANCS VANCS Trial question Is vasopressin superior to norepinephrine in reducing postoperative complications in patients with vasoplegic syndrome? Study design Single center Double blinded RCT Population Characteristics of study participants 46.2% female N = 330 53.8% male 330 patients (138 female, 162 male) Inclusion criteria: patients with vasoplegic shock (mean arterial pressure < 65 mmHg resistant to fluid challenge and cardiac index > 2.2 L/min/m ) after cardiac surgery Key exclusion criteria: aortic surgery, heart transplantation, preoperative use of vasopressor therapy, presence of a ventricular assist device other than an intraaortic balloon pump, severe hyponatremia, acute coronary syndrome, acute mesenteric ischemia, history of Raynaud disease, pregnancy and neoplasm Interventions N=149 vasopressin (0.01-0.06 U/min) N=151 norepinephrine (10-60 g/min) Primary outcome Rate of death or severe postoperative complications within 30 days 49.0 % 49 36.8 % 32 24.5 % Significant decrease 12.3 % https://web.pathway.md/studies/recyx5BwFB0XvLF0k 1/2 6/30/23, 12:10 AM VANCS Pathway NNT = 6 0.0 % Vasopressin Norepinephrine Significant decrease in the rate of death or severe postoperative complications within 30 days (32% vs. 49%; HR 0.55, 95% CI 0.38 to 0.8) Secondary outcomes Significant decrease in the rate of AF by day 30 (63.8% vs. 82.1%; OR 0.37, 95% CI 0.22 to 0.64) Safety outcomes No significant differences in adverse events including digital ischemia, mesenteric ischemia, hyponatremia, and myocardial infarction. Conclusion In patients with vasoplegic shock (mean arterial pressure < 65 mmHg resistant to fluid challenge and cardiac index > 2.2 L/min/m ) after cardiac surgery, vasopressin was superior to norepinephrine with respect to the rate of death or severe postoperative complications within 30 days. Reference Hajjar LA, Vincent JL, Barbosa Gomes Galas FR et al. Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery: The VANCS Randomized Controlled Trial. Anesthesiology. 2017 Jan;126(1):85-93. Open reference URL https://web.pathway.md/studies/recyx5BwFB0XvLF0k 2/2

6/30/23, 12:10 AM VANISH Pathway Feedback Search Clinical Topics Home Studies VANISH VANISH Disease Disease Dilated cardiomyopathy Ventricular arrhythmias Trial question What is the role of catheter ablation in patients with ischemic cardiomyopathy and an ICD who had VT despite use of antiarrhythmic drugs? Study design Multi-center Open label RCT Population Characteristics of study participants 7.0% female N = 259 93.0% male 259 patients (18 female, 241 male) Inclusion criteria: patients with ischemic cardiomyopathy and an ICD who had VT despite the use of antiarrhythmic drugs Key exclusion criteria: acute coronary syndrome, or another reversible cause of VT, ineligible to take amiodarone, ineligible for ablation, renal failure, recent coronary bypass surgery, prior ablation for VT Interventions N=132 catheter ablation (procedure within 14 days of randomization plus continued baseline antiarrhythmic medications) N=127 escalated antiarrhythmic therapy (dose of amiodarone increased if dose < 300 mg/day or mexiletine added if dose already 300 mg per day) Primary outcome https://web.pathway.md/studies/recEi9zo0AjTOqhFd 1/2 6/30/23, 12:10 AM VANISH Pathway Death, ventricular tachycardia storm, or appropriate implantable cardioverter-defibrillator shock 68.5 % 68.5 59.1 51.4 % 34.3 % Significant decrease 17.1 % NNT = 11 0.0 % Catheter ablation Escalated antiarrhythmic therapy Significant decrease in death, VT storm, or appropriate ICD shock (59.1% vs. 68.5%; HR 0.72, 95% CI 0.53 to 0.98) Secondary outcomes No significant difference in death (27.3% vs. 27.6%; HR 0.96, 96% CI 0.6 to 1.53) No significant difference in VT storm at 30 days (24.2% vs. 33.1%; HR 0.66, 95% CI 0.42 to 1.05) Significant decrease in sustained VT below ICD detection limit at any time (3% vs. 10.2%; HR 0.27, 95% CI 0.09 to 0.84) Safety outcomes No significant differences in procedural complications, vascular injury, cardiac perforation, and heart block. Significant differences in treatment-related adverse events (15.2% vs. 30.7%), hepatic dysfunction (0% vs. 4.7%), tremor or ataxia (0% vs. 4.7%), and drug therapy change (0% vs. 4.7%). Conclusion In patients with ischemic cardiomyopathy and an ICD who had VT despite the use of antiarrhythmic drugs, catheter ablation was superior to escalated antiarrhythmic therapy with respect to death, VT storm, or appropriate ICD shock. Reference Sapp JL, Wells GA, Parkash R et al. Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs. N Engl J Med. 2016 Jul 14;375(2):111-21. Open reference URL https://web.pathway.md/studies/recEi9zo0AjTOqhFd 2/2

6/30/23, 12:11 AM VASST Pathway Feedback Search Clinical Topics Home Studies VASST VASST Disease Sepsis and septic shock Trial question What is the role of vasopressin among patients with septic shock who were treated with catecholamine vasopressors? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.0% female N = 778 61.0% male 778 patients (304 female, 475 male) Inclusion criteria: patients who had septic shock and were receiving a minimum of 5 g of norepinephrine per minute Key exclusion criteria: anticipated death in 12 months, > 24 hours since the meeting of inclusion criteria, pregnancy, chronic heart disease, unstable angina or myocardial infarction within the previous 30 days, acute mesenteric ischemia, severe hyponatremia, Raynaud's phenomenon, systemic sclerosis, TBI Interventions N=396 vasopressin (at a dose of 0.01-0.03 U/min plus open-label vasopressors) N=382 norepinephrine (at a dose of 5-15 g/min plus open-label vasopressors) Primary outcome Death at day 28 https://web.pathway.md/studies/recTCyAk6bibwLXlY 1/2 6/30/23, 12:11 AM VASST Pathway 39.3 % 39.3 35.4 29.5 % 19.6 % 9.8 % No significant difference 0.0 % Vasopressin Norepinephrine No significant difference in death at day 28 (35.4% vs. 39.3%; RR 0.9, 95% CI 0.75 to 1.08) Secondary outcomes No significant difference in death at day 90 (43.9% vs. 49.6%; RR 0.88, 95% CI 0.76 to 1.03) No significant difference in length of stay in the ICU (15 days vs. 16 days; AD -1 days, 95% CI -2.33 to 0.33) No significant difference in length of stay in the hospital (27 days vs. 26 days; AD 1 days, 95% CI -0.63 to 2.63) Safety outcomes No significant difference in serious adverse events. Significant differences in cardiac arrest (0.8% vs. 2.1%), digital ischemia (2.0% vs. 0.5%). Conclusion In patients who had septic shock and were receiving a minimum of 5 g of norepinephrine per minute, vasopressin was not superior to norepinephrine with respect to death at day 28. Reference Russell JA, Walley KR, Singer J et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008 Feb 28;358(9):877-87. Open reference URL https://web.pathway.md/studies/recTCyAk6bibwLXlY 2/2

6/30/23, 12:39 AM Veburecestat in Alzheimer's disease Pathway Feedback Search Clinical Topics Home Studies Veburecestat in Alzheimer's disease Veburecestat in Alzheimer's disease Disease Alzheimer's disease Reference Egan MF, Kost J, Tariot PN et al. Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease. N Engl J Med. 2018 May 3;378(18):1691-1703. Open reference URL https://web.pathway.md/studies/recQWiX7DfKvttG7b 1/1

6/30/23, 12:11 AM VEST Pathway Feedback Search Clinical Topics Home Studies VEST VEST Disease Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Ventric Trial question What is the effect of a wearable cardioverter-defibrillator in patients with acute myocardial infarction and an ejection fraction 35%? Study design Multi-center Single blinded RCT Population Characteristics of study participants 26.3% female N = 2302 73.7% male 2302 patients (608 female, 1685 male) Inclusion criteria: patients with acute myocardial infarction and an ejection fraction 35% Key exclusion criteria: ICD or unipolar pacemaker, clinically significant valve disease, undergoing long-term hemodialysis, chest circumference too small or too large to accommodate the wearable cardioverter-defibrillator, pregnancy Interventions N=1524 use of a wearable cardioverter-defibrillator (wearable cardioverter-defibrillator plus guideline-directed medical therapy) N=778 standard medical therapy (guideline-directed medical therapy alone) Primary outcome Death due to arrhythmic causes 2.4 % 2.4 https://web.pathway.md/studies/recmMvJu3MGx6XTRd 1/2 6/30/23, 12:11 AM VEST Pathway 1.8 % 1.6 1.2 % 0.6 % No significant difference 0.0 % Use of a wearable cardioverter-defibrillator Standard medical therapy No significant difference in death due to arrhythmic causes (1.6% vs. 2.4%; RR 0.67, 95% CI 0.37 to 1.21) Secondary outcomes Significant decrease in death from any cause (3.1% vs. 4.9%; RR 0.64, 95% CI 0.43 to 0.98) Conclusion In patients with acute myocardial infarction and an ejection fraction 35%, use of a wearable cardioverter-defibrillator was not superior to standard medical therapy with respect to death due to arrhythmic causes. Reference Olgin JE, Pletcher MJ, Vittinghoff E et al. Wearable Cardioverter-Defibrillator after Myocardial Infarction. N Engl J Med. 2018 Sep 27;379(13):1205-1215. Open reference URL https://web.pathway.md/studies/recmMvJu3MGx6XTRd 2/2

6/30/23, 12:36 AM VET-COACH Pathway Feedback Search Clinical Topics Home Studies VET COACH VET COACH Disease Hypertension Trial question What is the effect of a peer health coaching program among veterans with cardiovascular risks? Study design Multi-center Open label RCT Population Characteristics of study participants 13.0% female N = 264 87.0% male 264 patients (35 female, 229 male) Inclusion criteria: veterans with a diagnosis of hypertension with at least 1 BP reading 150/90 mmHg in the past year, and 1 other cardiovascular risk factor Key exclusion criteria: hospitalization in the past 3 months for cardiovascular-related conditions, severe illness that precludes lifestyle program; nursing home resident; severe cognitive impairment; receipt of home-based primary care Interventions N=134 peer health coaching program (home visits from a peer health coach targeting disease self-management) N=130 usual care (continue to receive regular, usual primary care) Primary outcome Reduction in systolic blood pressure at 12 months 3.3 mm Hg 3.32 https://web.pathway.md/studies/rec3sif3V6zu5zuaQ 1/2 6/30/23, 12:36 AM VET-COACH Pathway 2.5 mm Hg 1.7 mm Hg 0.8 mm Hg No significant difference 0.4 0.0 mm Hg Peer health coaching program Usual care No significant difference in reduction in systolic BP at 12 months (3.32 mm Hg vs. 0.4 mm Hg; AD 2.05 mm Hg, 95% CI -2.55 to 7) Secondary outcomes Significant increase in improvement in mental health-related quality of life score (2.19 vs. -1.01; AD 3.64, 95% CI 0.66 to 6.63) No significant difference in improvement in physical health-related quality of life score (1.02 vs. 0.72; AD 0.51, 95% CI -1.76 to 2.77) No significant difference in reduction in Framingham Risk Score (0.01 vs. 0.01; AD 0.01, 95% CI -0.01 to 0.03) Conclusion In veterans with a diagnosis of hypertension with at least 1 BP reading 150/90 mmHg in the past year, and 1 other cardiovascular risk factor, peer health coaching program was not superior to usual care with respect to reduction in systolic BP at 12 months. Reference Karin M Nelson, Leslie Taylor, Jennifer L Williams et al. Effect of a Peer Health Coaching Intervention on Clinical Outcomes Among US Veterans With Cardiovascular Risks: The Vet- COACH Randomized Clinical Trial. JAMA Netw Open. 2023 Jun 1;6(6):e2317046. Open reference URL https://web.pathway.md/studies/rec3sif3V6zu5zuaQ 2/2

6/30/23, 12:36 AM VI-0521 in Obese Adolescents (mid-dose) Pathway Feedback Search Clinical Topics Home Studies VI 0521 in Obese Adolescents (mid-dose) VI 0521 in Obese Adolescents (mid-dose) Disease Disease Childhood obesity Obesity Trial question What is the role of mid-dose phentermine/topiramate in adolescents with obesity? Study design Multi-center Double blinded RCT Population Characteristics of study participants 53.0% female N = 110 47.0% male 110 patients (58 female, 52 male) Inclusion criteria: adolescents with obesity Key exclusion criteria: treatment with antiobesity medications; history of bariatric surgery or eating disorders; stimulant use; T1DM; congenital heart disease; obesity of a known genetic or endocrine origin Interventions N=54 mid-dose phentermine/topiramate (7.5 mg phentermine and 46 mg topiramate oral capsule once daily) N=56 placebo (matching placebo oral capsule) Primary outcome Significant increase in reduction in BMI at week 56 (4.78% vs. -3.34%; AD 8.11%, 95% CI 4.31 to 11.92) t https://web.pathway.md/studies/recY5u1Fq9AevnisW S d 1/2 6/30/23, 12:36 AM VI-0521 in Obese Adolescents (mid-dose) Pathway Secondary outcomes Significant increase in reduction in waist circumference (7.42 cm vs. -0.31 cm; AD 7.72 cm, 95% CI 4.02 to 11.43) Significant increase in improvement in high-density lipoprotein cholesterol (6.65% vs. -3.65%; AD 10.3%, 95% CI 2.91 to 17.7) Significant increase in reduction in triglycerides (12.79% vs. -8.35%; AD 21.14%, 95% CI 2.05 to 40.24) Safety outcomes No significant difference in any adverse event. Conclusion In adolescents with obesity, mid-dose phentermine/topiramate was superior to placebo with respect to reduction in BMI at week 56. Reference Aaron S Kelly, Megan O Bensignor, Daniel S Hsia et al. Phentermine/Topiramate for the Treatment of Adolescent Obesity. NEJM Evid. 2022 Jun;1(6):10.1056/evidoa2200014. Open reference URL https://web.pathway.md/studies/recY5u1Fq9AevnisW 2/2

6/30/23, 12:36 AM VI-0521 in Obese Adolescents (top-dose) Pathway Feedback Search Clinical Topics Home Studies VI 0521 in Obese Adolescents (top-dose) VI 0521 in Obese Adolescents (top-dose) Disease Disease Childhood obesity Obesity Trial question What is the role of top-dose phentermine/topiramate in adolescents with obesity? Study design Multi-center Double blinded RCT Population Characteristics of study participants 55.0% female N = 169 45.0% male 169 patients (93 female, 76 male) Inclusion criteria: adolescents with obesity Key exclusion criteria: treatment with antiobesity medications; history of bariatric surgery or eating disorders; stimulant use; T1DM; congenital heart disease; obesity of a known genetic or endocrine origin Interventions N=113 top-dose phentermine/topiramate (15 mg phentermine and 92 mg topiramate oral capsule once daily) N=56 placebo (matching placebo oral capsule) Primary outcome Significant increase in reduction in BMI at week 56 (7.11% vs. -3.34%; AD 10.44%, 95% CI 6.99 to 13.89) t https://web.pathway.md/studies/recq18gvvpFRnHlr2 S d 1/2 6/30/23, 12:36 AM VI-0521 in Obese Adolescents (top-dose) Pathway Secondary outcomes Significant increase in reduction in waist circumference (9.27 cm vs. -0.31 cm; AD 9.58 cm, 95% CI 6.33 to 12.83) Significant increase in improvement in high-density lipoprotein cholesterol (5.1% vs. -3.65%; AD 8.75%, 95% CI 2.15 to 15.35) Significant increase in reduction in triglycerides (12.37% vs. -8.35%; AD 20.72%, 95% CI 3.72 to 37.71) Safety outcomes No significant difference in adverse effects. Conclusion In adolescents with obesity, top-dose phentermine/topiramate was superior to placebo with respect to reduction in BMI at week 56. Reference Aaron S Kelly, Megan O Bensignor, Daniel S Hsia et al. Phentermine/Topiramate for the Treatment of Adolescent Obesity. NEJM Evid. 2022 Jun;1(6):10.1056/evidoa2200014. Open reference URL https://web.pathway.md/studies/recq18gvvpFRnHlr2 2/2

6/30/23, 12:37 AM VIOLET (lung cancer) Pathway Feedback Search Clinical Topics Home Studies VIOLET (lung cancer) VIOLET (lung cancer) Disease Disease Non-small cell lung cancer Small cell lung cancer Trial question Is video-assisted thoracoscopic surgery superior to open surgery in patients with early-stage lung cancer? Study design Multi-center Single blinded RCT Population Characteristics of study participants 50.0% female N = 502 50.0% male 502 patients (253 female, 249 male) Inclusion criteria: patients with early-stage lung cancer Key exclusion criteria: previous malignancy influencing life expectancy; planned pneumonectomy or non-anatomic resection; serious concomitant disorder compromising patient safety during surgery; planned robotic surgery Interventions N=247 VATS lobectomy (video-assisted thoracoscopic surgery) N=255 open lobectomy (conventional open surgery) Primary outcome Improvement in physical function at week 28 73.0 73 67 54 8 https://web.pathway.md/studies/recnyef3Pb9FqeGzX 1/2 6/30/23, 12:37 AM VIOLET (lung cancer) Pathway 54.8 36.5 18.3 Significant increase 0.0 VATS lobectomy Open lobectomy Significant increase in improvement in physical function at week 28 (73 vs. 67; MD 4.65, 95% CI 1.69 to 7.61) Secondary outcomes Significant decrease in pain score at day 2 post-op (3 vs. 4; MD -0.54, 95% CI -0.99 to -0.09) Safety outcomes No significant difference in serious adverse events in hospital. Significant differences in adverse events in hospital (32.8% vs. 44.3%), serious adverse events after discharge (30.7% vs. 37.8%). Conclusion In patients with early-stage lung cancer, VATS lobectomy was superior to open lobectomy with respect to improvement in physical function at week 28. Reference Eric Lim, F.R.C.S. (C-Th), Tim J.P. Batchelor et al. Video-Assisted Thoracoscopic or Open Lobectomy in Early-Stage Lung Cancer. NEJM Evid. 2022;1(3). Open reference URL https://web.pathway.md/studies/recnyef3Pb9FqeGzX 2/2

6/30/23, 12:37 AM VIOLET (vitamin D) Pathway Feedback Search Clinical Topics Home Studies VIOLET (vitamin D VIOLET (vitamin D Disease Vitamin D deficiency Trial question What is the effect of early high-dose vitamin D3 supplementation in critically ill, vitamin D- deficient patients? Study design Multi-center Double blinded RCT Population Characteristics of study participants 43.0% female N = 1078 57.0% male 1078 patients (467 female, 611 male) Inclusion criteria: critically ill, vitamin D-deficient patients who were at high risk for death Key exclusion criteria: an inability to take an enteral drug, a history of kidney stones, the presence of hypercalcemia at baseline, and informed consent not being obtained in a timely manner Interventions N=538 vitamin D (a single enteral dose of 540,000 IU of vitamin D3 in liquid form, administered within 2 hours after randomization) N=540 placebo (matched placebo in liquid form, administered within 2 hours after randomization) Primary outcome All-cause mortality at 90 days https://web.pathway.md/studies/rec4NWnyYq1dZjUTZ 1/2 6/30/23, 12:37 AM VIOLET (vitamin D) Pathway 23.5 % 23.5 20.6 17.6 % 11.8 % 5.9 % No significant difference 0.0 % Vitamin D Placebo No significant difference in all-cause mortality at 90 days (23.5% vs. 20.6%; AD 2.9%, 95% CI -2.1 to 7.9) Secondary outcomes No significant difference in in-hospital mortality at 90 days (17.1% vs. 13.4%; AD 3.7%, 95% CI -0.5 to 8) Borderline significant decrease in hospital length of stay at 90 days (9.1 days vs. 10.4 days; AD -1.4 days, 95% CI -2.7 to 0) No significant difference in ventilator-free days at 28 days (21.3 days vs. 22.1 days; AD -0.8 days, 95% CI -2.1 to 0.5) Safety outcomes No significant differences in serious and nonserious adverse events, hypercalcemia, kidney stones, fall-related fractures. Significant difference in total calcium level at 14 days (8.9 mg/dl vs. 8.8 mg/dl). Conclusion In critically ill, vitamin D-deficient patients who were at high risk for death, vitamin D was not superior to placebo with respect to a all-cause mortality at 90 days. Reference National Heart, Lung, and Blood Institute PETAL Clinical Trials Network et al. Early High-Dose Vitamin D 3 for Critically Ill, Vitamin D-Deficient Patients. N Engl J Med. 2019 Dec 26;381(26):2529-2540. Open reference URL https://web.pathway.md/studies/rec4NWnyYq1dZjUTZ 2/2

6/30/23, 12:37 AM VISEP Pathway Feedback Search Clinical Topics Home Studies VISEP VISEP Disease Sepsis and septic shock Trial question Is intensive insulin therapy superior to conventional insulin therapy in critically ill patients with sepsis? Study design Multi-center Open label RCT Population Characteristics of study participants 40.0% female N = 537 60.0% male 537 patients (215 female, 322 male) Inclusion criteria: adult patients with severe sepsis or septic shock Key exclusion criteria: age < 18 years; pre-existing kidney failure requiring dialysis; intracerebral hemorrhage; severe head trauma with edema; HF Interventions N=247 intensive insulin therapy (blood glucose target 80-110 mg/dL) N=290 conventional insulin therapy (blood glucose target 180-200 mg/dL) Primary outcome Death at day 28 26.0 % 26 24.7 19.5 % https://web.pathway.md/studies/recawpTsrLbYJKZ49 1/2 6/30/23, 12:37 AM VISEP Pathway 13.0 % 6.5 % No significant difference 0.0 % Intensive insulin therapy Conventional insulin therapy No significant difference in death at day 28 (24.7% vs. 26%; ARD -1.3, 95% CI -8.6 to 6) Secondary outcomes No significant difference in death at day 90 (39.7% vs. 35.4%; AD 4.3%, 95% CI -3.93 to 12.53) No significant difference in mean sequential organ failure assessment score (7.8 vs. 7.7; MD 0.1, 95% CI -1.1 to 1.3) No significant difference in acute renal failure (31.1% vs. 26.6%; AD 4.5%, 95% CI -3.12 to 12.12) Safety outcomes Significant differences in severe hypoglycemia (17.0% vs. 4.1%), serious adverse events (10.9% vs. 5.2%). Conclusion In adult patients with severe sepsis or septic shock, intensive insulin therapy was not superior to conventional insulin therapy with respect to death at day 28. Reference Frank M Brunkhorst, Christoph Engel, Frank Bloos et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008 Jan 10;358(2):125-39. Open reference URL https://web.pathway.md/studies/recawpTsrLbYJKZ49 2/2

6/30/23, 12:37 AM VITAL-DEP Pathway Feedback Search Clinical Topics Home Studies VITAL DEP VITAL DEP Disease Major depressive disorder Trial question What is the effect of long-term supplementation of marine omega-3 fatty acids in older adults without clinically relevant depressive symptoms? Study design Multi-center Double blinded RCT Population Characteristics of study participants 49.0% female N = 18353 51.0% male 18353 patients (9023 female, 9330 male) Inclusion criteria: adults aged 50 years at risk of incident depression or at risk of recurrent depression Key exclusion criteria: significant depressive symptoms, history of alcohol or substance disorder, use of psychotropics, hypothyroidism, major neurologic disorder or delirium episode in < 12 months Interventions N=9171 omega-3 (1 g/d of fish oil, including 465 mg of eicosapentaenoic acid and 375 mg of docosahexaenoic acid) N=9182 placebo (matching omega-3 placebo) Primary outcome Incidence of of depression or clinically relevant depressive symptoms https://web.pathway.md/studies/rec6bCPPlV6OQxhXe 1/2 6/30/23, 12:37 AM VITAL-DEP Pathway 13.9/1K py 13.9 12.3 10.4/1K py 7.0/1K py 3.5/1K py Significant increase 0.0/1K py Omega-3 Placebo Significant increase in the incidence of of depression or clinically relevant depressive symptoms (13.9 events /1000 py vs. 12.3 events /1000 py; HR 1.13, 95% CI 1.01 to 1.26) Safety outcomes No significant differences in suicide, gastrointestinal bleeding, easy bruising, stomach upset or pain. Conclusion In adults aged 50 years at risk of incident depression or at risk of recurrent depression, omega- 3 was inferior to placebo with respect to the incidence of of depression or clinically relevant depressive symptoms. Reference Olivia I Okereke, Chirag M Vyas, David Mischoulon et al. Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA. 2021 Dec 21;326(23):2385-2394. Open reference URL https://web.pathway.md/studies/rec6bCPPlV6OQxhXe 2/2

6/30/23, 12:37 AM VITAMINS Pathway Feedback Search Clinical Topics Home Studies VITAMINS VITAMINS Disease Sepsis and septic shock Trial question What is the effect of the combination of vitamin C, hydrocortisone, and thiamine among patients with septic shock? Study design Multi-center Open label RCT Population Characteristics of study participants 36.7% female N = 216 63.3% male 216 patients (78 female, 133 male) Inclusion criteria: patients in ICUs fulfilling the Sepsis-3 definition of septic shock Key exclusion criteria: age younger than 18 years, a do-not-resuscitate order, imminent death, diagnosis of septic shock > 24 hours ago, known or suspected disease with a strong indication or contraindication for any of the study drugs, and another indication for hydrocortisone than septic shock Interventions N=109 vitamin C, hydrocortisone and thiamine (vitamin C 1.5 g IV q6h, hydrocortisone 50 mg IV q6h, and thiamine 200 mg IV q12h until shock resolution or up to 10 days) N=107 hydrocortisone (hydrocortisone 50 mg IV q6h, until shock resolution or up to 10 days) Primary outcome Hours alive and vasopressor-free up to day 7 https://web.pathway.md/studies/recOlCzNpoDYeozsW 1/2 6/30/23, 12:37 AM VITAMINS Pathway 124.6 hours 124.6 122.1 93.4 hours 62.3 hours 31.1 hours No significant difference 0.0 hours Vitamin C, hydrocortisone and thiamine Hydrocortisone No significant difference in hours alive and vasopressor-free up to day 7 (122.1 hours vs. 124.6 hours; AD -0.6 hours, 95% CI -8.3 to 7.2) Secondary outcomes No significant difference in death at day 90 (28.6% vs. 24.5%; AD 4.1%, 95% CI -8 to 16.1) No significant difference in cumulative vasopressor-free days at day 28 (25.6 days vs. 25.8 days; AD -0.2 days, 95% CI -1.7 to 1.2) No significant difference in cumulative mechanical ventilation-free days at day 28 (25.3 days vs. 24.8 days; AD 0.4 days, 95% CI -2.6 to 3.4) Safety outcomes No significant differences in adverse events such as fluid overload, gastrointestinal bleeding, or hyperglycemia. Significant difference in the absolute change in SOFA score at day 3 (-2 vs. -1). Conclusion In patients in ICUs fulfilling the Sepsis-3 definition of septic shock, vitamin C, hydrocortisone and thiamine were not superior to hydrocortisone with respect to hours alive and vasopressor-free up to day 7. Reference Tomoko Fujii, Nora Luethi, Paul J Young et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. 2020 Feb 4;323(5):423-431. Open reference URL https://web.pathway.md/studies/recOlCzNpoDYeozsW 2/2

6/30/23, 12:38 AM VOYAGER PAD Pathway Feedback Search Clinical Topics Home Studies VOYAGER PAD VOYAGER PAD Disease Peripheral artery disease of low Trial question What is the role of rivaroxaban in patients with PAD after revascularization? Study design Multi-center Double blinded RCT Population Characteristics of study participants 26.0% female N = 6564 74.0% male 6564 patients (1704 female, 4860 male) Inclusion criteria: patients aged 50 years with PAD who had undergone revascularization Key exclusion criteria: clinically unstable condition; high risk for bleeding; known liver disease with coagulopathy or bleeding risk; receipt or anticipated to begin receiving prohibited concomitant medications including long-term treatment with clopidogrel Interventions N=3286 rivaroxaban (oral dose of 2.5 mg BID plus aspirin) N=3278 placebo (oral dose of matching placebo BID plus aspirin) Primary outcome Composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes 19.9 % 19.9 17.3 14 9 % https://web.pathway.md/studies/reca5QvzXktWfpyCn 1/2 6/30/23, 12:38 AM 14.9 % VOYAGER PAD Pathway 9.9 % Significant decrease 5.0 % NNT = 38 0.0 % Rivaroxaban Placebo Significant decrease in composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes (17.3% vs. 19.9%; HR 0.85, 95% CI 0.76 to 0.96) Secondary outcomes Significant decrease in composite outcome of acute limb ischemia, major amputation for a vascular cause, myocardial infarction, ischemic stroke, or death from coronary heart disease (14.7% vs. 18.2%; HR 0.8, 95% CI 0.71 to 0.91) Significant decrease in unplanned index-limb revascularization for recurrent limb ischemia (20% vs. 22.5%; HR 0.88, 95% CI 0.79 to 0.99) Significant decrease in hospitalization for thrombotic coronary or peripheral event (8.7% vs. 12.1%; HR 0.72, 95% CI 0.62 to 0.85) Safety outcomes No significant difference in major bleeding according to the Thrombolysis In Myocardial Infarction classification or intracranial hemorrhage. Significant difference in major bleeding according to the International Society on Thrombosis and Hemostasis criteria (5.94% vs. 4.06%). Conclusion In patients aged 50 years with PAD who had undergone revascularization, rivaroxaban was superior to placebo with respect to the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. Reference Marc P Bonaca, Rupert M Bauersachs, Sonia S Anand et al. Rivaroxaban in Peripheral Artery Disease after Revascularization. N Engl J Med. 2020 May 21;382(21):1994-2004. Open reference URL https://web.pathway.md/studies/reca5QvzXktWfpyCn 2/2

6/30/23, 12:38 AM VV116 for COVID-19 Pathway Feedback Search Clinical Topics Home Studies VV116 for COVID 19 VV116 for COVID 19 Disease COVID 19 infection Trial question Is VV116 noninferior to nirmatrelvir-ritonavir in adults with mild-to-moderate COVID-19 who were at risk for progression? Study design Multi-center Single blinded RCT Population Characteristics of study participants 50.0% female N = 771 50.0% male 771 patients (387 female, 384 male) Inclusion criteria: symptomatic adults with mild-to-moderate COVID-19 with a high risk of progression Key exclusion criteria: severe or critical COVID-19 or an anticipated need for mechanical ventilation before randomization; an ALT or AST level > 1.5 times the upper limit of the normal range; an eGFR < 60 mL/min Interventions N=384 VV116 (600 mg every 12 hours on day 1 and 300 mg every 12 hours on day 2 through 5) N=387 nirmatrelvir-ritonavir (300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days) Primary outcome https://web.pathway.md/studies/recXtpD025oG8jTgv 1/2 6/30/23, 12:38 AM VV116 for COVID-19 Pathway Time to sustained clinical recovery through day 28 5.0 days 5 4 3.8 days 2.5 days Difference not exceeding nonferiority margin 1.3 days 0.0 days VV116 Nirmatrelvir-ritonavir Difference not exceeding nonferiority margin in time to sustained clinical recovery through day 28 (4 days vs. 5 days; HR 0.85, 95% CI 0.73 to 0.98) Secondary outcomes No significant difference in time to sustained symptom resolution (7 days vs. 7 days; HR 1.06, 95% CI 0.91 to 1.22) Safety outcomes No significant difference in adverse events. Conclusion In symptomatic adults with mild-to-moderate COVID-19 with a high risk of progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to time to sustained clinical recovery through day 28. Reference Zhujun Cao, Weiyi Gao, Hong Bao et al. VV116 versus Nirmatrelvir-Ritonavir for Oral Treatment of Covid-19. N Engl J Med. 2023 Feb 2;388(5):406-417. Open reference URL https://web.pathway.md/studies/recXtpD025oG8jTgv 2/2

6/30/23, 12:47 AM Wang Pathway Feedback Search Clinical Topics Home Studies Wang Wang Disease COVID 19 infection Trial question What is the effect of remdesivir in the treatment of patients hospitalized with severe COVID-19? Study design Multi-center Double blinded RCT Population Characteristics of study participants 41.0% female N = 237 59.0% male 237 patients (96 female, 140 male) Inclusion criteria: adults (aged 18 years) admitted to hospital with laboratory-confirmed COVID-19, with an interval from symptom onset to the enrolment 12 days, oxygen saturation 94% on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen 300 mmHg , and radiologically confirmed pneumonia Key exclusion criteria: hepatic cirrhosis; ALT or AST > 5 times the ULN; known severe renal impairment or receipt of continuous RRT, hemodialysis, or peritoneal dialysis Interventions N=158 remdesivir (200 mg on day 1 followed by 100 mg on days 2-10 in single daily infusions) N=78 placebo (the same volume of matching placebo infusions for 10 days) Primary outcome Time to clinical improvement up to day 28 23 23 0 d 21 https://web.pathway.md/studies/recEhFFdGWFHtH76p 1/2 6/30/23, 12:47 AM 23.0 days Wang Pathway 21 17.3 days 11.5 days 5.8 days No significant difference 0.0 days Remdesivir Placebo No significant difference in time to clinical improvement up to day 28 (21 days vs. 23 days; HR 0.81, 95% CI 0.57 to 1.15) Secondary outcomes No significant difference in the rate of death by day 28 (14% vs. 13%; AD 1.1%, 95% CI -8.1 to 10.3) Safety outcomes No significant difference in adverse events. Significant differences in serious adverse events (18% vs. 26%), drug discontinuation due to adverse events or serious adverse events (12% vs. 5%). Conclusion In adults (aged 18 years) admitted to hospital with laboratory-confirmed COVID-19, with an interval from symptom onset to the enrolment 12 days, oxygen saturation 94% on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen 300 mmHg , and radiologically confirmed pneumonia, remdesivir was not superior to placebo with respect to time to clinical improvement up to day 28. Reference Yeming Wang, Dingyu Zhang, Guanhua Du et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 May 16;395(10236):1569-1578. Open reference URL https://web.pathway.md/studies/recEhFFdGWFHtH76p 2/2

6/30/23, 12:46 AM WARFASA Pathway Feedback Search Clinical Topics Home Studies WARFASA WARFASA Disease Disease Deep vein thrombosis Pulmonary embolism Trial question What is the effect of aspirin for the prevention of recurrent VTE? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 403 64.0% male 403 patients (145 female, 257 male) Inclusion criteria: patients with first-ever unprovoked VTE who had completed 6 to 18 months of OAC treatment Key exclusion criteria: cancer, major thrombophilia, an indication for long-term anticoagulant therapy for AF or prosthetic heart valve, active bleeding or high risk for bleeding, allergy or intolerance to aspirin, life expectancy < 6 months Interventions N=205 aspirin (100 mg daily for 2 years) N=197 placebo (matching placebo daily for 2 years) Primary outcome Recurrence of venous thromboembolism 11.2 % 11.2 https://web.pathway.md/studies/rec2yz7ldizptyxub 1/2 6/30/23, 12:46 AM WARFASA Pathway 8.4 % 6.6 5.6 % Significant decrease 2.8 % NNT = 22 0.0 % Aspirin Placebo Significant decrease in recurrence of VTE (6.6% vs. 11.2%; HR 0.58, 95% CI 0.36 to 0.93) Secondary outcomes Significant decrease in recurrence due to PE (6.7% vs. 13.5%; HR 0.38, 95% CI 0.17 to 0.88) No significant difference in recurrence due to deep vein thrombosis (6.5% vs. 10.2%; HR 0.65, 95% CI 0.65 to 1.2) No significant difference in death (1.4% vs. 1.3%; HR 1.04, 95% CI 0.32 to 3.42) Safety outcomes No significant difference in adverse events and major bleeding episode. Conclusion In patients with first-ever unprovoked VTE who had completed 6 to 18 months of OAC treatment, aspirin was superior to placebo with respect to recurrence of VTE. Reference Becattini C, Agnelli G, Schenone A et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012 May 24;366(21):1959-67. Open reference URL https://web.pathway.md/studies/rec2yz7ldizptyxub 2/2

6/30/23, 12:46 AM WARP (warfarin evaluation) Pathway Feedback Search Clinical Topics Home Studies WARP (warfarin evaluation) WARP (warfarin evaluation) Disease Disease Cancer-associated thrombosis Catheter-related thrombosis Trial question What is the role of warfarin thromboprophylaxis in cancer patients with central venous catheters? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 812 61.0% male 812 patients (313 female, 499 male) Inclusion criteria: patients aged 16 years with cancer receiving chemotherapy through central venous catheters Key exclusion criteria: contraindication to warfarin; patient on warfarin therapy, pregnancy; breastfeeding Interventions N=408 warfarin (an oral daily dose of warfarin) N=404 no warfarin (no treatment with warfarin) Primary outcome Catheter-related thrombotic events 6.0 % 6 6 4.5 % https://web.pathway.md/studies/recfTNOSNHyimOMxc 1/2 6/30/23, 12:46 AM WARP (warfarin evaluation) Pathway 3.0 % 1.5 % No significant difference 0.0 % Warfarin No warfarin No significant difference in catheter-related thrombotic events (6% vs. 6%; RR 0.99, 99% CI 0.57 to 1.72) Secondary outcomes No significant difference in thrombotic events (7% vs. 9%; RR 0.78, 95% CI 0.5 to 1.24) No significant difference in total major bleeding (1.73% vs. 0.25%; RR 6.93, 95% CI 0.86 to 56.08) No significant difference in thrombotic events and major bleeding events (9% vs. 10%; RR 0.94, 95% CI 0.61 to 1.44) Conclusion In patients aged 16 years with cancer receiving chemotherapy through central venous catheters, warfarin was not superior to no warfarin with respect to a catheter-related thrombotic events. Reference Annie M Young, Lucinda J Billingham, Gulnaz Begum et al. Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial. Lancet. 2009 Feb 14;373(9663):567-74. Open reference URL https://web.pathway.md/studies/recfTNOSNHyimOMxc 2/2

6/30/23, 12:46 AM WATERFALL Pathway Feedback Search Clinical Topics Home Studies WATERFALL WATERFALL Disease Acute pancreatitis Trial question Is early aggressive fluid resuscitation superior to moderate fluid resuscitation in patients with acute pancreatitis? Study design Multi-center Open label RCT Population Characteristics of study participants 51.0% female N = 249 49.0% male 249 patients (127 female, 122 male) Inclusion criteria: adult patients who presented to the emergency department with acute pancreatitis Key exclusion criteria: moderately severe or severe disease; HF; hypernatremia, hyponatremia, hyperkalemi; life expectancy < 1 year; chronic pancreatitis; chronic renal failure; decompensated cirrhosis Interventions N=122 aggressive fluid resuscitation (bolus of 20 mL/kg of body weight, followed by 3 mL/kg/hour) N=127 moderate fluid resuscitation (bolus of 10 mL/kg in patients with hypovolemia or no bolus in patients with normovolemia, followed by 1.5 mL/kg/hour) Primary outcome https://web.pathway.md/studies/recK3edHXKrTBCRGT 1/2 6/30/23, 12:46 AM WATERFALL Pathway Development of moderately severe or severe pancreatitis 22.1 % 22.1 17.3 16.6 % 11.1 % 5.5 % No significant difference 0.0 % Aggressive fluid resuscitation Moderate fluid resuscitation No significant difference in the development of moderately severe or severe pancreatitis (22.1% vs. 17.3%; RR 1.3, 95% CI 0.78 to 2.18) Secondary outcomes Significant increase in fluid overload (20.5% vs. 6.3%; RR 2.85, 95% CI 1.36 to 5.94) No significant difference in organ failure (7.4% vs. 3.9%; RR 1.23, 95% CI 0.47 to 3.23) No significant difference in respiratory failure (7.4% vs. 2.4%; RR 2.19, 95% CI 0.63 to 7.64) Safety outcomes No significant differences in dyspnea, local complications. Significant difference in fluid overload (20.5% vs. 6.3%). Conclusion In adult patients who presented to the emergency department with acute pancreatitis, aggressive fluid resuscitation was not superior to moderate fluid resuscitation with respect to the development of moderately severe or severe pancreatitis. Reference Enrique de-Madaria, James L Buxbaum, Patrick Maisonneuve et al. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis. N Engl J Med. 2022 Sep 15;387(11):989-1000. Open reference URL https://web.pathway.md/studies/recK3edHXKrTBCRGT 2/2

6/30/23, 12:46 AM WHI Pathway Feedback Search Clinical Topics Home Studies WHI WHI Disease Disease Coronary artery disease Menopause Trial question What is the role of estrogen plus progestin in healthy postmenopausal women? Study design Multi-center Double blinded RCT Population 16608 female patients Inclusion criteria: healthy postmenopausal women aged 50-79 years with an intact uterus at baseline Key exclusion criteria: any medical condition likely to be associated with a predicted survival of < 3 years, prior breast cancer, other prior cancer within the last 10 years except nonmelanoma skin cancer, low hematocrit or platelet counts, alcoholism, or dementia Interventions N=8506 estrogen plus progestin (conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet) N=8102 placebo (matching placebo tablet) Primary outcome Nonfatal myocardial infarction or cardiovascular death 0.4 % 0.37 0.3 0.3 % 0.2 % 0.1 % Borderline significant increase 0.0 % Estrogen plus progestin Placebo https://web.pathway.md/studies/reczMy2U49X8YHk2C 1/2 6/30/23, 12:46 AM WHI Pathway Borderline significant increase in nonfatal myocardial infarction or cardiovascular death (0.37% vs. 0.3%; HR 1.29, 95% CI 1.02 to 1.63) Secondary outcomes No significant difference in stroke (0.29% vs. 0.21%; HR 1.41, 95% CI 0.81 to 1.07) Borderline significant increase in venous thromboembolic disease (0.34% vs. 0.16%; HR 2.11, 95% CI 1.58 to 2.82) Borderline significant decrease in osteoporotic fractures (1.47% vs. 1.91%; HR 0.76, 95% CI 0.69 to 0.85) Safety outcomes No significant difference in death and cause of death. Significant difference in invasive breast cancer (0.38% per year vs. 0.30% per year). Conclusion In healthy postmenopausal women aged 50-79 years with an intact uterus at baseline, estrogen plus progestin was inferior to placebo with respect to nonfatal myocardial infarction or cardiovascular death. Reference Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33. Open reference URL https://web.pathway.md/studies/reczMy2U49X8YHk2C 2/2

6/30/23, 12:47 AM WISDOM Pathway Feedback Search Clinical Topics Home Studies WISDOM WISDOM Disease Chronic obstructive pulmonary Trial question What is the effect of withdrawal of ICSs in patients with a history of exacerbations of severe COPD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 18.0% female N = 2485 82.0% male 2485 patients (436 female, 2049 male) Inclusion criteria: patients with a history of exacerbation of COPD receiving triple therapy consisting of tiotropium (at a dose of 18 g once daily), salmeterol (50 g BID), and the ICS fluticasone propionate (500 g BID) during a 6-week run-in period Key exclusion criteria: current clinical diagnosis of asthma; history of thoracotomy with pulmonary resection; unstable or life-threatening cardiac arrhythmia; clinical diagnosis of bronchiectasis; a respiratory tract infection or COPD exacerbation occurring within 6 weeks prior to the initial screening; history of myocardial infarction within 3 months prior to initial screening; or hospitalization for cardiac failure within the past year Interventions N=1242 corticosteroid withdrawal (tiotropium 18 g once daily, salmeterol 50 g BID, and withdrawal of fluticasone in three steps over a 12-week period for 52-weeks) https://web.pathway.md/studies/recoDgQFZyM5NyUxL 1/2 6/30/23, 12:47 AM WISDOM Pathway N=1243 corticosteroid continuation (tiotropium 18 g once daily, salmeterol 50 g BID, and fluticasone 500 g BID for 52-weeks) Primary outcome Moderate or severe chronic obstructive pulmonary disease exacerbation 1.5 % 1.5 1.1 % 1.1 0.8 % Difference not exceeding nonferiority margin 0.4 % 0.0 % Corticosteroid withdrawal Corticosteroid continuation Difference not exceeding nonferiority margin in moderate or severe COPD exacerbation (1.5% vs. 1.1%; HR 1.06, 95% CI 0.94 to 1.19) Safety outcomes No significant difference in adverse events and serious adverse events. Conclusion In patients with a history of exacerbation of COPD receiving triple therapy consisting of tiotropium (at a dose of 18 g once daily), salmeterol (50 g BID), and the ICS fluticasone propionate (500 g BID) during a 6-week run-in period, corticosteroid withdrawal was noninferior to corticosteroid continuation with respect to moderate or severe COPD exacerbation. Reference Magnussen H, Disse B, Rodriguez-Roisin R et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014 Oct 2;371(14):1285-94. Open reference URL https://web.pathway.md/studies/recoDgQFZyM5NyUxL 2/2

6/30/23, 12:47 AM WOEST Pathway Feedback Search Clinical Topics Home Studies WOEST WOEST Disease Disease Coronary artery disease Perioperative management of an Trial question What is the role of double therapy with clopidogrel in patients receiving OACs and undergoing PCI? Study design Multi-center Open label RCT Population Characteristics of study participants 20.4% female N = 573 79.6% male 573 patients (115 female, 448 male) Inclusion criteria: adults receiving OACs and undergoing PCI Key exclusion criteria: history of intracranial bleeding; cardiogenic shock; contraindication to use of aspirin, clopidogrel, or both; peptic ulcer in the previous 6 months; thrombocytopenia; major bleeding in the past 12 months; and pregnancy. Interventions N=279 double antithrombotic therapy (anticoagulation plus clopidogrel) N=284 triple antithrombotic therapy (anticoagulation plus aspirin and clopidogrel) Primary outcome Bleeding complications at 1 year 44.4 % 44.4 https://web.pathway.md/studies/recJWWs5aN7HDkqtp 1/2 6/30/23, 12:47 AM WOEST Pathway 33.3 % 22.2 % 19.4 Significant decrease 11.1 % NNT = 4 0.0 % Double antithrombotic therapy Triple antithrombotic therapy Significant decrease in bleeding complications at 1 year (19.4% vs. 44.4%; HR 0.36, 95% CI 0.26 to 0.5) Secondary outcomes Significant decrease in death, myocardial infarction, stroke, target-vessel revascularisation, or stent thrombosis (11.1% vs. 17.6%; HR 0.6, 95% CI 0.38 to 0.94) No significant difference in myocardial infarction (3.2% vs. 4.6%; HR 0.69, 95% CI 0.29 to 1.6) No significant difference in stroke (1.1% vs. 2.8%; HR 0.37, 95% CI 0.1 to 1.4) Conclusion In adults receiving OACs and undergoing PCI, double antithrombotic therapy was superior to triple antithrombotic therapy with respect to bleeding complications at 1 year. Reference Dewilde WJ, Oirbans T, Verheugt FW et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open- label, randomised, controlled trial. Lancet. 2013 Mar 30;381(9872):1107-15. Open reference URL https://web.pathway.md/studies/recJWWs5aN7HDkqtp 2/2

6/30/23, 12:47 AM WOMAN Pathway Feedback Search Clinical Topics Home Studies WOMAN WOMAN Disease Postpartum hemorrhage Trial question What is the effect of early tranexamic acid administration in women with postpartum hemorrhage? Study design Multi-center Double blinded RCT Population 20060 female patients Inclusion criteria: women 16 years with a clinical diagnosis of postpartum hemorrhage after vaginal birth or C-section Key exclusion criteria: consideration of a clear indication or contraindication for tranexamic acid by the responsible clinician Interventions N=10051 tranexamic acid (an intravenous dose of 1 g plus usual care) N=10009 placebo (matching placebo plus usual care) Primary outcome Death due to bleeding 1.9 % 1.9 1.5 1.4 % 0.9 % Significant decrease 0.5 % NNT = 250 0.0 % Tranexamic acid Placebo Significant decrease in death due to bleeding (1.5% vs. 1.9%; RR 0.81, 95% CI 0.65 to 1) https://web.pathway.md/studies/recb1MQWkuhUOQzS9 1/2 6/30/23, 12:47 AM WOMAN Pathway Secondary outcomes No significant difference in death from all causes or hysterectomy at day 42 (5.3% vs. 5.6%; RR 0.97, 95% CI 0.87 to 1.09) Significant decrease in death due to bleeding in women given treatment within 3 hours of giving birth (1.2% vs. 1.7%; RR 0.69, 95% CI 0.52 to 0.91) No significant difference in hysterectomy (3.6% vs. 3.5%; RR 1.02, 95% CI 0.88 to 1.07) Safety outcomes No significant difference in adverse events including thromboembolic events. Significant differences in use of brace sutures (3.0% vs. 2.5%), laparotomy for bleeding (0.8% vs. 1.3%). Conclusion In women 16 years with a clinical diagnosis of postpartum hemorrhage after vaginal birth or C- section, tranexamic acid was superior to placebo with respect to death due to bleeding. Reference WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017 May 27;389(10084):2105-2116. Open reference URL https://web.pathway.md/studies/recb1MQWkuhUOQzS9 2/2

6/30/23, 12:47 AM WOSCOPS Pathway Feedback Search Clinical Topics Home Studies WOSCOPS WOSCOPS Disease Dyslipidemia Trial question What is the role of pravastatin therapy in male patients with hypercholesterolemia and no history of MI? Study design Multi-center Double blinded RCT Population 6595 male patients Inclusion criteria: male patients (45-64 years of age) with hypercholesterolemia and no history of MI Key exclusion criteria: serious ECG abnormalities or arrhythmia such as AF; history of myocardial infarction or other serious illness, or hospitalization for stable angina within the previous 12 months Interventions N=3302 pravastatin (40 mg each evening) N=3293 placebo (matching placebo each evening) Primary outcome Nonfatal MI or death from CHD 7.9 % 7.9 5.9 % 5.5 4.0 % Significant decrease 2.0 % NNT = 42 0.0 % Pravastatin Placebo https://web.pathway.md/studies/rec51ZFuxrG2dQQAy 1/2 6/30/23, 12:47 AM WOSCOPS Pathway Significant decrease in nonfatal MI or death from CHD (5.5% vs. 7.9%; RR 0.69, 95% CI 0.57 to 0.83) Secondary outcomes Significant decrease in definite nonfatal MI (4.6% vs. 6.5%; RR 0.69, 95% CI 0.55 to 0.85) Safety outcomes No significant differences in deaths from non-cardiovascular causes (56 vs. 62, p=0.54), strokes (46 vs. 51), or incident cancers (116 vs. 106, p=0.55). Conclusion In male patients (45-64 years of age) with hypercholesterolemia and no history of MI, pravastatin was superior to placebo with respect to nonfatal MI or death from CHD. Reference Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995 Nov 16;333(20):1301-7. Open reference URL https://web.pathway.md/studies/rec51ZFuxrG2dQQAy 2/2

6/30/23, 12:50 AM Zochios Pathway Feedback Search Clinical Topics Home Studies Zochios Zochios Disease Disease Disease Aortic regurgitation Aortic stenosis Corona Trial question What is the effect of prophylactic high-flow nasal oxygen use in cardiac surgical patients at high risk for postoperative respiratory complications? Study design Multi-center Open label RCT Population Characteristics of study participants 38.3% female N = 100 61.7% male 100 patients (36 female, 58 male) Inclusion criteria: adult patients with pre-existing respiratory disease undergoing elective cardiac surgery Key exclusion criteria: presence of a nasal septal defect, need for CPAP therapy pre operatively or unmet criteria for tracheal extubation the day after surgery Interventions N=51 high-flow nasal oxygen (the FiO2 titrated to provide oximetry saturation of at least 95% (93% for those at risk of hypercapnic respiratory failure); standard starting flow rate of 30 L/min) N=49 standard oxygen therapy (low flow oxygen via nasal prongs or a soft facemask titrated to provide oximetry saturations of at least 95% (93% for those at risk of hypercapnic respiratory failure)) P i t https://web.pathway.md/studies/recyYBmxos7damBAQ 1/2 6/30/23, 12:50 AM Zochios Pathway Primary outcome Total length of hospital stay 9.0 days 9 7 6.8 days 4.5 days 2.3 days Significant decrease 0.0 days High-flow nasal oxygen Standard oxygen therapy Significant decrease in the total length of hospital stay (7 days vs. 9 days; AD -2 days, 95% CI -3.56 to -0.44) Secondary outcomes Significant decrease in re-admission to ICU (2% vs. 15.6%; RR 0.13, 95% CI 0.02 to 0.24) No significant difference in mean postoperative six-minute walk test (207.3 m vs. 186.1 m; AD 21.3 m, 95% CI -44 to 86.6) No significant difference in FEV in one second (1.5 vs. 1.2; AD 0.3, 95% CI -0.14 to 0.74) Safety outcomes No significant difference in extra-pulmonary postoperative complications. Conclusion In adult patients with pre-existing respiratory disease undergoing elective cardiac surgery, high- flow nasal oxygen was superior to standard oxygen therapy with respect to the total length of hospital stay. Reference V Zochios, T Collier, G Blaudszun et al. The effect of high-flow nasal oxygen on hospital length of stay in cardiac surgical patients at high risk for respiratory complications: a randomised controlled trial. Anaesthesia. 2018 Dec;73(12):1478-1488. Open reference URL https://web.pathway.md/studies/recyYBmxos7damBAQ 2/2

6/30/23, 12:51 AM Zoledronate for osteopenia Pathway Feedback Search Clinical Topics Home Studies Zoledronate for osteopenia Zoledronate for osteopenia Disease Postmenopausal osteoporosis Trial question What is the role of zoledronate in fracture prevention in postmenopausal women with osteopenia? Study design Multi-center Double blinded RCT Population 2000 female patients Inclusion criteria: postmenopausal women with osteopenia Key exclusion criteria: an eGFR of < 30 mL/min/1.73 m of body-surface area, major systemic disease, cancer in the previous 2 years, metabolic bone disease, or regular use bone-active drugs in the previous year, and prednisone at a dose of 2.5 mg per day Interventions N=1000 zoledronate (four infusions of 5 mg at 18-month interval) N=1000 placebo (four infusions of normal saline at 18-month interval) Primary outcome Fragility fracture 19.0 % 19 14.3 % 12.2 9.5 % Significant decrease 4.8 % NNT = 15 0.0 % Zoledronate Placebo https://web.pathway.md/studies/recqztel2OWPdx3qI 1/2 6/30/23, 12:51 AM Zoledronate for osteopenia Pathway Significant decrease in fragility fracture (12.2% vs. 19%; HR 0.63, 95% CI 0.5 to 0.79) Secondary outcomes Significant decrease in height loss by at least 1 cm (32.2% vs. 41.3%; OR 0.67, 95% CI 0.55 to 0.82) Safety outcomes No significant difference in serious adverse events included fractures that resulted in hospitalization. Significant differences in serious adverse events (820 vs. 1017; OR 0.84, 95% CI 0.70-1.00). Conclusion In postmenopausal women with osteopenia, zoledronate was superior to placebo with respect to fragility fracture. Reference Reid IR, Horne AM, Mihov B et al. Fracture Prevention with Zoledronate in Older Women with Osteopenia. N Engl J Med. 2018 Dec 20;379(25):2407-2416. Open reference URL https://web.pathway.md/studies/recqztel2OWPdx3qI 2/2