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6/28/23, 11:36 PM INSPIRATION-S Pathway Feedback Search Clinical Topics Home Studies INSPIRATION S INSPIRATION S Disease COVID 19 infection Trial question What is the role of atorvastatin in critically ill adult patients with COVID-19? Study design Multi-center Double blinded RCT Population Characteristics of study participants 44.0% female N = 587 56.0% male 587 patients (256 female, 331 male) Inclusion criteria: adult patients with COVID-19 admitted to the ICU Key exclusion criteria: estimated survival < 24 hours; weight < 40 kg; major bleeding or serious bleeding diathesis within 30 days from enrollment; liver enzymes > 5 times the ULN; active liver disease; CK concentration > 500 U/L Interventions N=290 atorvastatin (20 mg per oral daily for 30 days) N=297 placebo (matching placebo) Primary outcome Venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or death from any cause at day 30 36.0 % 36 33 27 0 % https://web.pathway.md/studies/reczogvBxu5TNFfxR 1/2 6/28/23, 11:36 PM 27.0 % INSPIRATION-S Pathway 18.0 % 9.0 % No significant difference 0.0 % Atorvastatin Placebo No significant difference in venous or arterial thrombosis, treatment with ECMO, or death from any cause at day 30 (33% vs. 36%; OR 0.84, 95% CI 0.58 to 1.21) Secondary outcomes No significant difference in death from any cause (31% vs. 35%; OR 0.84, 95% CI 0.58 to 1.22) No significant difference in VTE (2% vs. 3%; OR 0.71, 95% CI 0.24 to 2.06) No significant difference in arterial thrombosis (ARD -0.3, 95% CI -0.9 to 0.3) Safety outcomes No significant differences in elevated liver enzymes, fatal bleeding. Conclusion In adult patients with COVID-19 admitted to the ICU, atorvastatin was not superior to placebo with respect to venous or arterial thrombosis, treatment with ECMO, or death from any cause at day 30. Reference INSPIRATION-S Investigators. Atorvastatin versus placebo in patients with covid-19 in intensive care: randomized controlled trial. BMJ. 2022 Jan 7;376:e068407. Open reference URL https://web.pathway.md/studies/reczogvBxu5TNFfxR 2/2

6/28/23, 11:36 PM INSTINCT Pathway Feedback Search Clinical Topics Home Studies INSTINCT INSTINCT Disease Disease Fournier's gangrene Necrotizing fasciitis Trial question What is the role of IgG in ICU patients with necrotizing soft tissue infection? Study design Single center Double blinded RCT Population Characteristics of study participants 38.0% female N = 100 62.0% male 100 patients (38 female, 62 male) Inclusion criteria: ICU patients with necrotizing soft tissue infection Key exclusion criteria: receipt of > 1 dose of IgG before randomization; necrotizing soft tissue infection for > 48 hours; known hypersensitivity to IgG; known hyperprolinemia Interventions N=50 intravenous polyspecific IgG (infusion at a dose of 25 g once daily for the first 3 days of ICU admission) N=50 placebo (an equal volume of 0.9% saline once daily for the first 3 days of ICU admission) Primary outcome Physical component summary score at 6 m 36.0 36 31 27.0 https://web.pathway.md/studies/recnzC1nSpXg3x0i7 1/2 6/28/23, 11:36 PM INSTINCT Pathway 18.0 9.0 No significant difference 0.0 Intravenous polyspecific immunoglobulin G Placebo No significant difference in physical component summary score at 6 m (36 vs. 31; MD 1, 95% CI -7 to 10) Secondary outcomes No significant difference in death at day 180 (22% vs. 28%; RR 0.8, 95% CI 0.4 to 1.59) No significant difference in the percentage of patients who received RRT (22% vs. 12%; RR 1.83, 95% CI 0.73 to 4.57) No significant difference in vasopressor or inotrope use in the ICU (92% vs. 94%; RR 0.98, 95% CI 0.88 to 1.09) Safety outcomes No significant differences in serious adverse events, bleeding and amputation at day 180. Conclusion In ICU patients with necrotizing soft tissue infection, intravenous polyspecific IgG was not superior to placebo with respect to physical component summary score at 6 m. Reference Martin B Madsen, Peter B Hjortrup, Marco B Hansen et al. Immunoglobulin G for patients with necrotising soft tissue infection (INSTINCT): a randomised, blinded, placebo-controlled trial. Intensive Care Med. 2017 Nov;43(11):1585-1593. Open reference URL https://web.pathway.md/studies/recnzC1nSpXg3x0i7 2/2

6/28/23, 11:41 PM Insulin-Only Bionic Pancreas Pathway Feedback Search Clinical Topics Home Studies Insulin-Only Bionic Pancreas Insulin-Only Bionic Pancreas Disease Diabetes mellitus type 1 Trial question What is the role of bionic pancreas in patients with T1DM? Study design Multi-center Open label RCT Population Characteristics of study participants 45.0% female N = 326 55.0% male 326 patients (148 female, 178 male) Inclusion criteria: participants 6 years of age with T1DM Key exclusion criteria: plan to change usual diabetes regimen in 3 months; Hgbopathy; history of cystic fibrosisl; pancreatitis; or other pancreatic diseases Interventions N=219 bionic pancreas (automated delivery of insulin aspart or insulin lispro for 13 weeks) N=107 standard care (any insulin-delivery method plus continuous glucose monitoring) Primary outcome Glycated hemoglobin level at week 13 7.7 % 7.7 7.3 5.8 % 3.9 % Significant decrease https://web.pathway.md/studies/recssWOpt6h2cLz9R 1/2 6/28/23, 11:41 PM Insulin-Only Bionic Pancreas Pathway Significant decrease 1.9 % NNT = 250 0.0 % Bionic pancreas Standard care Significant decrease in glycated Hgb level at week 13 (7.3% vs. 7.7%; ARD -0.5, 95% CI -0.6 to -0.3) Secondary outcomes Significant decrease in glucose level at week 13 (164 mg/dL vs. 181 mg/dL; AD -16 mg/dL, 95% CI -19 to -12) Significant increase in the percentage of time with glucose level 70-180 mg/dL at week 13 (65% vs. 54%; AD 11%, 95% CI 9 to 13) Safety outcomes No significant difference in severe hypoglycemia. Conclusion In participants 6 years of age with T1DM, bionic pancreas were superior to standard care with respect to glycated Hgb level at week 13. Reference Bionic Pancreas Research Group, Steven J Russell, Roy W Beck et al. Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes. N Engl J Med. 2022 Sep 29;387(13):1161-1172. Open reference URL https://web.pathway.md/studies/recssWOpt6h2cLz9R 2/2

6/28/23, 11:41 PM Intensive insulin therapy Pathway Feedback Search Clinical Topics Home Studies Intensive insulin therapy Intensive insulin therapy Disease In-hospital hyperglycemia Trial question What is the effect of intensive insulin therapy in critically ill patients who are receiving mechanical ventilation? Study design Single center Open label RCT Population Characteristics of study participants 29.0% female N = 1548 71.0% male 1548 patients (447 female, 1101 male) Inclusion criteria: adults admitted to surgical ICU who were receiving mechanical ventilation Key exclusion criteria: participation in other trials, moribund, or do-not-resuscitate orders Interventions N=765 intensive treatment (maintenance of blood glucose at a level between 80 and 110 mg/dL) N=783 conventional treatment (insulin infusion only if the blood glucose level > 215 mg/dL and maintenance of glucose at a level between 180 and 200 mg/dL) Primary outcome Death during intensive care 8.0 % 8 https://web.pathway.md/studies/recLaYzzznRvygFkr 1/2 6/28/23, 11:41 PM Intensive insulin therapy Pathway 6.0 % 4.6 4.0 % Significant increase 2.0 % NNH = 29 0.0 % Intensive treatment Conventional treatment Significant increase in death during intensive care (4.6% vs. 8%; RR 32, 95% CI 2 to 55) Secondary outcomes Significant decrease in death in the hospital (7.2% vs. 10.9%; RR 0.66, 95% CI 0.16 to 1.16) Significant decrease in the rate of prolonged ventilatory support for > 14 days (7.5% vs. 11.9%; RR 0.63, 95% CI 0.21 to 1.05) Safety outcomes No significant differences in red cell transfusion, inotropic or vasopressor treatment. Significant differences in dialysis or continuous venovenous hemofiltration (4.8% vs. 8.2%), septicemia during intensive care (4.2% vs. 7.8%), critical-illness polyneuropathy (28.7% vs. 51.9%). Conclusion In adults admitted to surgical ICU who were receiving mechanical ventilation, intensive treatment was superior to conventional treatment with respect to death during intensive care. Reference van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-67. Open reference URL https://web.pathway.md/studies/recLaYzzznRvygFkr 2/2

6/28/23, 11:37 PM INTERACT2 Pathway Feedback Search Clinical Topics Home Studies INTERACT2 INTERACT2 Disease Intracerebral hemorrhage Trial question What is the role of intensive lowering of elevated BP in patients with intracerebral hemorrhage? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 2829 63.0% male 2829 patients (1049 female, 1780 male) Inclusion criteria: patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic BP Key exclusion criteria: structural cerebral cause for the intracerebral hemorrhage; deep coma; massive hematoma with a poor prognosis; planned early surgery to evacuate the hematoma Interventions N=1399 intensive blood-pressure lowering (target systolic level <140 mm Hg within 1 hour) N=1430 guideline-recommended BP lowering (target systolic level <180 mm Hg) Primary outcome Death or major disability at day 90 55.6 % 55.6 52 41.7 % https://web.pathway.md/studies/reck7zbuoltGFwxpG 1/2 6/28/23, 11:37 PM INTERACT2 Pathway 27.8 % 13.9 % No significant difference 0.0 % Intensive blood-pressure lowering Guideline-recommended blood pressure lowering No significant difference in death or major disability at day 90 (52% vs. 55.6%; OR 0.87, 95% CI 0.75 to 1.01) Secondary outcomes No significant difference in death (11.9% vs. 12%; OR 0.99, 99% CI 0.79 to 1.25) No significant difference in problems with mobility (63.8% vs. 66.7%; OR 0.88, 95% CI 0.74 to 1.04) Safety outcomes No significant differences in nonfatal serious adverse events, neurologic deterioration in first 24 hours. Conclusion In patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic BP, intensive blood-pressure lowering was not superior to guideline-recommended BP lowering with respect to death or major disability at day 90. Reference Craig S Anderson, Emma Heeley, Yining Huang et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013 Jun 20;368(25):2355-65. Open reference URL https://web.pathway.md/studies/reck7zbuoltGFwxpG 2/2

6/28/23, 11:37 PM INVICTUS Pathway Feedback Search Clinical Topics Home Studies INVICTUS INVICTUS Disease Atrial fibrillation Trial question Is rivaroxaban noninferior to vitamin K antagonist in patients with rheumatic heart disease- associated AF? Study design Multi-center Open label RCT Population Characteristics of study participants 72.0% female N = 4531 28.0% male 4531 patients (3274 female, 1257 male) Inclusion criteria: patients with AF and echocardiographically documented rheumatic heart disease Key exclusion criteria: mechanical heart valve; dual antiplatelet therapy; treatment with dual strong inhibitors of CYP3A4 and P-glycoprotein; severe renal insufficiency; pregnancy Interventions N=2275 rivaroxaban (at a dose of 15-20 mg/day depending upon CrCl) N=2256 vitamin K antagonist (dose adjustment to maintain an INR of 2.0-3.0) Primary outcome Incidence of composite outcome of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes 8.2 %/yr 8.21 https://web.pathway.md/studies/reczdsRqRM8ZuYYO5 1/2 6/28/23, 11:37 PM INVICTUS Pathway 6.49 6.2 %/yr 4.1 %/yr Difference exceeding nonferiority margin 2.1 %/yr 0.0 %/yr Rivaroxaban Vitamin K antagonist Difference exceeding nonferiority margin in the incidence of composite outcome of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes (8.21 percent / y vs. 6.49 percent / y; HR 1.25, 95% CI 1.1 to 1.41) Secondary outcomes Borderline significant increase in the incidence of stroke (1.32 percent / y vs. 0.94 percent / y; HR 1.37, 95% CI 1 to 1.89) No significant difference in the incidence of systemic embolism (0.09 percent / y vs. 0.14 percent / y; HR 0.59, 95% CI 0.22 to 1.63) Borderline significant increase in the incidence of death from any cause (7.95 percent / y vs. 6.35 percent / y; HR 1.23, 95% CI 1.09 to 1.4) Safety outcomes No significant difference in major bleeding. Significant difference in fatal bleeding (0.07% vs. 0.22%). Conclusion In patients with AF and echocardiographically documented rheumatic heart disease, rivaroxaban was not noninferior to vitamin K antagonist with respect to the incidence of composite outcome of stroke, systemic embolism, myocardial infarction, or death from vascular or unknown causes. Reference Stuart J Connolly, Ganesan Karthikeyan, Mpiko Ntsekhe et al. Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation. N Engl J Med. 2022 Sep 15;387(11):978-988. Open reference URL https://web.pathway.md/studies/reczdsRqRM8ZuYYO5 2/2

6/28/23, 11:37 PM IPrEx Pathway Feedback Search Clinical Topics Home Studies IPrEx IPrEx Disease Human immunodeficiency virus i Trial question What is the role of preexposure chemoprophylaxis in HIV-seronegative men or transgender woMSM? Study design Multi-center Double blinded RCT Population Characteristics of study participants 1.0% female N = 2499 99.0% male 2499 patients (29 female, 2470 male) Inclusion criteria: HIV-seronegative men or transgender woMSM Key exclusion criteria: elevated hepatic aminotransferase levels, hyperbilirubinemia, and renal insufficiency, previous receipt of antiretroviral therapy, or acute hepatitis B infection, diabetes, tuberculosis, and cancer Interventions N=1251 oral antiretroviral drugs (emtricitabine and tenofovir disoproxil fumarate (FTC-TDF) once daily plus HIV testing, risk-reduction counseling, condoms, and management of STIs) N=1248 placebo (matching placebo plus HIV testing, risk-reduction counseling, condoms, and management of STIs) Primary outcome Emergence of HIV infection in modified intention-to-treat population https://web.pathway.md/studies/recaeREvqkDGreNNX 1/2 6/28/23, 11:37 PM IPrEx Pathway 64.0 64 48.0 36 32.0 16.0 Significant increase 0.0 Oral antiretroviral drugs Placebo Significant increase in emergence of HIV infection in the modified intention-to-treat population (36 vs. 64; RR 44, 95% CI 15 to 63) Secondary outcomes Borderline significant decrease in pill use on 50% days (23 vs. 47; HR 0.5, 95% CI 0.3 to 0.82) Safety outcomes No significant difference in serious adverse events (p=0.57). Significant difference in nausea during the first week more frequently reported in the FTC-TDF group than the placebo (p < 0.001). Conclusion In HIV-seronegative men or transgender woMSM, oral antiretroviral drugs were superior to placebo with respect to emergence of HIV infection in the modified intention-to-treat population. Reference Grant RM, Lama JR, Anderson PL et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99. Open reference URL https://web.pathway.md/studies/recaeREvqkDGreNNX 2/2

6/28/23, 11:38 PM IRIS Cricoid Trial Pathway Feedback Search Clinical Topics Home Studies IRIS Cricoid Trial IRIS Cricoid Trial Trial question Is cricoid pressure noninferior to a sham procedure in patients undergoing rapid sequence induction of anesthesia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 49.0% female N = 3472 51.0% male 3472 patients (1694 female, 1777 male) Inclusion criteria: patients undergoing anesthesia with rapid sequence induction Key exclusion criteria: contraindication for the use of the cricoid pressure or succinylcholine, pneumonia or pulmonary contusion, upper respiratory tract abnormalities, consciousness disorders Interventions N=1735 Sellick maneuver (application of an expected pressure equivalent to 30 N with the first 3 fingers on the cricoid cartilage) N=1736 sham application (fake Sellick maneuver with no pressure application) Primary outcome Pulmonary aspiration 0.6 % 0.6 0.5 0.4 % 0.3 % Difference exceeding nonferiority margin 0.1 % 0.0 % https://web.pathway.md/studies/recZSYWgS04060mzu 1/2 6/28/23, 11:38 PM IRIS Cricoid Trial Pathway Sellick maneuver Sham application Difference exceeding nonferiority margin in pulmonary aspiration (0.6% vs. 0.5%; RR 0.9, 95% CI 0.33 to 2.38) Secondary outcomes Significant increase in tracheal intubation time (27 seconds vs. 23 seconds; AD 4 seconds, 95% CI 1.63 to 6.37) No significant difference in death (2% vs. 2%; ARD -0.2, 95% CI -1 to 0.7) No significant difference in suspected pneumonia within 24 hours (0.9% vs. 0.6%; ARD -0.3, 95% CI -0.8 to 0.3) Safety outcomes No significant differences in adverse events, serious adverse events. Significant differences in intubation time > 30 seconds (47% vs. 40%), interruption of the cricoid pressure (14% vs. 5%). Conclusion In patients undergoing anesthesia with rapid sequence induction, Sellick maneuver was not noninferior to sham application with respect to pulmonary aspiration. Reference Aur lie Birenbaum, David Hajage, Sabine Roche et al. Effect of Cricoid Pressure Compared With a Sham Procedure in the Rapid Sequence Induction of Anesthesia: The IRIS Randomized Clinical Trial. JAMA Surg. 2019 Jan 1;154(1):9-17. Open reference URL https://web.pathway.md/studies/recZSYWgS04060mzu 2/2

6/28/23, 11:37 PM IRIS Pathway Feedback Search Clinical Topics Home Studies IRIS IRIS Disease Chronic myeloid leukemia Trial question What is the role of imatinib in patients with newly diagnosed chronic-phase CML? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 1106 59.0% male 1106 patients (455 female, 651 male) Inclusion criteria: patients with newly diagnosed chronic-phase CML Key exclusion criteria: uncontrolled serious medical conditions, prior chemotherapy or treatment with any investigational agent, hematopoietic-cell transplantation, major surgery within the preceding four weeks, or seropositive for the human immunodeficiency virus Interventions N=553 imatinib (400 mg PO daily) N=553 interferon alfa plus low-dose cytarabine (interferon alfa, target dose 5 million U per square meter of body-surface area per day and cytarabine subcutaneous 40 mg of maximal daily dose for 10 days every month) Primary outcome Complete cytogenetic response 76.2 % 76.2 https://web.pathway.md/studies/recGeHWBERvXXDDzR 1/2 6/28/23, 11:37 PM IRIS Pathway 57.2 % 38.1 % Significant increase 19.1 % NNT = 2 14.5 0.0 % Imatinib Interferon alfa plus low-dose cytarabine Significant increase in complete cytogenetic response (76.2% vs. 14.5%; RR 5.26, 95% CI 2.14 to 8.38) Secondary outcomes Significant increase in freedom from progression to accelerated-phase or blast-crisis CML (96.7% vs. 91.5%; RR 1.06, 95% CI 0.43 to 1.69) Significant increase in complete hematologic response (95.3% vs. 55.5%; RR 1.72, 95% CI 0.7 to 2.74) Safety outcomes Significant difference in discontinuation of treatment or crossover to the alternative treatment group (14.3% vs. 89.2%). Conclusion In patients with newly diagnosed chronic-phase CML, imatinib was superior to interferon alfa plus low-dose cytarabine with respect to complete cytogenetic response. Reference O'Brien SG, Guilhot F, Larson RA et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003 Mar 13;348(11):994-1004. Open reference URL https://web.pathway.md/studies/recGeHWBERvXXDDzR 2/2

6/28/23, 11:38 PM IRONOUT-HF Pathway Feedback Search Clinical Topics Home Studies IRONOUT HF IRONOUT HF Disease Disease Heart failure Iron deficiency anemia Trial question What is the effect of oral iron repletion on exercise capacity in patients with HFrEF and iron deficiency? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 225 64.0% male 225 patients (80 female, 145 male) Inclusion criteria: patients with HF with reduced LVEF < 40% and iron deficiency Key exclusion criteria: presence of neuromuscular, orthopedic or other noncardiac condition preventing patient from exercise testing, severe renal dysfunction, severe liver disease, IBD, known active infection, active gastrointestinal bleeding, active malignancy, iron overload disorders Interventions N=111 oral iron polysaccharide (150 mg BID for 16 weeks) N=114 placebo (matched placebo BID for 16 weeks) Primary outcome No significant difference in change in peak oxygen uptake at 16 weeks (23 + mL/min vs. -2 + mL/min; difference 21, 95% CI -34 to 76) https://web.pathway.md/studies/recvb8RMKhthNvsW0 1/2 6/28/23, 11:38 PM IRONOUT-HF Pathway Conclusion In patients with HF with reduced LVEF < 40% and iron deficiency, oral iron polysaccharide was not superior to placebo with respect to change in peak oxygen uptake at 16 weeks. Reference Lewis GD, Malhotra R, Hernandez AF et al. Effect of Oral Iron Repletion on Exercise Capacity in Patients With Heart Failure With Reduced Ejection Fraction and Iron Deficiency: The IRONOUT HF Randomized Clinical Trial. JAMA. 2017 May 16;317(19):1958-1966. Open reference URL https://web.pathway.md/studies/recvb8RMKhthNvsW0 2/2

6/28/23, 11:38 PM ISAR-TRIPLE Pathway Feedback Search Clinical Topics Home Studies ISAR TRIPLE ISAR TRIPLE Disease Disease Atrial fibrillation Coronary artery disease Trial question What is the optimum duration of triple therapy in patients requiring oral anticoagulation after drug-eluting stent implantation? Study design Multi-center Open label RCT Population Characteristics of study participants 23.0% female N = 614 77.0% male 614 patients (143 female, 471 male) Inclusion criteria: patients who underwent drug-eluting stent implantation and are receiving concomitant aspirin and oral anticoagulation Key exclusion criteria: age 18 years, previous ST, DES implantation in the left main stem, active bleeding or bleeding diathesis, or a history of intracranial bleeding Interventions N=307 clopidogrel treatment for 6 weeks (75 mg daily for 6 weeks; aspirin 75 to 200 mg once daily; and a vitamin K antagonist with either phenprocoumon or warfarin) N=307 clopidogrel treatment for 6 months (75 mg daily for 6 months; aspirin 75 to 200 mg once daily; and a vitamin K antagonist with either phenprocoumon or warfarin) Primary outcome Death, myocardial infarction, definite stent thrombosis, stroke, or TIMI major bleeding at 9 months https://web.pathway.md/studies/rechpWiSJ3mjpqUCC 1/2 6/28/23, 11:38 PM ISAR-TRIPLE Pathway 9.8 % 9.8 8.8 7.4 % 4.9 % 2.5 % No significant difference 0.0 % Clopidogrel treatment for 6 weeks Clopidogrel treatment for 6 months No significant difference in death, myocardial infarction, definite stent thrombosis, stroke, or TIMI major bleeding at 9 months (9.8% vs. 8.8%; HR 1.14, 95% CI 0.68 to 1.91) Secondary outcomes No significant difference in cardiac death, MI, definite stent thrombosis, or ischemic stroke (4% vs. 4.3%; HR 0.93, 95% CI 0.43 to 2.05) No significant difference in TIMI major bleeding (5.3% vs. 4%; HR 1.35, 95% CI 0.64 to 2.84) Conclusion In patients who underwent drug-eluting stent implantation and are receiving concomitant aspirin and oral anticoagulation, clopidogrel treatment for 6 weeks were not superior to clopidogrel treatment for 6 months with respect to death, myocardial infarction, definite stent thrombosis, stroke, or TIMI major bleeding at 9 months. Reference Fiedler KA, Maeng M, Mehilli J et al. Duration of Triple Therapy in Patients Requiring Oral Anticoagulation After Drug-Eluting Stent Implantation: The ISAR-TRIPLE Trial. J Am Coll Cardiol. 2015 Apr 28;65(16):1619-1629. Open reference URL https://web.pathway.md/studies/rechpWiSJ3mjpqUCC 2/2

6/28/23, 11:38 PM ISAT 1 Pathway Feedback Search Clinical Topics Home Studies ISAT 1 ISAT 1 Disease Subarachnoid hemorrhage Trial question What is the role of endovascular detachable coil treatment in patients with ruptured intracranial aneurysms? Study design Multi-center Double blinded RCT Population Characteristics of study participants 63.0% female N = 2143 37.0% male 2143 patients (1344 female, 799 male) Inclusion criteria: patients with ruptured intracranial aneurysms Key exclusion criteria: subarachnoid hemorrhage occurred > 28 days before randomisation, patient unsuitable for one or both treatments, consent was refused, patient participating in another randomised clinical trial of a treatment for subarachnoid hemorrhage Interventions N=1073 endovascular treatment (endovascular treatment by detachable platinum coils) N=1070 neurosurgical treatment (clipping the neck of the aneurysm) Primary outcome Dependency or death at 1 year 30.6 30.6 % 23 7 https://web.pathway.md/studies/recuVegJp4Wu6Iuqc 1/2 6/28/23, 11:38 PM ISAT 1 Pathway 23.7 23.0 % 15.3 % Significant decrease 7.7 % NNT = 14 0.0 % Endovascular treatment Neurosurgical treatment Significant decrease in dependency or death at 1 year (23.7% vs. 30.6%; RR 0.77, 95% CI 0.66 to 0.91) Safety outcomes No significant difference in frequency of preprocedural rebleeding. Significant difference in risk of rebleeding from ruptured aneurysm after 1 year (0.16% vs. 0%). Conclusion In patients with ruptured intracranial aneurysms, endovascular treatment was superior to neurosurgical treatment with respect to dependency or death at 1 year. Reference Andrew Molyneux, Richard Kerr, Irene Stratton et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002 Oct 26;360(9342):1267-74. Open reference URL https://web.pathway.md/studies/recuVegJp4Wu6Iuqc 2/2

6/28/23, 11:38 PM ISCHEMIA Pathway Feedback Search Clinical Topics Home Studies ISCHEMIA ISCHEMIA Disease Coronary artery disease Trial question What is the role of coronary revascularization in patients with stable CAD? Study design Multi-center Open label RCT Population Characteristics of study participants 23.0% female N = 5179 77.0% male 5179 patients (1191 female, 3988 male) Inclusion criteria: patients with stable ischemic heart disease and moderate or severe ischemia on noninvasive testing Key exclusion criteria: recent MI, eGFR < 30 mL/min, LVEF < 35%, LM stenosis > 50%, unacceptable angina Interventions N=2588 invasive management (cath +/- revascularization) N=2591 optimal medical therapy (no routine invasive therapy) Primary outcome CV death, nonfatal MI, resuscitated cardiac arrest, or hospitalization for UA or HF 15.5 % 15.5 13.3 11.6 % https://web.pathway.md/studies/recWIrS9k4aoLQnpA 1/2 6/28/23, 11:38 PM ISCHEMIA Pathway 7.8 % 3.9 % No significant difference 0.0 % Invasive management Optimal medical therapy No significant difference in CV death, nonfatal MI, resuscitated cardiac arrest, or hospitalization for UA or HF (13.3% vs. 15.5%; HR 0.93, 95% CI 0.8 to 1.08) Secondary outcomes No significant difference in death from any cause (6.4% vs. 6.5%; HR 1.05, 95% CI 0.83 to 1.32) No significant difference in cardiovascular death or MI (11.7% vs. 13.9%; HR 0.87, 95% CI 0.66 to 1.15) Borderline significant increase in periprocedural myocardial infarction (13.2% vs. 10.5%; HR 2.98, 95% CI 1.87 to 4.74) Conclusion In patients with stable ischemic heart disease and moderate or severe ischemia on noninvasive testing, invasive management was noninferior to optimal medical therapy with respect to CV death, nonfatal MI, resuscitated cardiac arrest, or hospitalization for UA or HF. Reference David J Maron, Judith S Hochman, Harmony R Reynolds et al. Initial Invasive or Conservative Strategy for Stable Coronary Disease. N Engl J Med. 2020 Apr 9;382(15):1395-1407. Open reference URL https://web.pathway.md/studies/recWIrS9k4aoLQnpA 2/2

6/28/23, 11:39 PM IST Pathway Feedback Search Clinical Topics Home Studies IST IST Disease Acute ischemic stroke Reference International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet. 1997 May 31;349(9065):1569-81. Open reference URL https://web.pathway.md/studies/recgEwVA1pTuNss7r 1/1

6/28/23, 11:39 PM ITAC Pathway Feedback Search Clinical Topics Home Studies ITAC ITAC Disease COVID 19 infection Trial question What is the role of hyperimmune IVIG in patients hospitalized with COVID-19? Study design Multi-center Double blinded RCT Population Characteristics of study participants 43.0% female N = 579 57.0% male 579 patients (250 female, 329 male) Inclusion criteria: hospitalized patients with symptomatic COVID-19 Key exclusion criteria: previous passive immunotherapies; end-organ failure; known IgA deficiency with anti-IgA antibodies; certain thrombotic conditions and prothrombotic disorders Interventions N=295 hyperimmune IVIG (single infusion of 400 mg/kg of hyperimmune immunoglobulin to COVID-19 plus remdesivir) N=284 placebo (a single infusion of saline plus remdesivir) Primary outcome Percentage of patients with favorable clinical categories 1 and 2 60.0 % 60 56 45.0 % https://web.pathway.md/studies/recv9VEC9QoqE1pMe 1/2 6/28/23, 11:39 PM ITAC Pathway 30.0 % 15.0 % No significant difference 0.0 % Hyperimmune intravenous immunoglobulin Placebo No significant difference in the percentage of patients with favorable clinical categories 1 and 2 (60% vs. 56%; RRR 1.11, 95% CI 0.91 to 1.35) Secondary outcomes No significant difference in the percentage of patients who were discharged or with favorable clinical category 1 (91% vs. 89%; RRR 1.07, 95% CI 0.92 to 1.26) No significant difference in death at day 28 (6% vs. 8%; HR 0.8, 95% CI 0.42 to 1.51) Safety outcomes No significant differences in the percentage of patients with composite safety outcome of death, serious adverse effects and infections at day 28. Significant difference in infusion reactions (18.6% vs. 9.5%). Conclusion In hospitalized patients with symptomatic COVID-19, hyperimmune IVIG was not superior to placebo with respect to the percentage of patients with favorable clinical categories 1 and 2. Reference ITAC (INSIGHT ) Study Group. Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial. Lancet. 2022 Feb 5;399(10324):530-540. Open reference URL https://web.pathway.md/studies/recv9VEC9QoqE1pMe 2/2

6/28/23, 11:40 PM ITACTIC Pathway Feedback Search Clinical Topics Home Studies ITACTIC ITACTIC Disease Traumatic hemorrhage Trial question What is the role of viscoelastic hemostatic assay augmented protocols for major traumatic hemorrhage? Study design Multi-center Single blinded RCT Population Characteristics of study participants 23.0% female N = 396 77.0% male 396 patients (92 female, 304 male) Inclusion criteria: adult trauma patients presenting with clinical signs of bleeding who received empiric major hemorrhage protocols Key exclusion criteria: no signs of hemorrhagic shock, not randomized within 3 hours of injury or 1 hour of admission to the emergency department Interventions N=201 viscoelastic hemostatic assays (analyses performed at the point of care) N=195 conventional coagulation tests (conventional coagulation tests performed in the laboratory) Primary outcome Patients alive and free of massive transfusion at 24 hours after injury 67 67 0 % 64 https://web.pathway.md/studies/recbeeKct1aNDhVQT 1/2 6/28/23, 11:40 PM 67.0 % ITACTIC Pathway 64 50.3 % 33.5 % 16.8 % No significant difference 0.0 % Viscoelastic hemostatic assays Conventional coagulation tests No significant difference in patients alive and free of massive transfusion at 24 hours after injury (67% vs. 64%; OR 1.15, 95% CI 0.76 to 1.73) Secondary outcomes No significant difference in death at 28 days (25% vs. 28%; OR 0.84, 95% CI 0.54 to 1.31) No significant difference in massive transfusion at 24 hours (26% vs. 28%; OR 0.91, 95% CI 0.59 to 1.42) No significant difference in PT ratio > 1.2 at hemostatis (15% vs. 11%; OR 1.37, 95% CI 0.7 to 2.69) Safety outcomes No significant difference in serious adverse events. Conclusion In adult trauma patients presenting with clinical signs of bleeding who received empiric major hemorrhage protocols, viscoelastic hemostatic assays were not superior to conventional coagulation tests with respect to patients alive and free of massive transfusion at 24 hours after injury. Reference K Baksaas-Aasen, L S Gall, J Stensballe et al. Viscoelastic haemostatic assay augmented protocols for major trauma haemorrhage (ITACTIC): a randomized, controlled trial. Intensive Care Med. 2021 Jan;47(1):49-59. Open reference URL https://web.pathway.md/studies/recbeeKct1aNDhVQT 2/2

6/28/23, 11:40 PM IVERCOR-COVID19 Pathway Feedback Search Clinical Topics Home Studies IVERCOR COVID19 IVERCOR COVID19 Disease COVID 19 infection Trial question What is the role of ivermectin in patients with COVID-19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 47.0% female N = 501 53.0% male 501 patients (237 female, 264 male) Inclusion criteria: adult outpatients with COVID-19 positive nasal swabs within 48 hours Key exclusion criteria: current home oxygen use, hospitalization requirement for COVID-19 at the time of diagnosis, or a history of hospitalization for COVID-19 Interventions N=250 ivermectin (a total dosage of 24-48 mg PO, based on weight) N=251 placebo (equivalent number of matching placebo tablets) Primary outcome Hospitalization 8.4 % 8.4 6.3 % 5.6 4 2 % https://web.pathway.md/studies/recE7uqddZTxCQYtm 1/2 6/28/23, 11:40 PM IVERCOR-COVID19 Pathway 4.2 % 2.1 % No significant difference 0.0 % Ivermectin Placebo No significant difference in hospitalization (5.6% vs. 8.4%; OR 0.65, 95% CI 0.32 to 1.31) Secondary outcomes No significant difference in death from all causes (1.6% vs. 1.2%; OR 1.34, 95% CI 0.3 to 6.07) No significant difference in invasive mechanical ventilation (1.6% vs. 1.2%; OR 1.34, 95% CI 0.3 to 6.07) No significant difference in dialysis (0.4% vs. 0.4%; OR 1, 95% CI 0.06 to 16.14) Safety outcomes No significant differences in dialysis, adverse events, or death from all causes. Significant difference in time to invasive mechanical ventilation (5.25 days vs. 10 days). Conclusion In adult outpatients with COVID-19 positive nasal swabs within 48 hours, ivermectin was not superior to placebo with respect to hospitalization. Reference Julio Vallejos, Rodrigo Zoni, Mar a Bangher et al. Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. BMC Infect Dis. 2021 Jul 2;21(1):635. Open reference URL https://web.pathway.md/studies/recE7uqddZTxCQYtm 2/2

6/28/23, 11:51 PM J-RHYTHM Pathway Feedback Search Clinical Topics Home Studies J RHYTHM J RHYTHM Disease Atrial fibrillation Trial question What is the role of rhythm control in patients with paroxysmal AF? Study design Multi-center Open label RCT Population Characteristics of study participants 31.0% female N = 823 69.0% male 823 patients (253 female, 570 male) Inclusion criteria: patients with paroxysmal AF Key exclusion criteria: initial AF episodes; contraindication for anticoagulation; AF occurring during the acute phase of myocardial infarction or cardiac surgery Interventions N=419 rhythm control (antiarrhythmic drugs selected according to the Japanese Guideline for AF Management) N=404 rate control (control of HR by -blockers, calcium-channel blockers, and digitalis) Primary outcome Composite of death, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure, or physical/psychological disability requiring alteration of treatment strategy 22.0 % 22 https://web.pathway.md/studies/recIOJmsujJod8Vsb 1/2 6/28/23, 11:51 PM J-RHYTHM Pathway 16.5 % 15.3 11.0 % Significant decrease NNT = 15 5.5 % 0.0 % Rhythm control Rate control Significant decrease in composite of death, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for HF, or physical/psychological disability requiring alteration of treatment strategy (15.3% vs. 22%; RR 0.7, 95% CI 0.15 to 1.25) Conclusion In patients with paroxysmal AF, rhythm control was superior to rate control with respect to the composite of death, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for HF, or physical/psychological disability requiring alteration of treatment strategy. Reference Satoshi Ogawa, Takeshi Yamashita, Tsutomu Yamazaki et al. Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study. Circ J. 2009 Feb;73(2):242-8. Open reference URL https://web.pathway.md/studies/recIOJmsujJod8Vsb 2/2

6/28/23, 11:51 PM JUPITER Pathway Feedback Search Clinical Topics Home Studies JUPITER JUPITER Disease Disease Disease Acute ischemic stroke Non-ST-elevation myocardial inf ST-elev Trial question What is the role of rosuvastatin in preventing vascular events among healthy men and women with elevated CRP? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.0% female N = 17802 62.0% male 17802 patients (6801 female, 11001 male) Inclusion criteria: healthy men and women with low-density lipoprotein (LDL) cholesterol levels < 130 mg/dL and hs-CRP levels 2.0 mg/L Key exclusion criteria: previous or current use of lipid-lowering therapy, current use of postmenopausal hormone-replacement therapy, evidence of hepatic dysfunction, diabetes, uncontrolled hypertension, uncontrolled hypothyroidism, and a recent history of alcohol or drug abuse Interventions N=8901 rosuvastatin (20 mg daily) N=8901 placebo (matching placebo daily) Primary outcome https://web.pathway.md/studies/rectkXYfMeBjURIsS 1/2 6/28/23, 11:51 PM JUPITER Pathway Myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes 1.4 1.36 1.0 0.77 0.7 0.3 Significant decrease 0.0 Rosuvastatin Placebo Significant decrease in myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes (0.77 vs. 1.36; HR 0.56, 95% CI 0.46 to 0.69) Secondary outcomes Significant decrease in myocardial infarction (0.17 vs. 0.37; HR 0.46, 95% CI 0.3 to 0.7) Significant decrease in stroke (0.18 vs. 0.34; HR 0.52, 95% CI 0.34 to 0.79) Significant decrease in myocardial infarction, stroke, or death from cardiovascular causes (0.45 vs. 0.85; HR 0.53, 95% CI 0.4 to 0.69) Safety outcomes No significant differences in serious adverse events (15.2% vs. 15.5%, p=0.60), myopathy (0.1% vs. 0.1%, p=0.82) or cancer (3.4% vs. 3.5%, p=0.51). Significant differences in physician-reported diabetes (3.0% vs. 2.4%, p = 0.01). Conclusion In healthy men and women with low-density lipoprotein (LDL) cholesterol levels < 130 mg/dL and hs-CRP levels 2.0 mg/L, rosuvastatin was superior to placebo with respect to myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. Reference Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207. Open reference URL https://web.pathway.md/studies/rectkXYfMeBjURIsS 2/2

6/28/23, 11:53 PM KarMMa-3 Pathway Feedback Search Clinical Topics Home Studies KarMMa-3 KarMMa-3 Disease Multiple myeloma Trial question What is the role of idecabtagene vicleucel in patients with relapsed and refractory multiple myeloma? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 386 61.0% male 386 patients (151 female, 235 male) Inclusion criteria: adults with triple-class-exposed relapsed and refractory multiple myeloma who had received 2-4 regimens previously Key exclusion criteria: nonsecretory multiple myeloma; inadequate pulmonary function; active history of plasma cell leukemia; known CNS involvement with myeloma Interventions N=254 ide-cel (dose range, 150 10 to 450 10 chimeric antigen receptor-positive T cells) N=132 standard regimen (either one of the regimens including daratumumab, pomalidomide, and dexamethasone; or daratumumab, bortezomib, and dexamethasone; or ixazomib, lenalidomide, and dexamethasone; or carfilzomib and dexamethasone; or elotuzumab, pomalidomide, and dexamethasone) Primary outcome https://web.pathway.md/studies/recq6SB47vqyvBxnJ 1/2 6/28/23, 11:53 PM KarMMa-3 Pathway Median progression-free survival 13.3 months 13.3 10.0 months 6.7 months 4.4 3.3 months Significant increase 0.0 months Ide-cel Standard regimen Significant increase in median progression-free survival (13.3 months vs. 4.4 months; AD 8.9 months, 95% CI 3.62 to 14.18) Secondary outcomes Significant increase in overall response (71% vs. 42%; AD 29%, 95% CI 11.79 to 46.21) Safety outcomes No significant difference in any adverse events. Significant differences in neutropenia (78% vs 44%), anemia (66% vs. 36%), thrombocytopenia (54% vs. 29%). Conclusion In adults with triple-class-exposed relapsed and refractory multiple myeloma who had received 2-4 regimens previously, ide-cel was superior to standard regimen with respect to median progression-free survival. Reference Paula Rodriguez-Otero, Sikander Ailawadhi, Bertrand Arnulf et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023 Mar 16;388(11):1002-1014. Open reference URL https://web.pathway.md/studies/recq6SB47vqyvBxnJ 2/2

6/28/23, 11:52 PM KEYNOTE-024 Pathway Feedback Search Clinical Topics Home Studies KEYNOTE 024 KEYNOTE 024 Disease Non-small cell lung cancer Trial question What is the effect of pembrolizumab in patients who had previously untreated PD-L1 positive advanced non-small cell lung cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 305 61.0% male 305 patients (118 female, 187 male) Inclusion criteria: patients with previously untreated advanced non-small cell lung cancer with PD-L expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the ALK gene Key exclusion criteria: receiving systemic corticosteroids (excluding daily corticosteroid- replacement therapy for conditions such as adrenal or pituitary insufficiency) or other immunosuppressive treatment or if they had untreated brain metastases, active autoimmune disease for which they had received systemic treatment during the previous 2 years, active ILD, or a history of pneumonitis for which they had received corticosteroids Interventions N=154 pembrolizumab (administered IV at a dose of 200 mg every 3 weeks for 35 cycles) N=151 chemotherapy (investigator's choice of one of the following five platinum-based chemotherapy regimens for 4 to 6 cycles: carboplatin plus pemetrexed, cisplatin plus https://web.pathway.md/studies/recBdUYAhGcbKmWQg 1/2 6/28/23, 11:52 PM KEYNOTE-024 Pathway pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, or carboplatin plus paclitaxel) Primary outcome Median progression-free survival 10.3 months 10.3 7.7 months 6 5.2 months 2.6 months Significant decrease 0.0 months Pembrolizumab Chemotherapy Significant decrease in median progression-free survival (10.3 months vs. 6 months; HR 0.5, 95% CI 0.37 to 0.68) Secondary outcomes Significant increase in overall survival at 6 months (80.2% vs. 72.4%; HR 1.66, 95% CI 1.12 to 2.43) Significant increase in objective response (44.8% vs. 27.8%; AD 16.6%, 95% CI 6 to 27) Safety outcomes No significant differences in serious treatment-related adverse events, discontinuation of treatment due to treatment-related adverse events. Significant differences in treatment-related adverse events (73.4% vs. 90.0%), and grade 3-5 treatment-related adverse events (26.6% vs. 53.3%). Conclusion In patients with previously untreated advanced non-small cell lung cancer with PD-L expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the ALK gene, pembrolizumab was superior to chemotherapy with respect to median progression-free survival. Reference Reck M, Rodriguez-Abreu D, Robinson AG et al. Pembrolizumab versus Chemotherapy for PD- L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. Open reference URL https://web.pathway.md/studies/recBdUYAhGcbKmWQg 2/2

6/28/23, 11:52 PM KEYNOTE-355 Pathway Feedback Search Clinical Topics Home Studies KEYNOTE 355 KEYNOTE 355 Trial question What is the role of pembrolizumab chemotherapy in patients with metastatic triple-negative breast cancer? Study design Multi-center Double blinded RCT Population 847 female patients Inclusion criteria: patients with untreated locally recurrent inoperable or metastatic triple- negative breast cancer Key exclusion criteria: treatment with an investigational agent within 4 weeks; failure to recover from adverse events owing to previously administered therapy; immunodeficiency or immunosuppressive therapy within the previous week; Interventions N=566 pembrolizumab chemotherapy (pembrolizumab 200 mg every 3 weeks plus nab- paclitaxel, paclitaxel, or gemcitabine/carboplatin) N=281 placebo chemotherapy (matching placebo plus nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) Primary outcome Progression-free survival in patients with Combined Positive Score 10 9.7 months 9.7 7.3 months 5.6 4.8 months 2.4 months Significant increase 0.0 months Pembrolizumab chemotherapy Placebo chemotherapy Significant increase in progression-free survival in patients with CPS 10 (9.7 months vs. 5.6 months; HR 1.35, 95% CI 1.12 to 1.64) Secondary outcomes https://web.pathway.md/studies/recorb7hkSAGQnMEO 1/2 6/28/23, 11:52 PM KEYNOTE-355 Pathway Significant increase in progression-free survival in patients with CPS 1 (7.6 months vs. 5.6 months; HR 1.54, 95% CI 1.16 to 2.04) No significant difference in progression-free survival in patients with CPS < 1 (6.3 months vs. 6.2 months; HR 1.08, 95% CI 0.77 to 1.53) Borderline significant increase in progression-free survival in intention to treat population (7.5 months vs. 5.6 months; HR 1.33, 95% CI 1.08 to 1.64) Safety outcomes No significant difference in any adverse event. Conclusion In patients with untreated locally recurrent inoperable or metastatic triple-negative breast cancer, pembrolizumab chemotherapy was superior to placebo chemotherapy with respect to a progression-free survival in patients with CPS 10. Reference Javier Cortes, David W Cescon, Hope S Rugo et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020 Dec 5;396(10265):1817-1828. Open reference URL https://web.pathway.md/studies/recorb7hkSAGQnMEO 2/2

6/28/23, 11:52 PM KIS-IV Pathway Feedback Search Clinical Topics Home Studies KIS IV KIS IV Disease Tobacco use Trial question What is the effect of varenicline as an addition to counseling in African-American adults who are daily smokers? Study design Single center Double blinded RCT Population Characteristics of study participants 52.0% female N = 500 48.0% male 500 patients (262 female, 238 male) Inclusion criteria: African-American adults who were daily smokers of all smoking levels Key exclusion criteria: renal impairment; clinically significant allergic reactions to varenicline; cardiovascular event in the past month; history of panic disorder; psychosis; bipolar disorder or eating disorders Interventions N=300 varenicline (1 mg BID added to smoking cessation counseling for 12 weeks) N=200 placebo (matching placebo added to smoking cessation counseling for 12 weeks) Primary outcome Smoking abstinence at week 26 15.7 % 15.7 https://web.pathway.md/studies/recDoY30wcrWWahRp 1/2 6/28/23, 11:52 PM KIS-IV Pathway 11.8 % 7.8 % 6.5 Significant increase 3.9 % NNH = 11 0.0 % Varenicline Placebo Significant increase in smoking abstinence at week 26 (15.7% vs. 6.5%; OR 2.7, 95% CI 1.4 to 5.1) Secondary outcomes Significant increase in smoking abstinence at week 12 (18.7% vs. 7%; OR 3, 95% CI 1.7 to 5.6) Significant increase in smoking abstinence among light smokers at week 12 (22.1% vs. 8.5%; OR 3, 95% CI 1.4 to 6.7) Significant increase in smoking abstinence among moderate to heavy smokers at week 12 (15.1% vs. 5.3%; OR 3.1, 95% CI 1.1 to 8.6) Safety outcomes No significant difference in adverse events. Conclusion In African-American adults who were daily smokers of all smoking levels, varenicline was superior to placebo with respect to smoking abstinence at week 26. Reference Lisa Sanderson Cox, Nicole L Nollen, Matthew S Mayo et al. Effect of Varenicline Added to Counseling on Smoking Cessation Among African American Daily Smokers: The Kick It at Swope IV Randomized Clinical Trial. JAMA. 2022 Jun 14;327(22):2201-2209. Open reference URL https://web.pathway.md/studies/recDoY30wcrWWahRp 2/2

6/28/23, 11:53 PM Kress Pathway Feedback Search Clinical Topics Home Studies Kress Kress Trial question What is the role of daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation? Study design Single center Open label RCT Population Characteristics of study participants 53.0% female N = 128 47.0% male 128 patients (68 female, 60 male) Inclusion criteria: adult patients who were receiving mechanical ventilation and continuous infusions of sedative drugs in a medical ICU Key exclusion criteria: pregnancy, transfer from an outside institution where sedatives had already been administered, and admission after resuscitation from cardiac arrest Interventions N=68 intervention (daily interruption of sedative infusions until the patients are awake) N=60 control (continuous infusion of sedatives with interruption only at the discretion of the clinicians in the ICU) Primary outcome Duration of mechanical ventilation 7.3 days 7.3 5.5 days 4.9 3.6 days 1.8 days Significant increase 0.0 days https://web.pathway.md/studies/rec1UWysXsTUlvK9W 1/2 6/28/23, 11:53 PM Kress Pathway y Intervention Control Significant increase in duration of mechanical ventilation (4.9 days vs. 7.3 days; RR 1.9, 95% CI 1.3 to 2.7) Secondary outcomes Significant increase in length of stay in the ICU (6.4 days vs. 9.9 days; RR 1.6, 95% CI 1.1 to 2.3) No significant difference in in-hospital death (36% vs. 46.7%; RR 0.77, 95% CI -0.53 to 2.07) Safety outcomes No significant differences in removal of the endotracheal tube by the patient, noninvasive ventilation after extubation, reintubation, tracheostomy, long-term ventilation, withdrawal of care. Significant differences in home discharge (59% vs. 40%), unawakened during the stay (0.10% vs. 0.25%), death in a coma (0.09% vs. 0.22%). Conclusion In adult patients who were receiving mechanical ventilation and continuous infusions of sedative drugs in a medical ICU, intervention was superior to control with respect to duration of mechanical ventilation. Reference Kress JP, Pohlman AS, O'Connor MF et al. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000 May 18;342(20):1471-7. Open reference URL https://web.pathway.md/studies/rec1UWysXsTUlvK9W 2/2

6/28/23, 10:56 PM LANDMARK Pathway Feedback Search Clinical Topics Home Studies LANDMARK LANDMARK Disease Chronic kidney disease Trial question Is lanthanum carbonate superior to calcium carbonate in patients with CKD and hyperphosphatemia undergoing hemodialysis? Study design Multi-center Open label RCT Population Characteristics of study participants 40.0% female N = 2135 60.0% male 2135 patients (864 female, 1271 male) Inclusion criteria: patients with CKD and hyperphosphatemia undergoing hemodialysis Key exclusion criteria: patients undergoing peritoneal dialysis; patients with contraindications to lanthanum carbonate or calcium carbonate; pregnancy Interventions N=1063 lanthanum carbonate (total daily dose of 750-2250 mg PO) N=1072 calcium carbonate (total daily dose of 3,000 mg PO) Primary outcome Cardiovascular events https://web.pathway.md/studies/recXcGyxCxDinfbza 1/2 6/28/23, 10:56 PM LANDMARK Pathway 13.8 % 13.8 12.5 10.4 % 6.9 % 3.5 % No significant difference 0.0 % Lanthanum carbonate Calcium carbonate No significant difference in cardiovascular events (13.8% vs. 12.5%; HR 1.11, 95% CI 0.88 to 1.41) Secondary outcomes No significant difference in death from any cause (15% vs. 13.8%; HR 1.1, 95% CI 0.88 to 1.37) Significant increase in death from cardiovascular causes (5.5% vs. 3.6%; HR 1.51, 95% CI 1.01 to 2.27) Significant increase in the percentage of patients with secondary hyperparathyroidism (9.9% vs. 6.3%; HR 1.62, 95% CI 1.19 to 2.2) Safety outcomes No significant difference in adverse events. Conclusion In patients with CKD and hyperphosphatemia undergoing hemodialysis, lanthanum carbonate was not superior to calcium carbonate with respect to cardiovascular events. Reference Hiroaki Ogata, Masafumi Fukagawa, Hideki Hirakata et al. Effect of Treating Hyperphosphatemia With Lanthanum Carbonate vs Calcium Carbonate on Cardiovascular Events in Patients With Chronic Kidney Disease Undergoing Hemodialysis: The LANDMARK Randomized Clinical Trial. JAMA. 2021 May 18;325(19):1946-1954. Open reference URL https://web.pathway.md/studies/recXcGyxCxDinfbza 2/2

6/28/23, 10:58 PM LDPEEPPC Pathway Feedback Search Clinical Topics Home Studies LDPEEPPC LDPEEPPC Disease Disease Disease Bronchiectasis Non-small cell lung cancer Small cell Trial question What is the effect of PEEP titration to the lowest driving pressure in patients undergoing selective lung resection surgery? Study design Single center Double blinded RCT Population Characteristics of study participants 47.0% female N = 207 53.0% male 207 patients (98 female, 109 male) Inclusion criteria: patients undergoing selective lung resection surgery Key exclusion criteria: age < 18 years; pregnancy Interventions N=104 PEEP titration to the lowest driving pressure (PEEP titration to the lowest driving pressure during one-lung ventilation) N=103 conventional low level of PEEP (PEEP level of 4 cmH O during one-lung ventilation) Primary outcome Rate of development of 4 Melbourne Group Scale variables within 3 postoperative days https://web.pathway.md/studies/recYybS0wOBUHRg6x 1/2 6/28/23, 10:58 PM LDPEEPPC Pathway 13.0 % 13 9.8 % 6.5 % 4 Significant decrease 3.3 % NNT = 11 0.0 % Positive end-expiratory pressure titration to the lowest driving pressure Conventional low level of positive end-expiratory pressure Significant decrease in the rate of development of 4 Melbourne Group Scale variables within 3 postoperative days (4% vs. 13%; RR 0.32, 95% CI 0.1 to 0.9) Secondary outcomes No significant difference in the rate of major postoperative pulmonary complications within 7 postoperative days (96% vs. 96%; RR 1, 95% CI 0.95 to 1.06) No significant difference in CXR atelectasis or infiltration (79% vs. 75%; RR 1.06, 95% CI 0.91 to 1.23) Conclusion In patients undergoing selective lung resection surgery, PEEP titration to the lowest driving pressure was superior to conventional low level of PEEP with respect to the rate of development of 4 Melbourne Group Scale variables within 3 postoperative days. Reference Junjie Yu, Zhijie Wu, Rui An et al. Association between driving pressure and postoperative pulmonary complications in patients undergoing lung resection surgery: A randomised clinical trial. Anaesth Crit Care Pain Med. 2022 Sep 19;42(1):101160. Open reference URL https://web.pathway.md/studies/recYybS0wOBUHRg6x 2/2

6/28/23, 10:58 PM LEADER Pathway Feedback Search Clinical Topics Home Studies LEADER LEADER Disease Diabetes mellitus type 2 Trial question What is the effect of liraglutide in patients with T2DM and high cardiovascular risk? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 9340 64.0% male 9340 patients (3337 female, 6003 male) Inclusion criteria: patients with T2DM who had a glycated Hgb level of 7.0% and high cardiovascular risk Key exclusion criteria: T1DM, calcitonin 50 ng/L, chronic HF, current continuous RRT, end-stage renal disease, history of solid organ transplant or awaiting solid organ transplant, malignant neoplasm, personal history of non-familial medullary thyroid carcinoma Interventions N=4668 liraglutide (1.8 mg or maximum tolerated dose once daily as a subcutaneous injection in addition to standard care) N=4672 placebo (matching placebo once daily as a subcutaneous injection in addition to standard care) https://web.pathway.md/studies/recToD4bL8Mx5VaVo 1/2 6/28/23, 10:58 PM LEADER Pathway Primary outcome Death due to cardiovascular causes 6.0 % 6 4.7 4.5 % 3.0 % Significant decrease 1.5 % NNT = 77 0.0 % Liraglutide Placebo Significant decrease in death due to cardiovascular causes (4.7% vs. 6%; HR 0.78, 95% CI 0.66 to 0.93) Safety outcomes No significant differences in adverse events (62.3% vs. 60.8%, p=0.12) and serious adverse events (49.7% vs. 50.4%, p=0.51). Significant differences in adverse event leading to discontinuation of trial regimen (9.5% vs. 7.3%, p < 0.001) and acute gallstone disease (3.1% vs. 1.9%, p < 0.001). Conclusion In patients with T2DM who had a glycated Hgb level of 7.0% and high cardiovascular risk, liraglutide was noninferior to placebo with respect to death due to cardiovascular causes. Reference Marso SP, Daniels GH, Brown-Frandsen K et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):311-22. Open reference URL https://web.pathway.md/studies/recToD4bL8Mx5VaVo 2/2

6/28/23, 10:58 PM LEAP2 Pathway Feedback Search Clinical Topics Home Studies LEAP2 LEAP2 Disease Community-acquired pneumonia Trial question Is oral lefamulin noninferior to moxifloxacin for early clinical response among adults with community- acquired bacterial pneumonia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 48.0% female N = 738 52.0% male 738 patients (351 female, 387 male) Inclusion criteria: adults aged 18 years or older with a Pneumonia Outcomes Research Team (PORT) risk class of II, III, or IV; radiographically documented pneumonia; acute illness; 3 community-acquired bacterial pneumonia symptoms; and 2 vital sign abnormalities Key exclusion criteria: receipt of > 1 dose of a short-acting oral or intravenous antibacterial for CABP within 72 hours before randomization, hospitalization for 2 days within 90 days, confirmed or suspected methicillin-resistant S aureus, being at risk for major cardiac events or dysfunction, and significant hepatic disease Interventions N=370 lefamulin (600 mg PO every 12 hours for 5 days) https://web.pathway.md/studies/recRwIMBMUcv5YGNU 1/2 6/28/23, 10:58 PM LEAP2 Pathway N=368 moxifloxacin (400 mg PO every 24 hours for 7 days) Primary outcome Early clinical response rate at 96 hours after first dose 90.8 % 90.8 90.8 68.1 % 45.4 % Difference not exceeding nonferiority margin 22.7 % 0.0 % Lefamulin Moxifloxacin Difference not exceeding nonferiority margin in early clinical response rate at 96 hours after first dose (90.8% vs. 90.8%; ARD 0.1, 97.5% CI -4.4 to Infinity) Secondary outcomes No significant difference in overall early clinical response by baseline community-acquired bacterial pneumonia pathogen in microbiological intent-to-treat population (90.7% vs. 93%; ARD -2.3, 95% CI -8.2 to 3.5) Safety outcomes No significant differences in serious adverse events, death at 28 days, adverse events leading to discontinuation of study drug or withdrawal from study. Significant differences in diarrhea (12.2% vs. 1.1%), nausea (5.2% vs. 1.9%), vomiting (3.3% vs. 0.8%). Conclusion In adults aged 18 years or older with a Pneumonia Outcomes Research Team (PORT) risk class of II, III, or IV; radiographically documented pneumonia; acute illness; 3 community-acquired bacterial pneumonia symptoms; and 2 vital sign abnormalities, lefamulin was noninferior to moxifloxacin with respect to early clinical response rate at 96 hours after first dose. Reference Elizabeth Alexander, Lisa Goldberg, Anita F Das et al. Oral Lefamulin vs Moxifloxacin for Early Clinical Response Among Adults With Community-Acquired Bacterial Pneumonia: The LEAP 2 Randomized Clinical Trial. JAMA. 2019 Sep 27;322(17):1661-1671. Open reference URL https://web.pathway.md/studies/recRwIMBMUcv5YGNU 2/2

6/28/23, 11:01 PM LenDex in High-Risk Smoldering Myeloma Pathway Feedback Search Clinical Topics Home Studies LenDex in High-Risk Smoldering Myeloma LenDex in High-Risk Smoldering Myeloma Disease Multiple myeloma Trial question What is the role of lenalidomide plus dexamethasone in patients with high-risk smoldering multiple myeloma? Study design Multi-center Open label RCT Population Characteristics of study participants 55.0% female N = 119 45.0% male 119 patients (66 female, 53 male) Inclusion criteria: patients with high-risk smoldering myeloma Key exclusion criteria: hypercalcemia, bone lesions, renal failure, or anemia Interventions N=57 early treatment (induction regimen with lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4- week intervals for nine cycles, followed by a maintenance regimen with lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle for 2 years) N=62 observation (no treatment until progression to symptomatic disease) https://web.pathway.md/studies/recGQ8posc4Bebhf7 1/2 6/28/23, 11:01 PM LenDex in High-Risk Smoldering Myeloma Pathway Primary outcome Survival at 5 years 94.0 % 94 78 70.5 % 47.0 % Significant decrease 23.5 % NNH = 6 0.0 % Early treatment Observation Significant decrease in survival at 5 years (94% vs. 78%; HR 0.28, 95% CI 0.09 to 0.91) Safety outcomes No significant differences in grade 1 or 2 infections, grade 1 or 2 asthenia, cumulative risk of a second primary tumor at 5 years. Significant difference in serious adverse events (12% vs. 3%). Conclusion In patients with high-risk smoldering myeloma, early treatment was superior to observation with respect to survival at 5 years. Reference Mateos MV, Hernandez MT, Giraldo P et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. Open reference URL https://web.pathway.md/studies/recGQ8posc4Bebhf7 2/2

6/28/23, 10:58 PM LESS Pathway Feedback Search Clinical Topics Home Studies LESS LESS Disease Lumbar spinal stenosis Trial question What is the role of epidural corticosteroid injections in patients with lumbar spinal stenosis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 55.0% female N = 400 45.0% male 400 patients (221 female, 179 male) Inclusion criteria: patients who had lumbar central spinal stenosis and moderate-to-severe leg pain and disability Key exclusion criteria: no stenosis of the central canal, spondylolisthesis requiring surgery, and a history of lumbar surgery or received epidural corticosteroid injections within the previous 6 months Interventions N=200 corticosteroid plus lidocaine (1 to 3 ml of 0.25% to 1% lidocaine followed by 1 to 3 ml of triamcinolone (60 to 120 mg), betamethasone (6 to 12 mg), dexamethasone (8 to 10 mg), or methylprednisolone (60 to 120 mg)) N=200 lidocaine (equivalent volume of 0.25% to 1% lidocaine alone) https://web.pathway.md/studies/recXpYJg83WrqsZcy 1/2 6/28/23, 10:58 PM LESS Pathway Primary outcome No significant difference in change in Roland-Morris Disability Questionnaire score at 6 weeks (-4.2 vs. -3.1; AD -1, 95% CI -2.1 to 0.1) Secondary outcomes No significant difference in intensity of leg pain (-2.8 vs. -2.6; AD -0.2, 95% CI -0.8 to 0.4) No significant difference in intensity of back pain at 6 weeks (4.3 vs. 4.4; AD -0.1, 95% CI -0.7 to 0.4) No significant difference in Brief Pain Inventory interference scale score at 6 weeks (3.5 vs. 3.8; AD -0.4, 95% CI -1 to 0.2) Safety outcomes No significant differences in 1 adverse event, serious adverse events. Significant difference in total adverse events (0.17 events vs. 0.29 events). Conclusion In patients who had lumbar central spinal stenosis and moderate-to-severe leg pain and disability, corticosteroid plus lidocaine was not superior to lidocaine with respect to change in Roland-Morris Disability Questionnaire score at 6 weeks. Reference Friedly JL, Comstock BA, Turner JA et al. A randomized trial of epidural glucocorticoid injections for spinal stenosis. N Engl J Med. 2014 Jul 3;371(1):11-21. Open reference URL https://web.pathway.md/studies/recXpYJg83WrqsZcy 2/2

6/28/23, 11:01 PM Leuven Surgical Trial Pathway Feedback Search Clinical Topics Home Studies Leuven Surgical Trial Leuven Surgical Trial Disease Disease Diabetes mellitus type 2 In-hospital hyperglycemia Trial question Is intensive insulin therapy superior to conventional treatment in critically ill patients? Study design Single center Double blinded RCT Population Characteristics of study participants 29.0% female N = 1548 71.0% male 1548 patients (447 female, 1101 male) Inclusion criteria: adults admitted to surgical ICU who were receiving mechanical ventilation Key exclusion criteria: participation in other trials, moribund state, or for whom there were do-not- resuscitate orders Interventions N=765 intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg/dL) N=783 conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg/dL and maintenance of glucose at a level between 180 and 200 mg/dL) Primary outcome https://web.pathway.md/studies/recFOFPNotDDh5RzM 1/2 6/28/23, 11:01 PM Leuven Surgical Trial Pathway Death 8.0 % 8 6.0 % 4.6 4.0 % Significant decrease 2.0 % NNT = 29 0.0 % Intensive insulin therapy Conventional treatment Significant decrease in death (4.6% vs. 8%; RR 0.58, 95% CI 0.38 to 0.78) Secondary outcomes Significant decrease in the rate of death, among patients who remained in the ICU for > 5 days (10.6% vs. 20.2%; RR 0.52, 95% CI 0.16 to 0.88) Conclusion In adults admitted to surgical ICU who were receiving mechanical ventilation, intensive insulin therapy was superior to conventional treatment with respect to death. Reference van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-67. Open reference URL https://web.pathway.md/studies/recFOFPNotDDh5RzM 2/2

6/28/23, 10:58 PM LEUVEN-2 Pathway Feedback Search Clinical Topics Home Studies LEUVEN 2 LEUVEN 2 Disease In-hospital hyperglycemia Trial question Is intensive insulin therapy superior to conventional insulin therapy in medical ICU patients? Study design Multi-center Open label RCT Population Characteristics of study participants 38.6% female N = 1200 61.4% male 1200 patients (462 female, 738 male) Inclusion criteria: patients who have a need for intensive care for at least three days Key exclusion criteria: being in a surgical ICU; able to receive oral nutrition; under do-not- resuscitate orders Interventions N=595 intensive insulin therapy (blood glucose target 80-110 mg/dL) N=605 conventional insulin therapy (blood glucose target 180-200 mg/dL) Primary outcome Hospital death 40 40 0 % 37 3 https://web.pathway.md/studies/recIqW3HHEAwpfDpx 1/2 6/28/23, 10:58 PM 40.0 % LEUVEN-2 Pathway 0 37.3 30.0 % 20.0 % 10.0 % No significant difference 0.0 % Intensive insulin therapy Conventional insulin therapy No significant difference in hospital death (40% vs. 37.3%; AD 2.7%, 95% CI -2.68 to 8.08) Secondary outcomes Significant decrease in the rate of hospital death in patients who stayed in the ICU for 3 days (43% vs. 52.5%; ARD -9.5, 95% CI -16.63 to -2.37) Significant decrease in reduction in newly acquired kidney injury (5.9% vs. 8.9%; ARD -3, 95% CI -5.87 to -0.13) No significant difference in death from any cause at day 90 (35.9% vs. 37.7%; ARD -1.8, 95% CI -7.27 to 3.67) Conclusion In patients who have a need for intensive care for at least three days, intensive insulin therapy was not superior to conventional insulin therapy with respect to hospital death. Reference Greet Van den Berghe, Alexander Wilmer, Greet Hermans et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006 Feb 2;354(5):449-61. Open reference URL https://web.pathway.md/studies/recIqW3HHEAwpfDpx 2/2

6/28/23, 10:58 PM LIBERTY-PN PRIME Pathway Feedback Search Clinical Topics Home Studies LIBERTY PN PRIME LIBERTY PN PRIME Disease Pruritus Trial question What is the role of dupilumab in patients with prurigo nodularis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 66.0% female N = 151 34.0% male 151 patients (100 female, 51 male) Inclusion criteria: adults with prurigo nodularis with 20 nodules and severe itch uncontrolled with topical therapies Key exclusion criteria: prurigo nodularis secondary to medications or medical conditions; severe renal conditions; uncontrolled thyroid disease; active tuberculosis or NTM infection Interventions N=75 dupilumab (at a dose of 300 mg SC every 2 weeks for 24 weeks) N=76 placebo (matching placebo SC every 2 weeks for 24 weeks) Primary outcome Reduction in Worst Itch Numeric Rating Scale by 4-point at week 24 https://web.pathway.md/studies/recsPOm9U3ICtcGMx 1/2 6/28/23, 10:58 PM LIBERTY-PN PRIME Pathway 60.0 % 60 45.0 % 30.0 % Significant increase 18.4 15.0 % NNT = 2 0.0 % Dupilumab Placebo Significant increase in reduction in Worst Itch NRS by 4-point at week 24 (60% vs. 18.4%; AD 42.7%, 95% CI 27.8 to 57.7) Secondary outcomes Significant increase in Investigator's Global Assessment for Prurigo Nodularis-Stage score of 0 or 1 at week 24 (48% vs. 18.4%; AD 28.3%, 95% CI 13.4 to 43.2) Significant increase in reduction in Worst Itch NRS by 4-point at week 12 (44% vs. 15.8%; AD 29.2%, 95% CI 14.5 to 43.8) Significant increase in concomitant reduction in Worst Itch NRS by 4 points and Investigator's Global Assessment for Prurigo Nodularis-Stage score of 0 or 1 at week 24 (38.7% vs. 9.2%; AD 29.6%, 95% CI 16.4 to 42.8) Safety outcomes No significant difference in treatment-emergent serious adverse events. Conclusion In adults with prurigo nodularis with 20 nodules and severe itch uncontrolled with topical therapies, dupilumab was superior to placebo with respect to reduction in Worst Itch NRS by 4- point at week 24. Reference Gil Yosipovitch, Nicholas Mollanazar, Sonja St nder et al. Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nat Med. 2023 May;29(5):1180-1190. Open reference URL https://web.pathway.md/studies/recsPOm9U3ICtcGMx 2/2

6/28/23, 11:00 PM LIBERTY-PN PRIME2 Pathway Feedback Search Clinical Topics Home Studies LIBERTY PN PRIME2 LIBERTY PN PRIME2 Disease Pruritus Trial question What is the role of dupilumab in patients with prurigo nodularis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 64.0% female N = 160 36.0% male 160 patients (103 female, 57 male) Inclusion criteria: adults with prurigo nodularis with 20 nodules and severe itch uncontrolled with topical therapies Key exclusion criteria: prurigo nodularis secondary to medications or medical conditions; severe renal conditions; uncontrolled thyroid disease; active tuberculosis or NTM infection Interventions N=78 dupilumab (at a dose of 300 mg SC every 2 weeks for 24 weeks) N=82 placebo (matching placebo SC every 2 weeks for 24 weeks) Primary outcome Reduction in Worst Itch Numeric Rating Scale by 4-point at week 12 https://web.pathway.md/studies/reclQ2aJFyTKkjphZ 1/2 6/28/23, 11:00 PM LIBERTY-PN PRIME2 Pathway 37.2 % 37.2 27.9 % 22 18.6 % Significant increase 9.3 % NNT = 7 0.0 % Dupilumab Placebo Significant increase in reduction in Worst Itch NRS by 4-point at week 12 (37.2% vs. 22%; AD 16.8%, 95% CI 2.3 to 31.2) Secondary outcomes Significant increase in Investigator's Global Assessment for Prurigo Nodularis-Stage score of 0 or 1 at week 24 (44.9% vs. 15.9%; AD 30.8%, 95% CI 16.4 to 45.2) Significant increase in reduction in Worst Itch NRS by 4-point at week 24 (57.7% vs. 19.5%; AD 42.6%, 95% CI 29.1 to 56.1) Significant increase in concomitant reduction in Worst Itch NRS by 4 points and Investigator's Global Assessment for Prurigo Nodularis-Stage score of 0 or 1 at week 24 (32.1% vs. 8.5%; AD 25.5%, 95% CI 13.1 to 37.9) Safety outcomes No significant difference in treatment-emergent serious adverse events. Conclusion In adults with prurigo nodularis with 20 nodules and severe itch uncontrolled with topical therapies, dupilumab was superior to placebo with respect to reduction in Worst Itch NRS by 4- point at week 12. Reference Gil Yosipovitch, Nicholas Mollanazar, Sonja St nder et al. Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nat Med. 2023 May;29(5):1180-1190. Open reference URL https://web.pathway.md/studies/reclQ2aJFyTKkjphZ 2/2

6/28/23, 11:02 PM Lidocaine in Hepatectomy Pathway Feedback Search Clinical Topics Home Studies Lidocaine in Hepatectomy Lidocaine in Hepatectomy Disease Disease Disease Cholangiocarcinoma Hepatic adenoma Hepatoce Trial question What is the effect of prolonged intravenous lidocaine infusion following hepatectomy? Study design Single center Double blinded RCT Population 260 patients Inclusion criteria: patients undergoing elective hepatectomy Key exclusion criteria: body weight < 40 kg or > 100 kg; metastases occurring in other distant organs; severe hepatic insufficiency; renal impairment; cardiac rhythm disorder or systolic HF Interventions N=130 lidocaine (infusion of intravenous lidocaine hydrochloride 1.5 mg/kg during anesthesia) N=130 placebo (infusion of 0.9% normal saline during anesthesia) Primary outcome Moderate-to-severe movement-evoked pain at 24 hour postoperatively 67.7 % 67.7 50.8 % 47.7 33.9 % Significant decrease 16.9 % NNT = 5 0.0 % Lidocaine Placebo https://web.pathway.md/studies/recRlHWeI7L3xdgvd 1/2 6/28/23, 11:02 PM Lidocaine in Hepatectomy Pathway Significant decrease in moderate-to-severe movement-evoked pain at 24 hour postoperatively (47.7% vs. 67.7%; RR 0.71, 95% CI 0.29 to 1.13) Secondary outcomes Significant decrease in moderate-to-severe movement-evoked pain at 48 hour postoperatively (38.5% vs. 58.5%; RR 0.66, 95% CI 0.27 to 1.05) Significant decrease in reduction in movement-evoked pain scores (3.7 vs. 4.2; AD -0.5, 95% CI -0.9 to -0.1) Significant decrease in morphine equivalent connsumption (47.2 mg vs. 52.6 mg; AD -5.4 mg, 95% CI -9.8 to -1) Conclusion In patients undergoing elective hepatectomy, lidocaine was superior to placebo with respect to a moderate-to-severe movement-evoked pain at 24 hour postoperatively. Reference Yan Xu, Mao Ye, Fei Liu et al. Efficacy of prolonged intravenous lidocaine infusion for postoperative movement-evoked pain following hepatectomy: a double-blinded, randomised, placebo-controlled trial. Br J Anaesth. 2023 May 16;S0007-0912(23)00169-1. Open reference URL https://web.pathway.md/studies/recRlHWeI7L3xdgvd 2/2

6/28/23, 11:00 PM LIFE Pathway Feedback Search Clinical Topics Home Studies LIFE LIFE Disease Hypertension Trial question Is losartan-based regimen superior to atenolol-based regimen in patients with essential hypertension and LV hypertrophy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 54.0% female N = 9193 46.0% male 9193 patients (4963 female, 4230 male) Inclusion criteria: patients aged 55-80 years with essential hypertension and LV hypertrophy ascertained by electrocardiography Key exclusion criteria: secondary hypertension, myocardial infarction or stroke within the previous 6 months, HF or LVEF 40% Interventions N=4605 a losartan-based regimen (titrated doses of losartan at 50-100 mg with/without hydrochlorothiazide 12.5-25 mg or other antihypertensive treatment for at least 4 years) N=4588 an atenolol-based regimen (titrated doses of atenolol at 50-100 mg with/without hydrochlorothiazide 12.5-25 mg or other antihypertensive treatment for at least 4 years) https://web.pathway.md/studies/recTdDPQGQUtXkyTM 1/2 6/28/23, 11:00 PM LIFE Pathway Primary outcome Death, myocardial infarction, or stroke 13.0 % 13 11 9.8 % 6.5 % Significant decrease 3.3 % NNT = 50 0.0 % A losartan-based regimen An atenolol-based regimen Significant decrease in death, myocardial infarction, or stroke (11% vs. 13%; aHR 0.87, 95% CI 0.77 to 0.98) Secondary outcomes No significant difference in death from cardiovascular causes (4% vs. 5%; aHR 0.89, 95% CI 0.73 to 1.07) Significant decrease in stroke (5% vs. 7%; aHR 0.75, 95% CI 0.63 to 0.89) Significant decrease in new-onset diabetes (6% vs. 8%; aHR 0.75, 95% CI 0.63 to 0.88) Safety outcomes No significant differences in angioedema, cancer, cough, dizziness, sleep disturbance. Significant differences in bradycardia (1% vs. 9%), cold extremities (4% vs. 6%), hypotension (3% vs. 2%), sexual disturbance (4% vs. 5%). Conclusion In patients aged 55-80 years with essential hypertension and LV hypertrophy ascertained by electrocardiography, a losartan-based regimen was superior to an atenolol-based regimen with respect to death, myocardial infarction, or stroke. Reference Bj rn Dahl f, Richard B Devereux, Sverre E Kjeldsen et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002 Mar 23;359(9311):995-1003. Open reference URL https://web.pathway.md/studies/recTdDPQGQUtXkyTM 2/2

6/28/23, 11:00 PM LIGHTMind Pathway Feedback Search Clinical Topics Home Studies LIGHTMind LIGHTMind Disease Disease Anxiety and depression in patien Major depressive disorder Trial question Is practitioner-supported mindfulness-based cognitive therapy self-help superior to practitioner- supported CBT self-help in adults with depression? Study design Multi-center Single blinded RCT Population Characteristics of study participants 62.0% female N = 410 38.0% male 410 patients (255 female, 155 male) Inclusion criteria: adults experiencing mild-to-moderate depression Key exclusion criteria: 20 points on the PHQ-9 screening; a score of 4 on the clinical interview schedule-revised suicidality scale; strong preference for one intervention over the other Interventions N=204 mindfulness-based cognitive therapy self-help (receipt of a copy of mindfulness-based cognitive therapy self-help workbook and 6 support sessions with a trained practitioner) N=206 CBT self-help (receipt of a copy of CBT self-help workbook and 6 support sessions with a trained practitioner) https://web.pathway.md/studies/rec3kbZy531SbbSrT 1/2 6/28/23, 11:00 PM LIGHTMind Pathway Primary outcome Patient health questionnaire score at 16 weeks post-randomization 8.6 8.6 7.2 6.4 4.3 2.1 Significant decrease 0.0 Mindfulness-based cognitive therapy self-help Cognitive behavioral therapy self-help Significant decrease in patient health questionnaire score at 16 weeks post-randomization (7.2 vs. 8.6; AD -1.5, 95% CI -2.6 to -0.4) Secondary outcomes Significant decrease in GAD 7-item scale score at 16 weeks (5.9 vs. 7; AD -0.95, 95% CI -1.88 to -0.01) No significant difference in short warwick-edinburgh mental well-being scale at 16 weeks (15.7 vs. 15.1; AD 0.97, 95% CI -0.05 to 1.99) No significant difference in work and social adjustment scale score at 16 weeks (11.8 vs. 12.7; AD -1.39, 95% CI -3.05 to 0.28) Conclusion In adults experiencing mild-to-moderate depression, mindfulness-based cognitive therapy self-help was superior to CBT self-help with respect to patient health questionnaire score at 16 weeks post- randomization. Reference Clara Strauss, Anna-Marie Bibby-Jones, Fergal Jones et al. Clinical Effectiveness and Cost- Effectiveness of Supported Mindfulness-Based Cognitive Therapy Self-help Compared With Supported Cognitive Behavioral Therapy Self-help for Adults Experiencing Depression: The Low- Intensity Guided Help Through Mindfulness (LIGHTMind) Randomized Clinical Trial. JAMA Psychiatry. 2023 Mar 22;e230222. Open reference URL https://web.pathway.md/studies/rec3kbZy531SbbSrT 2/2

6/28/23, 11:02 PM Liu Pathway Feedback Search Clinical Topics Home Studies Liu Liu Disease Sepsis and septic shock Trial question What is the role of terlipressin in patients with septic shock? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.2% female N = 617 62.8% male 617 patients (195 female, 331 male) Inclusion criteria: patients in the ICU with septic shock Key exclusion criteria: unstable coronary syndrome, previous use of terlipressin for arterial BP support before entry, malignancy or other irreversible disease with poor prognosis, acute mesenteric ischemia Interventions N=312 terlipressin (20-160 g/hour with maximum infusion rate of 4 mg/day before open-label vasopressors) N=305 norepinephrine (4-30 g/min before open-label vasopressors) Primary outcome https://web.pathway.md/studies/rec97MM7zG2CnomMS 1/2 6/28/23, 11:02 PM Liu Pathway Death at day 28 40.0 % 40 38 30.0 % 20.0 % 10.0 % No significant difference 0.0 % Terlipressin Norepinephrine No significant difference in death at day 28 (40% vs. 38%; RR 1.053, 95% CI 0.74 to 1.5) Secondary outcomes No significant difference in change in SOFA score on day 7 (-7 vs. -6; AD -1, 95% CI -2.27 to 0.27) No significant difference in days alive and free of vasopressor (15.5 days vs. 14.66 days; AD 0.84 days, 95% CI -1.19 to 2.87) Safety outcomes No significant differences in acute myocardial infarction or ischemia, life-threatening arrhythmia, hyponatremia, acute mesenteric ischemia. Significant differences in serious adverse events (30% vs. 12%), digital ischemia (12.6% vs. 0.35%), diarrhea (2.72% vs. 0.35%). Conclusion In patients in the ICU with septic shock, terlipressin was not superior to norepinephrine with respect to death at day 28. Reference Zi-Meng Liu, Juan Chen, Qiuye Kou et al. Terlipressin versus norepinephrine as infusion in patients with septic shock: a multicentre, randomised, double-blinded trial. Intensive Care Med. 2018 Nov;44(11):1816-1825. Open reference URL https://web.pathway.md/studies/rec97MM7zG2CnomMS 2/2

6/28/23, 11:02 PM Lo-Coco 2013 Pathway Feedback Search Clinical Topics Home Studies Lo-Coco 2013 Lo-Coco 2013 Disease Disease Acute myeloid leukemia Acute promyelocytic leukemia Trial question What is the role of all-trans retinoic acid plus arsenic trioxide among patients with acute promyelocytic leukemia? Study design Multi-center Open label RCT Population Characteristics of study participants 51.0% female N = 156 49.0% male 156 patients (80 female, 76 male) Inclusion criteria: patients with acute promyelocytic leukemia classified as low-to-intermediate risk Key exclusion criteria: age < 18 and 71 years, uncontrolled life-threatening infections, severe non-controlled pulmonary or cardiac disease, other active malignancy at the time of study entry, pregnancy Interventions N=77 ATRA-arsenic trioxide (all-trans retinoic acid plus arsenic trioxide for induction and consolidation therapy) N=79 ATRA-chemotherapy (standard all-trans retinoic acid-idarubicin induction therapy followed by three cycles of consolidation therapy with all-trans retinoic acid plus chemotherapy and https://web.pathway.md/studies/recwVBXiC5sktrhy8 1/2 6/28/23, 11:02 PM Lo-Coco 2013 Pathway maintenance therapy with low-dose chemotherapy and all-trans retinoic acid) Primary outcome Event-free survival at 2 years 97.0 % 97 86 72.8 % 48.5 % Significant increase 24.3 % NNT = 9 0.0 % ATRA-arsenic trioxide ATRA-chemotherapy Significant increase in event-free survival at 2 years (97% vs. 86%; AD 11%, 95% CI 2 to 22) Secondary outcomes Significant increase in overall survival at 2 years (99% vs. 91%; AD 8%, 95% CI 1.25 to 14.75) No significant difference in disease-free survival at 2 years (97% vs. 90%; AD 7%, 95% CI -1.59 to 15.59) No significant difference in relapse at 2 years (1% vs. 6%; ARD -5, 95% CI -13.3 to 3.3) Safety outcomes No significant difference in kinetics of minimal residual disease. Significant difference in hematologic toxicity (26 episodes vs. 59 episodes) and grade 3 or 4 hepatic toxicity (63% vs. 6%). Conclusion In patients with acute promyelocytic leukemia classified as low-to-intermediate risk, ATRA-arsenic trioxide was superior to ATRA-chemotherapy with respect to a event-free survival at 2 years. Reference Lo-Coco F, Avvisati G, Vignetti M et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. Open reference URL https://web.pathway.md/studies/recwVBXiC5sktrhy8 2/2

6/28/23, 11:01 PM LOCO2 Pathway Feedback Search Clinical Topics Home Studies LOCO2 LOCO2 Disease Acute respiratory distress syndr Trial question Is conservative oxygenation strategy superior to liberal oxygenation strategy in patients with ARDS? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 201 64.0% male 201 patients (72 female, 129 male) Inclusion criteria: patients who had undergone intubation and had been receiving mechanical ventilation for < 12 hours for ARDS Key exclusion criteria: long-term oxygen therapy or noninvasive ventilation at home; hospitalization for cardiac arrest, TBI, or cranial hypertension Interventions N=99 a conservative oxygen strategy (target partial pressure of arterial oxygen between 55 and 70 mmHg; oxygen saturation as measured by pulse oximetry between 88 and 92% for 7 days) N=102 a liberal oxygen strategy (target partial pressure of arterial oxygen of 90 to 105 mmHg; oxygen saturation as measured by pulse oximetry 96% for 7 days) https://web.pathway.md/studies/recVUDlA5djtrmksE 1/2 6/28/23, 11:01 PM LOCO2 Pathway Primary outcome Death at 28 days 34.3 % 34.3 26.5 25.7 % 17.1 % 8.6 % No significant difference 0.0 % A conservative oxygen strategy A liberal oxygen strategy No significant difference in death at 28 days (34.3% vs. 26.5%; AD 7.8%, 95% CI -4.8 to 20.6) Secondary outcomes Significant increase in death at 90 days (44.4% vs. 30.4%; AD 14%, 95% CI 0.7 to 27.2) Safety outcomes No significant differences in infections, mechanical ventilation, seizure or delirium. Significant difference in mesenteric ischemia (5.1% vs. 0%). Conclusion In patients who had undergone intubation and had been receiving mechanical ventilation for < 12 hours for ARDS, a conservative oxygen strategy was not superior to a liberal oxygen strategy with respect to death at 28 days. Reference Loic Barrot, Pierre Asfar, Frederic Mauny et al. Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome. N Engl J Med. 2020 Mar 12;382(11):999-1008. Open reference URL https://web.pathway.md/studies/recVUDlA5djtrmksE 2/2

6/28/23, 11:01 PM LODESTAR Pathway Feedback Search Clinical Topics Home Studies LODESTAR LODESTAR Disease Disease Coronary artery disease Dyslipidemia Trial question Is a treat-to-target strategy noninferior to a strategy of high-intensity statins in patients with coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 28.0% female N = 4400 72.0% male 4400 patients (1228 female, 3172 male) Inclusion criteria: patients with a coronary artery disease diagnosis Key exclusion criteria: pregnancy; allergy to statins; life expectancy < 3 years; risk factors for myopathy with hereditary muscle disorder; hypothyroidism; AUD; severe hepatic dysfunction Interventions N=2200 treat-to-target strategy (titrated-intensity statin therapy with LDL cholesterol level between 50-70 mg/dL as the target) N=2200 high-intensity statin strategy (rosuvastatin 20 mg or atorvastatin 40 mg once daily) Primary outcome https://web.pathway.md/studies/recPLaijCHCasKK52 1/2 6/28/23, 11:01 PM LODESTAR Pathway Composite of death, myocardial infarction, stroke, or coronary revascularization at 3 years 8.7 % 8.7 8.1 6.5 % 4.3 % Difference not exceeding nonferiority margin 2.2 % 0.0 % Treat-to-target strategy High-intensity statin strategy Difference not exceeding nonferiority margin in composite of death, myocardial infarction, stroke, or coronary revascularization at 3 years (8.1% vs. 8.7%; ARD -0.6, 95% CI -0.96 to -0.24) Secondary outcomes No significant difference in new-onset diabetes (5.6% vs. 7%; ARD -1.3, 95% CI -2.8 to 0.1) No significant difference in discontinuation of statin therapy (1.5% vs. 2.2%; ARD -0.7, 95% CI -1.5 to 0.1) Significant decrease in composite of new-onset diabetes, aminotransferase or CK elevation, or end-stage kidney disease (6.1% vs. 8.2%; ARD -2.1, 95% CI -3.6 to -0.5) Conclusion In patients with a coronary artery disease diagnosis, treat-to-target strategy was noninferior to high- intensity statin strategy with respect to the composite of death, myocardial infarction, stroke, or coronary revascularization at 3 years. Reference Sung-Jin Hong, Yong-Joon Lee, Seung-Jun Lee et al. Treat-to-Target or High-Intensity Statin in Patients With Coronary Artery Disease: A Randomized Clinical Trial. JAMA. 2023 Mar 6;e232487. Open reference URL https://web.pathway.md/studies/recPLaijCHCasKK52 2/2

6/28/23, 11:02 PM LoDoCo Pathway Feedback Search Clinical Topics Home Studies LoDoCo LoDoCo Disease Coronary artery disease Trial question What is the role of low-dose colchicine in patients with clinically stable coronary disease? Study design Multi-center Open label RCT Population Characteristics of study participants 11.0% female N = 532 89.0% male 532 patients (59 female, 473 male) Inclusion criteria: patients with stable coronary disease receiving aspirin and/or clopidogrel and statins Key exclusion criteria: contraindication to colchicine, history of bypass surgery < 10 years ago, unwilling to provide consent, or major competing comorbidities Interventions N=282 colchicine (0.5 mg/day) N=250 control (no colchicine) Primary outcome Acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke https://web.pathway.md/studies/recorBqAmzbNrTOwN 1/2 6/28/23, 11:02 PM LoDoCo Pathway 16.0 % 16 12.0 % 8.0 % Significant decrease 5.3 4.0 % NNT = 9 0.0 % Colchicine Control Significant decrease in acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke (5.3% vs. 16%; HR 0.33, 95% CI 0.18 to 0.59) Secondary outcomes Significant decrease in acute coronary syndrome (4.6% vs. 13.6%; HR 0.33, 95% CI 0.18 to 0.63) Significant decrease in Acute coronary syndrome nonstent-related (3.2% vs. 12%; HR 0.26, 95% CI 0.12 to 0.55) Significant decrease in nonstent-related acute myocardial infarction (1.6% vs. 5.6%; HR 0.25, 95% CI 0.08 to 0.76) Conclusion In patients with stable coronary disease receiving aspirin and/or clopidogrel and statins, colchicine was superior to control with respect to acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke. Reference Nidorf SM, Eikelboom JW, Budgeon CA et al. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013 Jan 29;61(4):404-410. Open reference URL https://web.pathway.md/studies/recorBqAmzbNrTOwN 2/2

6/28/23, 11:01 PM LOMAGHI (high-dose MgSO4) Pathway Feedback Search Clinical Topics Home Studies LOMAGHI (high-dose MgSO4 LOMAGHI (high-dose MgSO4 Disease Atrial fibrillation Trial question What is the role of high-dose magnesium sulfate in patients with rapid AF of > 120 beats/min? Study design Multi-center Double blinded RCT Population Characteristics of study participants 40.0% female N = 302 60.0% male 302 patients (121 female, 181 male) Inclusion criteria: adult patients admitted to the emergency department for rapid AF of > 120 beats/min Key exclusion criteria: arterial hypotension; impaired consciousness; renal failure; wide-complex ventricular response; contraindication to magnesium sulfate Interventions N=153 high-dose magnesium (9 g intravenous magnesium sulfate in 100 mL of normal saline plus atrioventricular nodal blocking agents) N=149 placebo (100 mL of intravenous normal saline plus atrioventricular nodal blocking agents) Primary outcome https://web.pathway.md/studies/recxemkVhBPLVinbL 1/2 6/28/23, 11:01 PM LOMAGHI (high-dose MgSO4) Pathway Composite outcome of reduction of baseline ventricular rate to 90 beats/min, or reduction of VR by 20% from baseline at 4 hours 59.5 % 59.5 44.6 % 43.6 29.8 % 14.9 % Borderline significant increase 0.0 % High-dose magnesium Placebo Borderline significant increase in composite outcome of reduction of baseline ventricular rate to 90 beats/min, or reduction of VR by 20% from baseline at 4 hours (59.5% vs. 43.6%; RR 1.89, 95% CI 1.2 to 2.99) Secondary outcomes Borderline significant increase in composite outcome of reduction of baseline ventricular rate to 90 beats/min, or reduction of VR by 20% from baseline at 24 hours (94.1% vs. 83.3%; RR 3.22, 95% CI 1.45 to 7.17) Safety outcomes Significant difference in adverse events (13.7% vs. 2.0%). Conclusion In adult patients admitted to the emergency department for rapid AF of > 120 beats/min, high-dose magnesium was superior to placebo with respect to the composite outcome of reduction of baseline ventricular rate to 90 beats/min, or reduction of VR by 20% from baseline at 4 hours. Reference Wahid Bouida, Kaouthar Beltaief, Mohamed Amine Msolli et al. Low-dose Magnesium Sulfate Versus High Dose in the Early Management of Rapid Atrial Fibrillation: Randomized Controlled Double-blind Study (LOMAGHI Study). Acad Emerg Med. 2019 Feb;26(2):183-191. Open reference URL https://web.pathway.md/studies/recxemkVhBPLVinbL 2/2

6/28/23, 11:01 PM LOMAGHI (low-dose MgSO4) Pathway Feedback Search Clinical Topics Home Studies LOMAGHI (low-dose MgSO4 LOMAGHI (low-dose MgSO4 Disease Atrial fibrillation Trial question What is the role of low-dose magnesium sulfate in patients with rapid AF of > 120 beats/min? Study design Multi-center Double blinded RCT Population Characteristics of study participants 41.0% female N = 297 59.0% male 297 patients (123 female, 174 male) Inclusion criteria: adult patients admitted to the emergency department for rapid AF of > 120 beats/min Key exclusion criteria: arterial hypotension; impaired consciousness; renal failure; wide-complex ventricular response; contraindication to magnesium sulfate Interventions N=148 low-dose magnesium (4.5 g intravenous magnesium sulfate in 100 mL of normal saline plus atrioventricular nodal blocking agents) N=149 placebo (100 mL of intravenous normal saline plus atrioventricular nodal blocking agents) Primary outcome https://web.pathway.md/studies/recw3tCsjVVFxFblu 1/2 6/28/23, 11:01 PM LOMAGHI (low-dose MgSO4) Pathway Composite outcome of reduction of baseline ventricular rate to 90 beats/min, or reduction of VR by 20% from baseline at 4 hours 64.2 % 64.2 48.2 % 43.6 32.1 % 16.1 % Borderline significant increase 0.0 % Low-dose magnesium Placebo Borderline significant increase in composite outcome of reduction of baseline ventricular rate to 90 beats/min, or reduction of VR by 20% from baseline at 4 hours (64.2% vs. 43.6%; RR 2.31, 95% CI 1.45 to 3.69) Secondary outcomes Borderline significant increase in composite outcome of reduction of baseline ventricular rate to 90 beats/min, or reduction of VR by 20% from baseline at 24 hours (97.9% vs. 83.3%; RR 9.74, 95% CI 2.87 to 17.05) No significant difference in resolution time (6.1 hours vs. 8.4 hours; AD -2.3 hours, 95% CI -4.6 to 0) Significant increase in sinus rhythm control rate at 24 hours (22.9% vs. 10.7%; AD 12.2%, 95% CI 3.69 to 20.71) Safety outcomes No significant difference in adverse events. Conclusion In adult patients admitted to the emergency department for rapid AF of > 120 beats/min, low-dose magnesium was superior to placebo with respect to the composite outcome of reduction of baseline ventricular rate to 90 beats/min, or reduction of VR by 20% from baseline at 4 hours. Reference Wahid Bouida, Kaouthar Beltaief, Mohamed Amine Msolli et al. Low-dose Magnesium Sulfate Versus High Dose in the Early Management of Rapid Atrial Fibrillation: Randomized Controlled Double-blind Study (LOMAGHI Study). Acad Emerg Med. 2019 Feb;26(2):183-191. Open reference URL https://web.pathway.md/studies/recw3tCsjVVFxFblu 2/2

6/28/23, 11:02 PM Look AHEAD Pathway Feedback Search Clinical Topics Home Studies Look AHEAD Look AHEAD Disease Disease Diabetes mellitus type 2 Obesity Trial question What is the role of intensive lifestyle intervention in patients with T2DM who are overweight or obese? Study design Multi-center Open label RCT Population Characteristics of study participants 60.0% female N = 5145 40.0% male 5145 patients (3063 female, 2082 male) Inclusion criteria: patients with T2DM who are overweight or obese Key exclusion criteria: schizophrenia or other psychotic disorders, hospitalization for depression in the past six months, alcohol or substance abuse within the past 12 months, use of medications for weight loss, history of bariatric surgery, or pregnancy or nursing Interventions N=2570 an intensive lifestyle intervention (promoted weight loss through decreased caloric intake and increased physical activity) N=2575 standard lifestyle counseling (diabetes support and education) https://web.pathway.md/studies/recKSl80uu11sHzd2 1/2 6/28/23, 11:02 PM Look AHEAD Pathway Primary outcome Incidence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina 1.9/100 py 1.92 1.83 1.4/100 py 1.0/100 py 0.5/100 py No significant difference 0.0/100 py An intensive lifestyle intervention Standard lifestyle counseling No significant difference in the incidence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina (1.83 /100 py vs. 1.92 /100 py; HR 0.95, 95% CI 0.83 to 1.09) Secondary outcomes No significant difference in the incidence of cardiovascular death, myocardial infarction or stroke (1.17 /100 py vs. 1.25 /100 py; HR 0.93, 95% CI 0.79 to 1.1) No significant difference in all cause death (0.73 vs. 0.86; HR 0.85, 95% CI 0.69 to 1.04) Safety outcomes No significant differences in severe hypoglycemia, gallstones, amputations, adjudicated fractures, and congestive HF. Significant differences in self-reported fractures (2.51 vs. 2.16 events per 100 person-years, p = 0.01). Conclusion In patients with T2DM who are overweight or obese, an intensive lifestyle intervention was not superior to standard lifestyle counseling with respect to the incidence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. Reference Look AHEAD Research Group, Wing RR, Bolin P et al. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013 Jul 11;369(2):145-54. Open reference URL https://web.pathway.md/studies/recKSl80uu11sHzd2 2/2

6/28/23, 11:01 PM LOTUS China Pathway Feedback Search Clinical Topics Home Studies LOTUS China LOTUS China Disease COVID 19 infection Trial question What is the effect of lopinavir-ritonavir in adults hospitalized with severe COVID-19? Study design Single center Open label RCT Population Characteristics of study participants 40.0% female N = 199 60.0% male 199 patients (79 female, 120 male) Inclusion criteria: hospitalized adult patients with confirmed COVID-19 infection Key exclusion criteria: known allergy or hypersensitivity to lopinavir-ritonavir, known severe liver disease, use of medications that are contraindicated with lopinavir-ritonavir and that could not be replaced or stopped during the trial period, pregnancy or breast-feeding, or known HIV infection Interventions N=99 lopinavir-ritonavir (400 mg and 100 mg twice a day for 14 days plus standard care for 14 days) N=100 standard care (standard care alone for 14 days) Primary outcome https://web.pathway.md/studies/recSVRCSAarMLjD4V 1/2 6/28/23, 11:01 PM LOTUS China Pathway Time to clinical improvement 16.0 days 16 16 12.0 days 8.0 days 4.0 days No significant difference 0.0 days Lopinavir-ritonavir Standard care No significant difference in time to clinical improvement (16 days vs. 16 days; HR 1.31, 95% CI 0.95 to 1.85) Secondary outcomes Borderline significant decrease in length of ICU stay (6 days vs. 11 days; AD -5 days, 95% CI -9 to 0) No significant difference in duration of invasive mechanical ventilation (4 days vs. 5 days; AD -1 days, 95% CI -4 to 2) Safety outcomes No significant difference in adverse events or shock. Significant differences in gastrointestinal adverse events, which were more common in the placebo group - and serious adverse events, which were more common in the standard care group. Conclusion In hospitalized adult patients with confirmed COVID-19 infection, lopinavir-ritonavir was not superior to standard care with respect to time to clinical improvement. Reference Cao B, Wang Y, Wen D et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid- 19. N Engl J Med. 2020 May 7;382(19):1787-1799. Open reference URL https://web.pathway.md/studies/recSVRCSAarMLjD4V 2/2

6/28/23, 11:01 PM LOVIT Pathway Feedback Search Clinical Topics Home Studies LOVIT LOVIT Disease Sepsis and septic shock Trial question What is the role of intravenous vitamin C in adult patients with sepsis in the ICU? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.0% female N = 862 62.0% male 862 patients (324 female, 538 male) Inclusion criteria: adult patients with sepsis receiving vasopressor therapy in the ICU Key exclusion criteria: contraindication to vitamin C therapy; receipt of open-label vitamin C; expected death or withdrawal of life-sustaining therapy within 48 hours Interventions N=429 vitamin C (at a dose of 50 mg/kg of body weight every 6 hours for up to 96 hours) N=433 placebo (dextrose 5% in water or normal saline every 6 hours for up to 96 hours) Primary outcome Composite of death or persistent organ dysfunction at day 28 44.5 % 44.5 https://web.pathway.md/studies/recO3qtrEwNbN4kER 1/2 6/28/23, 11:01 PM LOVIT Pathway 5 38.5 33.4 % 22.3 % Significant increase 11.1 % NNH = 17 0.0 % Vitamin C Placebo Significant increase in composite of death or persistent organ dysfunction at day 28 (44.5% vs. 38.5%; RR 1.21, 95% CI 1.04 to 1.4) Secondary outcomes No significant difference in death at day 28 (35.4% vs. 31.6%; RR 1.17, 95% CI 0.98 to 1.4) No significant difference in median days without organ dysfunction at day 28 (17 days vs. 19.5 days; MD -2.43, 95% CI -7.23 to 2.37) No significant difference in sequential organ failure assessment score at day 28 (6.5 vs. 7.9; AD -1.42, 95% CI -3.98 to 1.14) Safety outcomes No significant differences in stage 3 AKI, hypoglycemia. Conclusion In adult patients with sepsis receiving vasopressor therapy in the ICU, vitamin C was inferior to placebo with respect to the composite of death or persistent organ dysfunction at day 28. Reference Fran ois Lamontagne, Marie-H l ne Masse, Julie Menard et al. Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. N Engl J Med. 2022 Jun 23;386(25):2387-2398. Open reference URL https://web.pathway.md/studies/recO3qtrEwNbN4kER 2/2

6/28/23, 11:02 PM Low-dose amoxicillin in syphilis Pathway Feedback Search Clinical Topics Home Studies Low-dose amoxicillin in syphilis Low-dose amoxicillin in syphilis Disease Syphilis infection Trial question Is low-dose amoxicillin monotherapy noninferior to the combination of amoxicillin and probenecid for treating syphilis in patients with human immunodeficiency virus infection? Study design Single center Open label RCT Population 112 patients Inclusion criteria: patients with human immunodeficiency virus infection and syphilis Key exclusion criteria: pregnancy; amoxicillin or probenecid allergy; diagnosis of otosyphilis, ocular syphilis or neurosyphilis; antibiotic use 3 weeks before diagnosis Interventions N=56 amoxicillin monotherapy (at a dose of 500 mg PO TID) N=56 amoxicillin plus probenecid (amoxicillin 1,000 mg PO TID plus probenecid 250 mg PO TID) Primary outcome Rate of serological cure rate for overall syphilis within 12 months 94.4 % 94.4 90.6 70.8 % 47.2 % Difference exceeding nonferiority margin 23.6 % 0.0 % https://web.pathway.md/studies/recaOxPxsTckSy6qw 1/2 6/28/23, 11:02 PM Low-dose amoxicillin in syphilis Pathway Amoxicillin monotherapy Amoxicillin plus probenecid Difference exceeding nonferiority margin in the rate of serological cure rate for overall syphilis within 12 months (90.6% vs. 94.4%; ARD -3.8, 95% CI -13.48 to 5.88) Conclusion In patients with human immunodeficiency virus infection and syphilis, amoxicillin monotherapy was not noninferior to amoxicillin plus probenecid with respect to the rate of serological cure rate for overall syphilis within 12 months. Reference Naokatsu Ando, Daisuke Mizushima, Kazumi Omata et al. Combination of Amoxicillin 3,000 mg and Probenecid versus 1,500 mg Amoxicillin Monotherapy for Treating Syphilis in Patients with HIV: an Open-Label, Randomized, Controlled, Non-Inferiority Trial. Clin Infect Dis. 2023 May 9;ciad278. Open reference URL https://web.pathway.md/studies/recaOxPxsTckSy6qw 2/2

6/28/23, 11:02 PM Low-dose dopamine in patients with early renal dysfunction Pathway Feedback Search Clinical Topics Home Studies Low-dose dopamine in patients with early renal dysfunction Low-dose dopamine in patients with early renal dysfunction Disease Acute kidney injury Trial question What is the role of low-dose dopamine in critically ill patients at risk of renal failure? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.4% female N = 328 60.6% male 328 patients (128 female, 196 male) Inclusion criteria: critically ill patients at risk of renal failure Key exclusion criteria: age < 18 years; an episode of acute renal failure within the previous 3 months; previous renal transplantation; use of dopamine at any dose during the current hospital stay; and unsuitability for use of RRT Interventions N=161 low-dose dopamine (2 g/kg/min through central venous catheter while in the ICU) N=163 placebo (matching placebo through central venous catheter while in the ICU) Primary outcome Peak serum creatinine concentration https://web.pathway.md/studies/recx3uLgfTY0LDdhq 1/2 6/28/23, 11:02 PM Low-dose dopamine in patients with early renal dysfunction Pathway 249.0 249 245 186.8 124.5 62.3 No significant difference 0.0 Low-dose dopamine Placebo No significant difference in peak serum creatinine concentration (245 vs. 249; difference 4, 95% CI -28 to 36) Secondary outcomes No significant difference in requirement of RRT (35 vs. 40; difference 5, 95% CI -10 to 20) Conclusion In critically ill patients at risk of renal failure, low-dose dopamine was not superior to placebo with respect to peak serum creatinine concentration. Reference Bellomo R, Chapman M, Finfer S et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000 Dec 23-30;356(9248):2139-43. Open reference URL https://web.pathway.md/studies/recx3uLgfTY0LDdhq 2/2

6/28/23, 11:01 PM LPV/r for COVID-19 Pathway Feedback Search Clinical Topics Home Studies LPV/r for COVID 19 LPV/r for COVID 19 Disease COVID 19 infection Trial question What is the role of lopinavir-ritonavir in patients with severe COVID-19? Study design Single center Open label RCT Population Characteristics of study participants 33.3% female N = 199 66.7% male 199 patients (59 female, 120 male) Inclusion criteria: hospitalized adult patients with severe COVID-19 Key exclusion criteria: pregnancy or breast-feeding, known severe liver disease, known HIV infection Interventions N=99 lopinavir-ritonavir (for 14 days) N=100 no antiviral therapy (standard of care) Primary outcome Time to clinical improvement 16.0 days 16 16 https://web.pathway.md/studies/recCxgJ6Na5PI7p9x 1/2 6/28/23, 11:01 PM LPV/r for COVID-19 Pathway y 6 6 12.0 days 8.0 days 4.0 days No significant difference 0.0 days Lopinavir-ritonavir No antiviral therapy No significant difference in time to clinical improvement (16 days vs. 16 days; HR 1.31, 95% CI 0.95 to 1.85) Safety outcomes No significant difference in adverse events (48.4% vs. 49.5%). Conclusion In hospitalized adult patients with severe COVID-19, lopinavir-ritonavir was not superior to no antiviral therapy with respect to time to clinical improvement. Reference Cao B, Wang Y, Wen D et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid- 19. N Engl J Med. 2020 May 7;382(19):1787-1799. Open reference URL https://web.pathway.md/studies/recCxgJ6Na5PI7p9x 2/2

6/28/23, 11:01 PM LTOT Pathway Feedback Search Clinical Topics Home Studies LTOT LTOT Disease Disease Chronic obstructive pulmonary Dyspnea in palliative care Trial question What is the role of long-term supplemental oxygen in patients with stable COPD and resting or exercise-induced moderate desaturation? Study design Multi-center Open label RCT Population Characteristics of study participants 27.0% female N = 738 73.0% male 738 patients (196 female, 542 male) Inclusion criteria: patients with stable COPD who had moderate resting desaturation (SpO2 89- 93%) and moderate exercise-induced desaturation (during the 6-minute walk test, SpO2 80% for 5 minutes and < 90% for 10 seconds) Key exclusion criteria: COPD exacerbations requiring antibiotics, thoracic surgery or other procedures in the 6 months before randomization, non-COPD lung disease affecting oxygenation or survival, Epworth Sleepiness Scale score > 15, desaturation < 80% for at least 1 minute during the 6-minute walk, or disease or condition expected to cause death or inability to perform procedures within 6 months of randomization Interventions https://web.pathway.md/studies/recz8dh3ZorH2gtX8 1/2 6/28/23, 11:01 PM LTOT Pathway N=368 supplemental oxygen (long-term supplemental oxygen with 24-h oxygen for patients with resting desaturation and oxygen during exercise and sleep for patients with desaturation only during exercise) N=370 no supplemental oxygen (no long-term supplemental oxygen) Primary outcome Incidence of death or first hospitalization 36.4/100 py 36.4 34.2 27.3/100 py 18.2/100 py 9.1/100 py No significant difference 0.0/100 py Supplemental oxygen No supplemental oxygen No significant difference in the incidence of death or first hospitalization (36.4 /100 py vs. 34.2 /100 py; HR 1.06, 95% CI 0.89 to 1.26) Secondary outcomes No significant difference in the incidence of death (5.7 /100 py vs. 5.2 /100 py; HR 1.11, 95% CI 0.8 to 1.56) No significant difference in the incidence of hospitalization (34.5 /100 py vs. 31.6 /100 py; HR 1.09, 95% CI 0.9 to 1.29) Safety outcomes Significant difference in adverse events (51 vs. 0). Conclusion In patients with stable COPD who had moderate resting desaturation (SpO2 89-93%) and moderate exercise-induced desaturation (during the 6-minute walk test, SpO2 80% for 5 minutes and < 90% for 10 seconds), supplemental oxygen was not superior to no supplemental oxygen with respect to the incidence of death or first hospitalization. Reference Long-Term Oxygen Treatment Trial Research Group, Albert RK, Au DH et al. A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation. N Engl J Med. 2016 Oct 27;375(17):1617-1627. Open reference URL https://web.pathway.md/studies/recz8dh3ZorH2gtX8 2/2

6/28/23, 11:16 PM MADIT-CRT Pathway Feedback Search Clinical Topics Home Studies MADIT CRT MADIT CRT Disease Disease Disease Coronary artery disease Dilated cardiomyopathy Heart failu Trial question What is the role of cardiac resynchronization therapy in addition to ICD in patients with mild cardiac symptoms, a reduced ejection fraction, and a wide QRS complex? Study design Multi-center Open label RCT Population Characteristics of study participants 25.0% female N = 1820 75.0% male 1820 patients (453 female, 1367 male) Inclusion criteria: patients with ischemic or nonischemic cardiomyopathy, an ejection fraction 30%, a QRS duration 30 ms, and NYHA class I or II symptoms Key exclusion criteria: existing indication for CRT; NYHA class III or IV symptoms, previous CABG, PCI, or an enzyme-positive myocardial infarction within 3 months before enrollment; AF within 1 month before enrollment Interventions N=1089 CRT plus ICD implantation (cardiac resynchronization therapy with biventricular pacing plus ICD) N=731 ICD implantation only (ICD) https://web.pathway.md/studies/recuJgDvvzF9H6gws 1/2 6/28/23, 11:16 PM MADIT-CRT Pathway Primary outcome Death from any cause or a nonfatal heart-failure event 25.3 % 25.3 19.0 % 17.2 12.7 % Significant decrease 6.3 % NNT = 12 0.0 % CRT plus ICD implantation ICD implantation only Significant decrease in death from any cause or a nonfatal heart-failure event (17.2% vs. 25.3%; HR 0.66, 95% CI 0.52 to 0.84) Secondary outcomes Significant decrease in HF (13.9% vs. 22.8%; HR 0.59, 95% CI 0.47 to 0.74) No significant difference in death (6.8% vs. 7.3%; HR 1, 95% CI 0.69 to 1.44) Safety outcomes No significant differences in serious adverse events, including pneumothorax, infection, and pocket hematoma requiring evacuation. Conclusion In patients with ischemic or nonischemic cardiomyopathy, an ejection fraction 30%, a QRS duration 30 ms, and NYHA class I or II symptoms, CRT plus ICD implantation was superior to ICD implantation only with respect to death from any cause or a nonfatal heart-failure event. Reference Moss AJ, Hall WJ, Cannom DS et al. Cardiac-resynchronization therapy for the prevention of heart- failure events. N Engl J Med. 2009 Oct 1;361(14):1329-38. Open reference URL https://web.pathway.md/studies/recuJgDvvzF9H6gws 2/2

6/28/23, 11:16 PM MADIT-II Pathway Feedback Search Clinical Topics Home Studies MADIT II MADIT II Disease ST-elevation myocardial infarction Trial question Is implantable defibrillator superior to conventional medical therapy in patients with myocardial infarction and reduced ejection fraction? Study design Multi-center Open label RCT Population Characteristics of study participants 16.0% female N = 1232 84.0% male 1232 patients (192 female, 1040 male) Inclusion criteria: patients with myocardial infarction and reduced ejection fraction Key exclusion criteria: indication for an implantable defibrillator, NYHA functional class IV at enrollment, coronary revascularization within the preceding three months, myocardial infarction within the past month, advanced cerebrovascular disease Interventions N=742 ICD implantation (with standard techniques, plus medical therapy) N=490 conventional medical therapy ( -blockers, ACE inhibitors, and lipid lowering drugs) Primary outcome https://web.pathway.md/studies/recdICA4dZmsEIrTi 1/2 6/28/23, 11:16 PM MADIT-II Pathway Rate of death at an average follow-up of 20 months 19.8 % 19.8 14.9 % 14.2 9.9 % Significant decrease 5.0 % NNT = 18 0.0 % ICD implantation Conventional medical therapy Significant decrease in the rate of death at an average follow-up of 20 months (14.2% vs. 19.8%; HR 0.69, 95% CI 0.51 to 0.93) Secondary outcomes No significant difference in hospitalized with HF (19.9% vs. 14.9%; RR 1.36, 95% CI -0.21 to 2.93) Safety outcomes Significant difference in hospitalization with HF (19.9% vs. 14.9%). Conclusion In patients with myocardial infarction and reduced ejection fraction, ICD implantation was superior to conventional medical therapy with respect to the rate of death at an average follow-up of 20 months. Reference Moss AJ, Zareba W, Hall WJ et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002 Mar 21;346(12):877-83. Open reference URL https://web.pathway.md/studies/recdICA4dZmsEIrTi 2/2

6/28/23, 11:16 PM MAGELLAN Pathway Feedback Search Clinical Topics Home Studies MAGELLAN MAGELLAN Disease Disease Deep vein thrombosis Pulmonary embolism Trial question Is rivaroxaban noninferior to enoxaparin for thromboprophylaxis in acutely ill medical patients? Study design Multi-center Double blinded RCT Population Characteristics of study participants 46.0% female N = 8101 54.0% male 8101 patients (3712 female, 4389 male) Inclusion criteria: patients 40 years of age who were hospitalized for an acute medical illness Key exclusion criteria: contraindication for LMWH enoxaparin, risk of bleeding, known allergy to rivaroxaban, severe renal insufficiency, known HIV infection at screening, or history of ongoing drug or alcohol abuse Interventions N=4050 rivaroxaban (subcutaneous placebo for 10 +/- 4 days and oral rivaroxaban, 10 mg once daily, for 35 +/- 4 days) N=4051 enoxaparin (subcutaneous enoxaparin, 40 mg once daily, for 10 +/- 4 days and oral placebo for 35 +/- 4 days) https://web.pathway.md/studies/recZH9vG65mV4VYkt 1/2 6/28/23, 11:16 PM MAGELLAN Pathway Primary outcome Asymptomatic proximal or symptomatic venous thromboembolism at day 10 2.7 % 2.7 2.7 2.0 % 1.4 % Difference not exceeding nonferiority margin 0.7 % 0.0 % Rivaroxaban Enoxaparin Difference not exceeding nonferiority margin in asymptomatic proximal or symptomatic VTE at day 10 (2.7% vs. 2.7%; RR 0.97, 95% CI 0.71 to 1.31) Secondary outcomes Significant decrease in asymptomatic proximal or symptomatic VTE at 35 days (4.4% vs. 5.7%; RR 0.77, 95% CI 0.62 to 0.96) Safety outcomes Significant differences in composite of major or clinically relevant nonmajor bleeding at day 10 (2.8% vs. 1.2%, p < 0.001) and at day 35 (4.1% vs. 1.7%, p < 0.001). Conclusion In patients 40 years of age who were hospitalized for an acute medical illness, rivaroxaban was noninferior to enoxaparin with respect to asymptomatic proximal or symptomatic VTE at day 10. Reference Cohen AT, Spiro TE, Buller HR et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013 Feb 7;368(6):513-23. Open reference URL https://web.pathway.md/studies/recZH9vG65mV4VYkt 2/2

6/28/23, 11:16 PM MAGIC Pathway Feedback Search Clinical Topics Home Studies MAGIC MAGIC Disease Disease Esophageal cancer Gastric cancer Trial question Is perioperative chemotherapy plus surgery superior to surgery alone in patients with resectable gastroesophageal cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 21.0% female N = 503 79.0% male 503 patients (107 female, 396 male) Inclusion criteria: patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus Key exclusion criteria: receipt of cytotoxic chemotherapy or radiotherapy; uncontrolled cardiac disease; CrCl 60 ml/min Interventions N=250 perioperative chemotherapy plus surgery (A regimen consisting of epirubicin, cisplatin, and fluorouracil for three cycles perioperatively and three cycles postoperatively plus surgery) N=253 surgery alone (surgery alone without chemotherapy) https://web.pathway.md/studies/recrx0m339kJu6u0W 1/2 6/28/23, 11:16 PM MAGIC Pathway Primary outcome Overall survival 40.4 % 40.4 32.8 30.3 % 20.2 % 10.1 % Borderline significant increase 0.0 % Perioperative chemotherapy plus surgery Surgery alone Borderline significant increase in overall survival (40.4% vs. 32.8%; HR 1.33, 95% CI 1.06 to 1.67) Secondary outcomes Significant decrease in diameter of resected tumor (3 cm vs. 5 cm; AD -2 cm, 95% CI -3.19 to -0.81) Safety outcomes No significant differences in postoperative complications, deaths within 30 days after surgery. Conclusion In patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus, perioperative chemotherapy plus surgery was superior to surgery alone with respect to overall survival. Reference David Cunningham, William H Allum, Sally P Stenning et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. Open reference URL https://web.pathway.md/studies/recrx0m339kJu6u0W 2/2

6/28/23, 11:16 PM MAGPIE Pathway Feedback Search Clinical Topics Home Studies MAGPIE MAGPIE Disease Disease Eclampsia Preeclampsia Trial question What is the role of magnesium sulfate in women with pre-eclampsia, and their babies? Study design Multi-center Double blinded RCT Population 10141 female patients Inclusion criteria: women who had not given birth or were 24 h postpartum with BP 140/90 mmHg and proteinuria 1+ Key exclusion criteria: hypersensitivity to magnesium, hepatic coma with a risk of renal failure, or myasthenia gravis Interventions N=5071 magnesium sulfate (5 g IV) N=5070 placebo (10 mL normal saline) Primary outcome Eclampsia 1.9 % 1.9 1.4 % 0.9 % 0.8 0.5 % https://web.pathway.md/studies/recfYK1lBXhuodRBD 1/2 6/28/23, 11:16 PM MAGPIE Pathway Borderline significant decrease 0.0 % Magnesium sulfate Placebo Borderline significant decrease in eclampsia (0.8% vs. 1.9%; RR 0.42, 95% CI 0.29 to 0.6) Secondary outcomes No significant difference in maternal death (0.2% vs. 0.4%; RR 0.55, 95% CI 0.26 to 1.14) No significant difference in neonatal death (12.7% vs. 12.4%; RR 1.02, 99% CI 0.92 to 1.14) Safety outcomes Significant difference in side effects (24% vs. 5%). Conclusion In women who had not given birth or were 24 h postpartum with BP 140/90 mmHg and proteinuria 1+, magnesium sulfate was superior to placebo with respect to eclampsia. Reference Altman D, Carroli G, Duley L et al. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet. 2002 Jun 1;359(9321):1877-90. Open reference URL https://web.pathway.md/studies/recfYK1lBXhuodRBD 2/2

6/28/23, 11:16 PM MANAGE Pathway Feedback Search Clinical Topics Home Studies MANAGE MANAGE Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is role of dabigatran in patients with myocardial injury after noncardiac surgery? Study design Multi-center Double blinded RCT Population Characteristics of study participants 49.0% female N = 1754 51.0% male 1754 patients (858 female, 896 male) Inclusion criteria: patients who had undergone noncardiac surgery and were within 35 days of myocardial injury after noncardiac surgery Key exclusion criteria: hypersensitivity or known allergy to dabigatran, history of intracranial, intraocular or spinal bleeding, hemorrhagic disorder or bleeding diathesis, pregnant or breastfeeding women, or conditions necessitating therapeutic dose anticoagulation Interventions N=877 dabigatran (110 mg PO BID for a maximum of 2 years or until termination of the trial) N=877 placebo (matched for a maximum of 2 years) Primary outcome https://web.pathway.md/studies/reckvSbNfmLJlNj0r 1/2 6/28/23, 11:16 PM MANAGE Pathway Major vascular complications 15.0 % 15 11.3 % 11 7.5 % Significant decrease 3.8 % NNT = 25 0.0 % Dabigatran Placebo Significant decrease in major vascular complications (11% vs. 15%; HR 0.72, 95% CI 0.55 to 0.93) Secondary outcomes No significant difference in vascular death (6% vs. 7%; HR 0.8, 95% CI 0.56 to 1.16) Safety outcomes No significant differences in life-threatening, critical, or major organ bleeding. Significant differences in 3% vs. 4%, p = 0.76; HR 0.92, 95% CI 0.55-1.53. Conclusion In patients who had undergone noncardiac surgery and were within 35 days of myocardial injury after noncardiac surgery, dabigatran was superior to placebo with respect to major vascular complications. Reference Devereaux PJ, Duceppe E, Guyatt G et al. Dabigatran in patients with myocardial injury after non- cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial. Lancet. 2018 Jun 9;391(10137):2325-2334. Open reference URL https://web.pathway.md/studies/reckvSbNfmLJlNj0r 2/2

6/28/23, 11:16 PM MAPP1 Pathway Feedback Search Clinical Topics Home Studies MAPP1 MAPP1 Disease Posttraumatic stress disorder Trial question What is the role of MDMA-assisted therapy in patients with severe posttraumatic stress disorder? Study design Multi-center Double blinded RCT Population Characteristics of study participants 66.0% female N = 90 34.0% male 90 patients (59 female, 31 male) Inclusion criteria: patients with severe posttraumatic stress disorder, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma Key exclusion criteria: primary psychotic disorder, bipolar I disorder, dissociative identity disorder, eating disorders with active purging, major depressive disorder with psychotic features, personality disorders, current alcohol and substance use disorders Interventions N=46 MDMA-assisted therapy (manualized MDMA-assisted psychotherapy with three preparatory and nine integrative therapy sessions) https://web.pathway.md/studies/rec3vf9xNXnGF8aMK 1/2 6/28/23, 11:16 PM MAPP1 Pathway N=44 placebo with therapy (inactive placebo-assisted psychotherapy with three preparatory and nine integrative therapy sessions) Primary outcome Reduction in posttraumatic stress disorder symptoms, as measured by Clinician-Administered PTSD Scale for DSM-5 at 18 weeks 24.4 24.4 18.3 13.9 12.2 6.1 Significant increase 0.0 MDMA-assisted therapy Placebo with therapy Significant increase in reduction in posttraumatic stress disorder symptoms, as measured by the Clinician-Administered PTSD Scale for DSM-5 at 18 weeks (24.4 vs. 13.9; AD 10.5, 95% CI 5.25 to 15.75) Secondary outcomes Significant increase in reduction in functional impairment score, as measured with the Sheehan Disability Scale (3.1 vs. 2; AD 1.1, 95% CI 0.25 to 1.95) Significant increase in reduction in depressive symptoms, as measured by the Beck Depression Inventory II (19.7 vs. 10.8; AD 8.9, 95% CI 3.12 to 14.68) Safety outcomes No significant differences in suicidality, QT prolongation. Significant difference in the percentage of patients with remission after three sessions (33% vs. 5%). Conclusion In patients with severe posttraumatic stress disorder, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma, MDMA-assisted therapy was superior to placebo with therapy with respect to reduction in posttraumatic stress disorder symptoms, as measured by the Clinician-Administered PTSD Scale for DSM-5 at 18 weeks. Reference Jennifer M Mitchell, Michael Bogenschutz, Alia Lilienstein et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med. 2021 Jun;27(6):1025-1033. Open reference URL https://web.pathway.md/studies/rec3vf9xNXnGF8aMK 2/2

6/28/23, 11:16 PM MARINER Pathway Feedback Search Clinical Topics Home Studies MARINER MARINER Disease Disease Deep vein thrombosis Pulmonary embolism Trial question What is the effect of rivaroxaban in medically ill patients who were at an increased risk for VTE on the basis of a modified International Medical Prevention Registry on VTE score of 4? Study design Multi-center Double blinded RCT Population Characteristics of study participants 48.0% female N = 12024 52.0% male 12024 patients (5735 female, 6284 male) Inclusion criteria: medically ill patients who were at an increased risk of VTE on the basis of a modified International Medical Prevention Registry on VTE score of 4 or a score of 2 or 3 plus a plasma D-dimer level of > 2 times the upper limit of the normal range assigned at hospital discharge Key exclusion criteria: anticoagulant or dual antiplatelet therapy, active cancer, history of recent bleeding (within 3 months), or a high risk of bleeding, or other contraindications to rivaroxaban Interventions N=6007 rivaroxaban (a dose of 10 mg, with the dose adjusted for renal insufficiency for 45 days) N=6012 placebo (for 45 days) https://web.pathway.md/studies/recZqQMdD0eW5P1ZU 1/2 6/28/23, 11:16 PM MARINER Pathway Primary outcome Symptomatic venous thromboembolism or death due to venous thromboembolism 1.1 % 1.1 0.8 % 0.83 0.6 % 0.3 % No significant difference 0.0 % Rivaroxaban Placebo No significant difference in symptomatic VTE or death due to VTE (0.83% vs. 1.1%; HR 0.76, 95% CI 0.52 to 1.09) Secondary outcomes Borderline significant decrease in symptomatic nonfatal VTE (0.18% vs. 0.42%; HR 0.44, 95% CI 0.22 to 0.89) Safety outcomes No significant difference in adverse events. Significant differences in major bleeding (0.28% vs. 0.15%; HR 1.88, 95% CI 0.84-4.23). Conclusion In medically ill patients who were at an increased risk of VTE on the basis of a modified International Medical Prevention Registry on VTE score of 4 or a score of 2 or 3 plus a plasma D- dimer level of > 2 times the upper limit of the normal range assigned at hospital discharge, rivaroxaban was not superior to placebo with respect to symptomatic VTE or death due to VTE. Reference Spyropoulos AC, Ageno W, Albers GW et al. Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness. N Engl J Med. 2018 Sep 20;379(12):1118-1127. Open reference URL https://web.pathway.md/studies/recZqQMdD0eW5P1ZU 2/2

6/28/23, 11:16 PM MASS Pathway Feedback Search Clinical Topics Home Studies MASS MASS Disease Abdominal aortic aneurysm Trial question What is the role of screening men for AAA? Study design Multi-center Open label RCT Population 67770 male patients Inclusion criteria: men aged 65-74 years Key exclusion criteria: females, age < 65 and > 74 years, terminally ill men, other serious health problems, and previous AAA repair Interventions N=33883 ultrasound screening for AAA (invitation to screening program) N=33887 no ultrasound screening (not routinely offered screening) Primary outcome Death related to abdominal aortic aneurysm at 10 years 0.9 % 0.87 0.7 % 0.46 0.4 % 0.2 % Borderline significant decrease 0.0 % https://web.pathway.md/studies/recnjzl37afj4s48r 1/2 6/28/23, 11:16 PM MASS Pathway Ultrasound screening for abdominal aortic aneurysm No ultrasound screening Borderline significant decrease in death related to AAA at 10 years (0.46% vs. 0.87%; HR 0.52, 95% CI 0.43 to 0.63) Secondary outcomes No significant difference in death at 30 days (4% vs. 6%; RR 0.67, 95% CI -0.42 to 1.76) Conclusion In men aged 65-74 years, ultrasound screening for AAA was superior to no ultrasound screening with respect to death related to AAA at 10 years. Reference Thompson SG, Ashton HA, Gao L et al. Screening men for abdominal aortic aneurysm: 10 year mortality and cost effectiveness results from the randomised Multicentre Aneurysm Screening Study. BMJ. 2009 Jun 24;338:b2307. Open reference URL https://web.pathway.md/studies/recnjzl37afj4s48r 2/2

6/28/23, 11:16 PM MASTER Anaesthesia Pathway Feedback Search Clinical Topics Home Studies MASTER Anaesthesia MASTER Anaesthesia Disease Postoperative pain Trial question What is the effect of epidural anesthesia and analgesia in high-risk patients undergoing major abdominal surgery? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 915 59.0% male 915 patients (371 female, 544 male) Inclusion criteria: high-risk status patients undergoing major abdominal surgery Key exclusion criteria: age < 18 years, surgery within 12 hours of admission to hospital, contraindications to the use of epidural block, infection at the epidural insertion site, or a neurological disorder Interventions N=461 epidural (intraoperative epidural anesthesia and postoperative epidural analgesia for 72 h with general anesthesia) N=454 control (general anesthesia based on a balanced technique with intraoperative and postoperative opioids) https://web.pathway.md/studies/recj5GqGUKPpghYni 1/2 6/28/23, 11:16 PM MASTER Anaesthesia Pathway Primary outcome Death or at least one postsurgical morbidity at 30 days 60.7 % 60.7 57.1 45.5 % 30.4 % 15.2 % No significant difference 0.0 % Epidural Control No significant difference in death or at least one postsurgical morbidity at 30 days (57.1% vs. 60.7%; RR 0.94, 95% CI -0.79 to 2.67) Secondary outcomes No significant difference in death at 30 days (5.1% vs. 4.3%; RR 1.19, 95% CI -4.06 to 6.44) Significant decrease in respiratory failure (23.3% vs. 30.2%; RR 0.77, 95% CI 0.12 to 1.42) No significant difference in cardiovascular event (25.7% vs. 24%; RR 1.07, 95% CI -2.9 to 5.04) Safety outcomes No significant differences in renal failure, gastrointestinal failure, hepatic failure, sepsis, hematological failure,. Significant differences in pain scores on day 1 (11.4 vs. 15.2), day 2 (9.9 vs. 11.9), and day 3 (8.0 vs. 9.7). Conclusion In high-risk status patients undergoing major abdominal surgery, epidural was not superior to control with respect to death or at least one postsurgical morbidity at 30 days. Reference John R A Rigg, Konrad Jamrozik, Paul S Myles et al. Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial. Lancet. 2002 Apr 13;359(9314):1276-82. Open reference URL https://web.pathway.md/studies/recj5GqGUKPpghYni 2/2

6/28/23, 11:16 PM MATCH Pathway Feedback Search Clinical Topics Home Studies MATCH MATCH Disease Disease Acute ischemic stroke Transient ischemic attack Trial question What is the role of aspirin and clopidogrel in high-risk patients with recent ischemic stroke or TIA? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 7599 63.0% male 7599 patients (2821 female, 4778 male) Inclusion criteria: high-risk patients with recent ischemic stroke or TIA and at least one additional vascular risk factor who were already receiving clopidogrel 75 mg/day Key exclusion criteria: age < 40 years, severe comorbid conditions, increased risk of bleeding, scheduled for major surgery or vascular surgery, and contraindications for aspirin or clopidogrel Interventions N=3797 aspirin (75 mg/day) N=3802 placebo (matching placebo daily) Primary outcome Ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia https://web.pathway.md/studies/recrcdxje9kNK2G2M 1/2 6/28/23, 11:16 PM MATCH Pathway 16.7 % 16.7 15.7 12.5 % 8.3 % 4.2 % No significant difference 0.0 % Aspirin Placebo No significant difference in ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia (15.7% vs. 16.7%; RR 0.94, 95% CI 0.84 to 1.05) Secondary outcomes No significant difference in myocardial infarction, ischemic stroke, or vascular death (12% vs. 12%; RR 0.94, 95% CI 0.83 to 1.07) No significant difference in death from any cause (5% vs. 5%; RR 0.99, 99% CI 0.79 to 1.18) Safety outcomes Significant difference in life-threatening bleedings (2.6% vs. 1.3%) and major bleeds (1.12% vs. 0.29%). Conclusion In high-risk patients with recent ischemic stroke or TIA and at least one additional vascular risk factor who were already receiving clopidogrel 75 mg/day, aspirin was not superior to placebo with respect to ischemic stroke, myocardial infarction, vascular death, or rehospitalization for acute ischemia. Reference Diener HC, Bogousslavsky J, Brass LM et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004 Jul 24-30;364(9431):331-7. Open reference URL https://web.pathway.md/studies/recrcdxje9kNK2G2M 2/2

6/28/23, 11:16 PM MDPIT Pathway Feedback Search Clinical Topics Home Studies MDPIT MDPIT Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the effect of diltiazem in patients with previous myocardial infarction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 20.0% female N = 2466 80.0% male 2466 patients (493 female, 1973 male) Inclusion criteria: patients aged 25-75 years with previous myocardial infarction Key exclusion criteria: ongoing cardiogenic shock or symptomatic hypotension; pulmonary hypertension with RV failure; hypersensitivity to diltiazem Interventions N=1232 diltiazem (at a dose of 240 mg/day for 12-52 months) N=1234 placebo (matching placebo for 12-52 months) Primary outcome Death from all causes 13.5 % 13.53 13.47 https://web.pathway.md/studies/recHwWwOymt13Iqe8 1/2 6/28/23, 11:16 PM 3 5 % MDPIT Pathway 3 53 13.47 10.1 % 6.8 % 3.4 % No significant difference 0.0 % Diltiazem Placebo No significant difference in death from all causes (13.47% vs. 13.53%; HR 0.98, 95% CI 0.78 to 1.22) Secondary outcomes No significant difference in first recurrent cardiac event (16.4% vs. 18.31%; HR 0.9, 95% CI 0.74 to 1.08) No significant difference in death from cardiac causes (8.4% vs. 8.9%; ARD 0.5, 95% CI 0 to 1) No significant difference in nonfatal reinfarction (8% vs. 9.4%; ARD -1.4, 95% CI -5.38 to 2.58) Safety outcomes No significant difference in adverse events. Conclusion In patients aged 25-75 years with previous myocardial infarction, diltiazem was not superior to placebo with respect to death from all causes. Reference Multicenter Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med. 1988 Aug 18;319(7):385-92. Open reference URL https://web.pathway.md/studies/recHwWwOymt13Iqe8 2/2

6/28/23, 11:19 PM Medical masks in COVID-19 Pathway Feedback Search Clinical Topics Home Studies Medical masks in COVID 19 Medical masks in COVID 19 Disease COVID 19 infection Trial question Is medical mask noninferior to N95 respirator for COVID-19 prevention in healthcare workers? Study design Multi-center Open label RCT Population Characteristics of study participants 70.0% female N = 1004 30.0% male 1004 patients (699 female, 305 male) Inclusion criteria: healthcare workers who provided direct care to patients with suspected or confirmed COVID-19 Key exclusion criteria: nurses with 1 comorbidities; nurses who cannot pass an N95 respirator fit-test Interventions N=497 medical mask (medical mask worn when providing care to patient with febrile respiratory illness) N=507 N95 respirator (N95 respirator worn when providing care to patient with febrile respiratory illness) https://web.pathway.md/studies/reckdb65DCOKyVoYF 1/2 6/28/23, 11:19 PM Medical masks in COVID-19 Pathway Primary outcome Reverse transcriptase-polymerase chain reaction-confirmed COVID-19 10.5 % 10.46 9.27 7.8 % 5.2 % Difference not exceeding nonferiority margin 2.6 % 0.0 % Medical mask N95 respirator Difference not exceeding nonferiority margin in reverse transcriptase-PCR-confirmed COVID-19 (10.46% vs. 9.27%; HR 1.14, 95% CI 0.77 to 1.69) Secondary outcomes No significant difference in acute respiratory illness (5.4% vs. 6.1%; HR 0.89, 95% CI 0.53 to 1.49) No significant difference in lower respiratory infection or pneumonia (0.6% vs. 0.6%; HR 1.02, 95% CI 0.21 to 5.04) No significant difference in laboratory-confirmed infection (14.5% vs. 13.6%; HR 1.08, 95% CI 0.75 to 1.55) Safety outcomes No significant difference in adverse events. Conclusion In healthcare workers who provided direct care to patients with suspected or confirmed COVID-19, medical mask was noninferior to N95 respirator with respect to reverse transcriptase-PCR- confirmed COVID-19. Reference Mark Loeb, Amy Bartholomew, Madiha Hashmi et al. Medical Masks Versus N95 Respirators for Preventing COVID-19 Among Health Care Workers. Ann Intern Med. 2022 Dec;175(12):1629-1638. Open reference URL https://web.pathway.md/studies/reckdb65DCOKyVoYF 2/2

6/28/23, 11:19 PM Melatonin in IBS Pathway Feedback Search Clinical Topics Home Studies Melatonin in IBS Melatonin in IBS Disease Irritable bowel syndrome Trial question What is the effect of melatonin on IBS patients with and without sleep disorders? Study design Single center Double blinded RCT Population Characteristics of study participants 54.0% female N = 136 46.0% male 136 patients (74 female, 62 male) Inclusion criteria: patients with a diagnosis of IBS based on Rome IV criteria Key exclusion criteria: allergies; side effects or compromised adherence to the treatment Interventions N=68 melatonin (at a dose of 3 mg BID for 2 months) N=68 placebo (matching placebo for 2 months) Primary outcome Moderate-to-severe irritable bowel syndrome in patients with sleep disorders 70.6 % 70.6 https://web.pathway.md/studies/recXNEQH19wjWQVrD 1/2 6/28/23, 11:19 PM Melatonin in IBS Pathway 52.9 % 41.2 35.3 % Significant decrease 17.6 % NNT = 3 0.0 % Melatonin Placebo Significant decrease in moderate-to-severe IBS in patients with sleep disorders (41.2% vs. 70.6%; RR 0.58, 95% CI 0.08 to 1.08) Secondary outcomes Significant decrease in moderate-to-severe IBS in patients without sleep disorders (41.2% vs. 76.5%; RR 0.54, 95% CI 0.07 to 1.01) Significant decrease in quite severe-to-severe abdominal pain in patients with sleep disorders (20.6% vs. 32.3%; RR 0.64, 95% CI 0.05 to 1.23) Conclusion In patients with a diagnosis of IBS based on Rome IV criteria, melatonin was superior to placebo with respect to a moderate-to-severe IBS in patients with sleep disorders. Reference Masood Faghih Dinevari, Farzaneh Jafarzadeh, Amirreza Jabbaripour Sarmadian et al. The effect of melatonin on irritable bowel syndrome patients with and without sleep disorders: a randomized double-blinded placebo-controlled trial study. BMC Gastroenterol. 2023 Apr 25;23(1):135. Open reference URL https://web.pathway.md/studies/recXNEQH19wjWQVrD 2/2

6/28/23, 11:16 PM MENDS Pathway Feedback Search Clinical Topics Home Studies MENDS MENDS Disease ICU delirium Trial question Is dexmedetomidine superior to lorazepam in mechanically ventilated patients? Study design Multi-center Double blinded RCT Population Characteristics of study participants 49.0% female N = 103 51.0% male 103 patients (50 female, 53 male) Inclusion criteria: mechanically ventilated adult patients in medical and surgical ICU Key exclusion criteria: neurological disease; Childs-Pugh class B or C liver disease; moribund state with planned withdrawal of life support; alcohol abuse; active myocardial ischemia, severe dementia; benzodiazepine dependency Interventions N=52 dexmedetomidine (maximum infusion at 1.5 g/kg/hour titrated to achieve Richmond Agitation-Sedation Scale score) N=51 lorazepam (maximum infusion at 10 mg/hour titrated to achieve Richmond Agitation- Sedation Scale score) https://web.pathway.md/studies/recNRLT2KJyiI09oE 1/2 6/28/23, 11:16 PM MENDS Pathway Primary outcome Days alive without delirium or coma 7.0 days 7 5.3 days 3.5 days 3 1.8 days Significant increase 0.0 days Dexmedetomidine Lorazepam Significant increase in days alive without delirium or coma (7 days vs. 3 days; AD 4 days, 95% CI 0.96 to 7.04) Secondary outcomes Significant increase in the percentage of patients with delirium or coma (45% vs. 50%; ARD 5, 95% CI 0.48 to 9.52) Significant increase in Richmond Agitation-Sedation Scale score within 1 point of sedation goal (80% vs. 67%; AD 13%, 95% CI 0.57 to 25.43) No significant difference in death at day 28 (17% vs. 27%; RR 0.63, 95% CI -0.29 to 1.55) Safety outcomes No significant differences in seizures, self-extubations. Significant difference in sinus bradycardia (17% vs. 4%). Conclusion In mechanically ventilated adult patients in medical and surgical ICU, dexmedetomidine was superior to lorazepam with respect to days alive without delirium or coma. Reference Pratik P Pandharipande, Brenda T Pun, Daniel L Herr et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007 Dec 12;298(22):2644-53. Open reference URL https://web.pathway.md/studies/recNRLT2KJyiI09oE 2/2

6/28/23, 11:16 PM MEPEX Pathway Feedback Search Clinical Topics Home Studies MEPEX MEPEX Disease Disease Disease Eosinophilic granulomatosis wit Granulomatosis with polyangiitis Microscop Trial question What is the role of plasma exchange in patients with newly diagnosed autoantibodies to neutrophil cytoplasmic antigens-associated systemic vasculitis presenting with renal failure? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 137 61.0% male 137 patients (53 female, 84 male) Inclusion criteria: patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine > 500 micromol/L Key exclusion criteria: age < 18 or > 80 yr; pregnancy; previous malignancy; hepatitis B antigenemia, anti-HCV, or anti-HIV antibody; other multisystem autoimmune disease; or life- threatening nonrenal manifestations of vasculitis Interventions N=70 plasma exchange (total of seven plasma exchanges within 14 days of study entry plus oral cyclophosphamide and oral prednisolone) https://web.pathway.md/studies/recX2HyglA9TrgdOe 1/2 6/28/23, 11:16 PM MEPEX Pathway N=67 methylprednisolone (intravenous 1,000 mg/d for 3 consecutive months plus oral cyclophosphamide and oral prednisolone) Primary outcome Dialysis independence at 3 months 69.0 % 69 51.8 % 49 34.5 % Significant increase 17.3 % NNH = 5 0.0 % Plasma exchange Methylprednisolone Significant increase in dialysis independence at 3 months (69% vs. 49%; RR 1.41, 95% CI 18 to 35) Secondary outcomes Significant decrease in progression to ESRD at 12 months (19% vs. 43%; HR 0.47, 95% CI 0.24 to 0.91) Safety outcomes No significant differences in severe adverse events (50% vs. 48%, p=0.68) and survival at 1 year (73% vs. 76%, p=0.80). Conclusion In patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine > 500 micromol/L, plasma exchange was superior to methylprednisolone with respect to dialysis independence at 3 months. Reference Jayne DR, Gaskin G, Rasmussen N et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007 Jul;18(7):2180-8. Open reference URL https://web.pathway.md/studies/recX2HyglA9TrgdOe 2/2

6/28/23, 11:16 PM MERIT-HF Pathway Feedback Search Clinical Topics Home Studies MERIT HF MERIT HF Disease Heart failure Trial question Is conventional therapy plus metoprolol CR/XR once daily superior to conventional therapy alone in patients with HF, a LVEF 40%, and NYHA class II-IV symptoms? Study design Multi-center Double blinded RCT Population Characteristics of study participants 35.4% female N = 3991 64.6% male 3991 patients (898 female, 1693 male) Inclusion criteria: patients with HF, an LVEF 40%, and NYHA class II-IV symptoms Key exclusion criteria: acute myocardial infarction or unstable angina within 28 days before randomization; indication or contraindication for treatment with beta blockers, HF secondary to systemic disease or alcohol abuse; or AV block of the second and third degree Interventions N=1990 conventional therapy plus metoprolol CR/XR once daily (12.5 mg for NYHA III-IV or 25.0 mg once daily for NYHA II, target dose 200 mg once daily plus optimum standard therapy) N=2001 placebo (conventional therapy alone) https://web.pathway.md/studies/rechlJN240XGynIFR 1/2 6/28/23, 11:16 PM MERIT-HF Pathway Primary outcome All-cause death 11.0 % 11 8.3 % 7.2 5.5 % Significant decrease 2.8 % NNT = 26 0.0 % Conventional therapy plus metoprolol CR/XR once daily Placebo Significant decrease in all-cause death (7.2% vs. 11%; RR 0.66, 95% CI 0.53 to 0.81) Secondary outcomes Significant decrease in sudden cardiac death (0.19% vs. 0.132%; RR 0.59, 95% CI 0.28 to 0.9) Significant decrease in worsening HF (0.3% vs. 0.58%; RR 0.51, 95% CI 0.33 to 0.79) Conclusion In patients with HF, an LVEF 40%, and NYHA class II-IV symptoms, conventional therapy plus metoprolol CR/XR once daily was superior to placebo with respect to a all-cause death. Reference MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999 Jun 12;353(9169):2001-7. Open reference URL https://web.pathway.md/studies/rechlJN240XGynIFR 2/2

6/28/23, 11:16 PM METEOR Pathway Feedback Search Clinical Topics Home Studies METEOR METEOR Trial question What is the role of surgery in symptomatic patients with a meniscal tear and knee OA? Study design Multi-center Open label RCT Population Characteristics of study participants 56.4% female N = 351 43.6% male 351 patients (187 female, 143 male) Inclusion criteria: symptomatic patients 45 years of age with a meniscal tear and evidence of mild-to-moderate OA on imaging Key exclusion criteria: chronically locked knee, inflammatory arthritis or clinically symptomatic chondrocalcinosis, injection with viscosupplementation, contraindication to surgery or physical therapy, bilateral symptomatic meniscal tear, or prior surgery on index knee Interventions N=161 surgical meniscectomy (arthroscopic partial meniscectomy and postoperative physical therapy) N=169 physical therapy alone (standardized physical-therapy regimen) Primary outcome Mean improvement in WOMAC score at 6 months 20.9 points 20.9 18.5 15.7 points 10.4 points https://web.pathway.md/studies/recDKfqzeYUjMykC4 1/2 6/28/23, 11:16 PM METEOR Pathway 5.2 points No significant difference 0.0 points Surgical meniscectomy Physical therapy alone No significant difference in mean improvement in the WOMAC score at 6 months (20.9 points vs. 18.5 points; MD 2.4, 95% CI -1.8 to 6.5) Secondary outcomes No significant difference in mean improvement in the KOOS pain score after 6 months (24.2 vs. 21.3; MD 2.9, 95% CI -1.2 to 7) No significant difference in mean improvement in the SF-36 physical-activity score after 6 months (24.2 vs. 23.1; MD 1.1, 95% CI -4.4 to 6.6) Safety outcomes No significant difference in adverse events. Conclusion In symptomatic patients 45 years of age with a meniscal tear and evidence of mild-to-moderate OA on imaging, surgical meniscectomy was not superior to physical therapy alone with respect to mean improvement in the WOMAC score at 6 months. Reference Katz JN, Brophy RH, Chaisson CE et al. Surgery versus physical therapy for a meniscal tear and osteoarthritis. N Engl J Med. 2013 May 2;368(18):1675-84. Open reference URL https://web.pathway.md/studies/recDKfqzeYUjMykC4 2/2

6/28/23, 11:16 PM METEORIC-HF Pathway Feedback Search Clinical Topics Home Studies METEORIC HF METEORIC HF Disease Heart failure Trial question What is the effect of omecamtiv mecarbil, a novel cardiac myosin activator, in patients with chronic HFrEF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 15.0% female N = 276 85.0% male 276 patients (42 female, 234 male) Inclusion criteria: patients with chronic HFrEF Key exclusion criteria: major medical event or procedure within the previous 3 months; conditions limiting exercise capacity during exercise testing; inability to achieve a respiratory exchange ratio 1.05 on baseline cardiopulmonary exercise testing Interventions N=185 omecamtiv mecarbil (a dose of 25 mg, 37.5 mg, or 50 mg based on target plasma levels for 20 weeks) N=91 placebo (matching placebo) https://web.pathway.md/studies/recGSPAiJY7hXmQRJ 1/2 6/28/23, 11:16 PM METEORIC-HF Pathway Primary outcome No significant difference in improvement in exercise capacity after 20 weeks of therapy (-0.24 mL/kg/min vs. 0.21 mL/kg/min; AD -0.45 mL/kg/min, 95% CI -1.02 to 0.13) Secondary outcomes No significant difference in improvement in ventilatory efficiency (0.28 vs. -0.14; AD 0.41, 95% CI -0.8 to 1.6) No significant difference in improvement in total daily activities by actigraphy (-0.2 vs. -0.5; AD 0.3, 95% CI -0.6 to 1.1) Significant decrease in improvement in peak workload achieved (-3.8 W vs. 1.6 W; AD -5.4 W, 95% CI -10.1 to -0.7) Safety outcomes No significant difference in adverse events. Conclusion In patients with chronic HFrEF, omecamtiv mecarbil was not superior to placebo with respect to improvement in exercise capacity after 20 weeks of therapy. Reference Gregory D Lewis, Adriaan A Voors, Alain Cohen-Solal et al. Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial. JAMA. 2022 Jul 19;328(3):259-269. Open reference URL https://web.pathway.md/studies/recGSPAiJY7hXmQRJ 2/2

6/28/23, 11:16 PM MICHELLE Pathway Feedback Search Clinical Topics Home Studies MICHELLE MICHELLE Disease COVID 19 infection Trial question What is the role of rivaroxaban in patients at high risk for VTE discharged after hospitalization due to COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 40.0% female N = 318 60.0% male 318 patients (127 female, 191 male) Inclusion criteria: patients hospitalized with COVID-19 at increased risk for VTE Key exclusion criteria: IMPROVE-VTE score < 4 and D-dimer within normal range, severe renal failure, indication for anticoagulation therapy, contraindications to anticoagulation Interventions N=159 rivaroxaban (10 mg/day for 35 days) N=159 no anticoagulation (regular follow-up for 35 days) Primary outcome https://web.pathway.md/studies/recZ4IWYy6S2Jt0mH 1/2 6/28/23, 11:16 PM MICHELLE Pathway Symptomatic or fatal venous thromboembolism, asymptomatic venous thromboembolism on bilateral lower-limb venous ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism, and cardiovascular death at day 35 9.4 % 9.43 7.1 % 4.7 % Significant decrease 3.14 NNT = 16 2.4 % 0.0 % Rivaroxaban No anticoagulation Significant decrease in symptomatic or fatal VTE, asymptomatic VTE on bilateral lower-limb venous ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism, and cardiovascular death at day 35 (3.14% vs. 9.43%; RR 0.33, 95% CI 0.13 to 0.9) Secondary outcomes Significant decrease in symptomatic and fatal VTE (0.63% vs. 5.03%; RR 0.13, 95% CI 0.02 to 0.99) No significant difference in symptomatic VTE and all-cause mortality (2.52% vs. 5.66%; RR 0.44, 95% CI 0.14 to 1.41) Significant decrease in symptomatic VTE, myocardial infarction stroke, cardiovascular death (0.63% vs. 5.66%; RR 0.11, 95% CI 0.01 to 0.87) Safety outcomes No significant differences in clinically relevant non-major bleeding, other bleeding. Conclusion In patients hospitalized with COVID-19 at increased risk for VTE, rivaroxaban was superior to no anticoagulation with respect to symptomatic or fatal VTE, asymptomatic VTE on bilateral lower-limb venous ultrasound and CT pulmonary angiogram, symptomatic arterial thromboembolism, and cardiovascular death at day 35. Reference Eduardo Ramacciotti, Leandro Barile Agati, Daniela Calderaro et al. Rivaroxaban versus no anticoagulation for post-discharge thromboprophylaxis after hospitalisation for COVID-19 (MICHELLE): an open-label, multicentre, randomised, controlled trial. Lancet. 2021 Dec 15;S0140- 6736(21)02392-8. Open reference URL https://web.pathway.md/studies/recZ4IWYy6S2Jt0mH 2/2

6/28/23, 11:16 PM MIDA Pathway Feedback Search Clinical Topics Home Studies MIDA MIDA Disease Mitral regurgitation Trial question What is the role of early surgical intervention in patients with flail mitral valve regurgitation? Study design Multi-center Open label Observational study Population Characteristics of study participants 27.1% female N = 2097 72.9% male 2097 patients (278 female, 743 male) Inclusion criteria: patients with mitral valve regurgitation due to flail mitral leaflets Key exclusion criteria: current HF symptoms, LVEF < 60%, LV end-systolic diameter 40 mm, or contraindication to surgery due to comorbidity Interventions N=446 early mitral surgery (performed within 3 months from diagnosis) N=575 initial medical management (during the first 3 months of follow-up then either medical or surgical treatment thereafter) Primary outcome Survival at 10 years https://web.pathway.md/studies/recLT7XHRC0H0hZCF 1/2 6/28/23, 11:16 PM MIDA Pathway 86.0 % 86 69 64.5 % 43.0 % Significant increase 21.5 % NNT = 6 0.0 % Early mitral surgery Initial medical management Significant increase in survival at 10 years (86% vs. 69%; HR 1.81, 95% CI 1.38 to 2.43) Secondary outcomes Significant decrease in long-term HF risk, at 10 years (7% vs. 23%; HR 0.29, 95% CI 0.19 to 0.43) No significant difference in death at 3 months (1.1% vs. 0.5%; RR 2.2, 95% CI -1.76 to 6.16) Conclusion In patients with mitral valve regurgitation due to flail mitral leaflets, early mitral surgery was superior to initial medical management with respect to survival at 10 years. Reference Suri RM, Vanoverschelde JL, Grigioni F et al. Association between early surgical intervention vs watchful waiting and outcomes for mitral regurgitation due to flail mitral valve leaflets. JAMA. 2013 Aug 14;310(6):609-16. Open reference URL https://web.pathway.md/studies/recLT7XHRC0H0hZCF 2/2

6/28/23, 11:16 PM MIDAS Pathway Feedback Search Clinical Topics Home Studies MIDAS MIDAS Disease Sepsis and septic shock Trial question What is the role of midodrine on time to vasopressor discontinuation in patients with persistent hypotension in the ICU? Study design Multi-center Double blinded RCT Population Characteristics of study participants 48.5% female N = 136 51.5% male 136 patients (64 female, 68 male) Inclusion criteria: adult patients with hypotension requiring a single-agent intravenous vasopressor for 24 hours Key exclusion criteria: clinical evidence of inadequate tissue oxygenation, hypovolemic shock or hypotension due to adrenal insufficiency, liver failure, chronic renal failure, severe organic heart disease, acute urinary retention, pheochromocytoma, thyrotoxicosis, bradycardia Interventions N=66 midodrine (20 mg PO every 8 hours plus standard care) N=66 placebo (matching placebo every 8 hours plus standard care) https://web.pathway.md/studies/recfCad2ppszzdeH2 1/2 6/28/23, 11:16 PM MIDAS Pathway Primary outcome Median time to vasopressor discontinuation 23.5 hours 23.5 22.5 17.6 hours 11.8 hours 5.9 hours No significant difference 0.0 hours Midodrine Placebo No significant difference in median time to vasopressor discontinuation (23.5 hours vs. 22.5 hours; AD 1 hours, 95% CI -10.4 to 12.3) Secondary outcomes No significant difference in median hospital length of stay (11 days vs. 14 days; AD -3 days, 95% CI -6.3 to 0.3) Safety outcomes No significant difference in adverse event rates. Significant difference in bradycardia (7.6% vs. 0%). Conclusion In adult patients with hypotension requiring a single-agent intravenous vasopressor for 24 hours, midodrine was not superior to placebo with respect to median time to vasopressor discontinuation. Reference Peter Santer, Matthew H Anstey, Maria D Patroc nio et al. Effect of midodrine versus placebo on time to vasopressor discontinuation in patients with persistent hypotension in the intensive care unit (MIDAS): an international randomised clinical trial. Intensive Care Med. 2020 Oct;46(10):1884-1893. Open reference URL https://web.pathway.md/studies/recfCad2ppszzdeH2 2/2

6/28/23, 11:16 PM MIRACL Pathway Feedback Search Clinical Topics Home Studies MIRACL MIRACL Disease Non-ST-elevation myocardial inf Trial question What is the role of atorvastatin in patients (aged 18 years) with unstable angina or non-Q-wave acute myocardial infarction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 35.0% female N = 3086 65.0% male 3086 patients (1074 female, 2012 male) Inclusion criteria: patients (aged 18 years) with unstable angina or non-Q-wave acute myocardial infarction Key exclusion criteria: Q-wave acute myocardial infarction within the preceding 4 weeks, left bundle-branch block or paced ventricular rhythm, severe congestive HF, severe anemia, renal failure requiring dialysis, or hepatic dysfunction Interventions N=1538 atorvastatin (80 mg/day between 24 to 96 hours after hospitalization) N=1548 placebo (matching placebo between 24 and 96 hours after hospitalization) https://web.pathway.md/studies/recKv5W6kPoetWJzJ 1/2 6/28/23, 11:16 PM MIRACL Pathway Primary outcome Death, nonfatal myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency hospitalization 17.4 % 17.4 14.8 13.0 % 8.7 % 4.3 % Borderline significant decrease 0.0 % Atorvastatin Placebo Borderline significant decrease in death, nonfatal myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency hospitalization (14.8% vs. 17.4%; RR 0.84, 95% CI 0.7 to 1) Secondary outcomes Significant decrease in symptomatic ischemia with objective evidence and requiring emergency rehospitalization (6.2% vs. 8.4%; RR 0.74, 95% CI 0.57 to 0.95) Significant increase in abnormal liver transaminases (2.5% vs. 0.6%; RR 4.17, 95% CI 1.7 to 6.64) Safety outcomes Significant differences in abnormal liver transaminases (2.5% vs. 0.6%, p < 0.001). Conclusion In patients (aged 18 years) with unstable angina or non-Q-wave acute myocardial infarction, atorvastatin was superior to placebo with respect to death, nonfatal myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency hospitalization. Reference Schwartz GG, Olsson AG, Ezekowitz MD et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001 Apr 4;285(13):1711-8. Open reference URL https://web.pathway.md/studies/recKv5W6kPoetWJzJ 2/2

6/28/23, 11:16 PM MODIGLIA-NI Pathway Feedback Search Clinical Topics Home Studies MODIGLIA NI MODIGLIA NI Disease Pulmonary embolism Trial question What is the effect of a diagnostic strategy using an elevated age-adjusted D-dimer threshold in ED patients with suspected PE? Study design Multi-center Open label RCT Population Characteristics of study participants 58.0% female N = 1414 42.0% male 1414 patients (823 female, 591 male) Inclusion criteria: adult patients who had a low clinical risk of PE not excluded by the PE rule-out criteria rule or a subjective clinical intermediate risk of PE Key exclusion criteria: high or low clinical probability of PE; pregnancy; other obvious cause for chest pain, syncope or dyspnea; concurrent anticoagulation treatment Interventions N=648 modified diagnostic strategy (use of YEARS rule combined with age-adjusted D-dimer testing) N=623 a conventional diagnostic strategy (test with D-dimer using the age-adjusted threshold level) https://web.pathway.md/studies/recO2qaue1vshmOmk 1/2 6/28/23, 11:16 PM MODIGLIA-NI Pathway Primary outcome Venous thromboembolism at 3 months 0.8 % 0.8 0.6 % 0.4 % Difference not exceeding nonferiority margin 0.2 % 0.15 0.0 % Modified diagnostic strategy A conventional diagnostic strategy Difference not exceeding nonferiority margin in VTE at 3 months (0.15% vs. 0.8%; AD -0.64%, 97.5% CI -Infinity to 0.21) Secondary outcomes Significant decrease in need of chest imaging (30.4% vs. 40%; AD -8.7%, 95% CI -13.8 to -3.5) Significant increase in ED median length of stay (6 hours vs. 6 hours; AD 1.6 hours, 95% CI -2.3 to -0.9) Conclusion In adult patients who had a low clinical risk of PE not excluded by the PE rule-out criteria rule or a subjective clinical intermediate risk of PE, modified diagnostic strategy was noninferior to a conventional diagnostic strategy with respect to VTE at 3 months. Reference Yonathan Freund, Anthony Chauvin, Sonia Jimenez et al. Effect of a Diagnostic Strategy Using an Elevated and Age-Adjusted D-Dimer Threshold on Thromboembolic Events in Emergency Department Patients With Suspected Pulmonary Embolism: A Randomized Clinical Trial. JAMA. 2021 Dec 7;326(21):2141-2149. Open reference URL https://web.pathway.md/studies/recO2qaue1vshmOmk 2/2

6/28/23, 11:19 PM MoDUS Pathway Feedback Search Clinical Topics Home Studies MoDUS MoDUS Disease ICU delirium Trial question What is the effect of early administration of simvastatin in critically ill patients with delirium undergoing mechanical ventilation? Study design Single center Double blinded RCT Population Characteristics of study participants 42.0% female N = 142 58.0% male 142 patients (60 female, 82 male) Inclusion criteria: critically ill patients needing mechanical ventilation within 72 h of ICU admission Key exclusion criteria: age < 18 years; pregnant or breastfeeding; known allergy to statins; CK concentration > 10 times the ULN range; ALT concentration > 8 times the ULN range Interventions N=71 simvastatin (80 mg by enteral administration daily for up to a maximum of 28 days) N=71 placebo (matching placebo by enteral administration daily for up to a maximum of 28 days) Primary outcome Days alive without delirium and coma at 14 days https://web.pathway.md/studies/recUEDnwOdcsYrfIg 1/2 6/28/23, 11:19 PM MoDUS Pathway 6.1 days 6.1 5.7 4.6 days 3.0 days 1.5 days No significant difference 0.0 days Simvastatin Placebo No significant difference in days alive without delirium and coma at 14 days (5.7 days vs. 6.1 days; AD -0.4 days, 95% CI -1.3 to 2.1) Secondary outcomes No significant difference in ventilator-free days at 28 days (13.7 days vs. 15.5 days; AD -1.8 days, 95% CI -2.1 to 5.6) No significant difference in organ failure-free days at 28 days (14.3 days vs. 15.7 days; AD -1.5 days, 95% CI -2.4 to 5.3) No significant difference in length of hospital stay until death or discharge (20.3 days vs. 20.4 days; AD -0.2 days, 95% CI -6.3 to 6.7) Safety outcomes No significant differences in death from all causes at 6 months, increase in alanine transaminase to > eight times the upper limit or normal. Significant difference in percentage of patients with creatinine kinase concentration > ten times the ULN (11% vs. 4%). Conclusion In critically ill patients needing mechanical ventilation within 72 h of ICU admission, simvastatin was not superior to placebo with respect to days alive without delirium and coma at 14 days. Reference Valerie J Page, Annalisa Casarin, E Wesley Ely et al. Evaluation of early administration of simvastatin in the prevention and treatment of delirium in critically ill patients undergoing mechanical ventilation (MoDUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2017 Sep;5(9):727-737. Open reference URL https://web.pathway.md/studies/recUEDnwOdcsYrfIg 2/2

6/28/23, 11:19 PM MoLish Pathway Feedback Search Clinical Topics Home Studies MoLish MoLish Disease Hemorrhoids Trial question Is modified ligation procedure superior to stapled hemorrhoidectomy in patients with symptomatic hemorrhoids? Study design Single center Single blinded RCT Population Characteristics of study participants 53.0% female N = 130 47.0% male 130 patients (69 female, 61 male) Inclusion criteria: patients with symptomatic hemorrhoids Key exclusion criteria: acute hemorrhoidal edema; infection; bleeding; IBD, acute or chronic diarrhea; anal fistula; perianal sepsis; colorectal malignancy Interventions N=64 modified ligation procedure (application of a rubber band and a silk loop to each ligation site via a proctoscope) N=66 stapled hemorrhoidectomy (performed with a PaH32 stapler) Primary outcome https://web.pathway.md/studies/recWEw4TbJjZwWCog 1/2 6/28/23, 11:19 PM MoLish Pathway Cure rate at 6 months 90.6 % 90.6 69.7 67.9 % 45.3 % Significant increase 22.6 % NNH = 5 0.0 % Modified ligation procedure Stapled hemorrhoidectomy Significant increase in cure rate at 6 months (90.6% vs. 69.7%; AD 20.9%, 95% CI 7.12 to 34.68) Secondary outcomes Significant decrease in median hemorrhoid symptom severity score at 6 months (MD -1, 95% CI -1.66 to -0.34) Significant decrease in Wexner incontinence score at 1 month (AD -1, 95% CI -1.94 to -0.06) Significant decrease in median postoperative pain score at day 7 (1 vs. 2; AD -1, 95% CI -1.79 to -0.21) Safety outcomes No significant differences in urinary retention, perianal haematoma. Significant differences in cutaneous bridge edema (32.8% vs. 6.1%), anal distension (37.5% vs. 54.5%). Conclusion In patients with symptomatic hemorrhoids, modified ligation procedure was superior to stapled hemorrhoidectomy with respect to cure rate at 6 months. Reference Haibo Yang, Zhan Shi, Wei Chen et al. Modified ligation procedure for prolapsed haemorrhoids versus stapled haemorrhoidectomy for the management of symptomatic haemorrhoids (MoLish): randomized clinical trial. BJS Open. 2022 May 2;6(3):zrac064. Open reference URL https://web.pathway.md/studies/recWEw4TbJjZwWCog 2/2

6/28/23, 11:16 PM MOMENTUM 3 Pathway Feedback Search Clinical Topics Home Studies MOMENTUM 3 MOMENTUM 3 Disease Heart failure Trial question Is magnetically levitated centrifugal continuous-flow circulatory pump superior to mechanical- bearing axial continuous-flow pump in patients with advanced HF? Study design Multi-center Open label RCT Population Characteristics of study participants 20.0% female N = 366 80.0% male 366 patients (73 female, 293 male) Inclusion criteria: patients with advanced HF that was refractory to guideline-mandated medical management Key exclusion criteria: active infection, irreversible end-organ dysfunction, or expected use of biventricular circulatory support Interventions N=190 centrifugal-flow pump LVAD (HeartMate3 fully magnetically levitated centrifugal continuous-flow pump) N=176 axial-flow pump LVAD (HeartMate II mechanical-bearing axial continuous-flow pump) https://web.pathway.md/studies/recahvRvxtpZVZK7R 1/2 6/28/23, 11:16 PM MOMENTUM 3 Pathway Primary outcome Survival free of disabling stroke at 2 years 79.5 % 79.5 59.6 % 60.2 39.8 % Significant increase 19.9 % NNT = 5 0.0 % Centrifugal-flow pump LVAD Axial-flow pump LVAD Significant increase in survival free of disabling stroke at 2 years (79.5% vs. 60.2%; HR 2.17, 95% CI 1.44 to 3.22) Secondary outcomes Significant decrease in reoperation for pump malfunction (1.6% vs. 17%; HR 0.08, 95% CI 0.03 to 0.27) Significant decrease in pump thrombosis (1.1% vs. 15.7%; HR 0.06, 95% CI 0.01 to 0.26) Significant decrease in stroke (10.1% vs. 19.2%; HR 0.47, 95% CI 0.27 to 0.84) Safety outcomes No significant differences in hemorrhagic stroke, right HF, surgical and nonsurgical bleeding, and infection. Conclusion In patients with advanced HF that was refractory to guideline-mandated medical management, centrifugal-flow pump LVAD was superior to axial-flow pump LVAD with respect to survival free of disabling stroke at 2 years. Reference Mehra MR, Goldstein DJ, Uriel N et al. Two-Year Outcomes with a Magnetically Levitated Cardiac Pump in Heart Failure. N Engl J Med. 2018 Apr 12;378(15):1386-1395. Open reference URL https://web.pathway.md/studies/recahvRvxtpZVZK7R 2/2

6/28/23, 11:16 PM MOPETT Pathway Feedback Search Clinical Topics Home Studies MOPETT MOPETT Disease Disease Deep vein thrombosis Pulmonary embolism Trial question What is the role of low-dose thrombolysis in patients with moderate PE? Study design Single center Open label RCT Population Characteristics of study participants 55.0% female N = 121 45.0% male 121 patients (66 female, 55 male) Inclusion criteria: patients with moderate PE Key exclusion criteria: eligibility for full-dose thrombolysi,contraindication to unfractionated or low- molecular-weight heparin, severe thrombocytopenia, major bleeding within < 2 months requiring transfusion, surgery or major trauma within < 2 weeks, brain mass Interventions N=61 thrombolysis ("safe dose" of tPA plus anticoagulation) N=60 control (anticoagulation alone) Primary outcome Pulmonary hypertension at 28 months https://web.pathway.md/studies/recAd1q4kvXPIXnl0 1/2 6/28/23, 11:16 PM MOPETT Pathway 57.0 % 57 42.8 % 28.5 % Significant decrease 16 14.3 % NNT = 2 0.0 % Thrombolysis Control Significant decrease in pulmonary hypertension at 28 months (16% vs. 57%; RR 0.28, 95% CI 0.11 to 0.45) Secondary outcomes Significant decrease in pulmonary hypertension or recurrent PE (16% vs. 63%; RR 0.25, 95% CI 0.1 to 0.4) Significant decrease in death or recurrent PE (1.6% vs. 10%; RR 0.16, 95% CI 0 to 0.32) Significant decrease in duration of hospitalization (2.2 vs. 4.9; AD -2.7, 95% CI -4.3 to -1.1) Conclusion In patients with moderate PE, thrombolysis were superior to control with respect to pulmonary hypertension at 28 months. Reference Sharifi M, Bay C, Skrocki L et al. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol. 2013 Jan 15;111(2):273-7. Open reference URL https://web.pathway.md/studies/recAd1q4kvXPIXnl0 2/2

6/28/23, 11:16 PM MOSAIC Pathway Feedback Search Clinical Topics Home Studies MOSAIC MOSAIC Disease Peripheral artery disease of low Trial question Is a motivating, home-based, walking exercise behavior change intervention superior to usual care for walking in adults with PAD? Study design Multi-center Open label RCT Population Characteristics of study participants 30.0% female N = 190 70.0% male 190 patients (57 female, 133 male) Inclusion criteria: adults with PAD and intermittent claudication Key exclusion criteria: unstable intermittent claudication; walking > 90 minutes/week; contraindications to walking exercise; completion of prescribed supervised exercise sessions in the previous 6 months Interventions N=95 motivating structured walking activity treatment (home-based, walking exercise behavior change intervention delivered by physical therapists trained to use a motivational approach) N=95 usual care (initial assessment, drug therapy, and simple advice to walk provided by a vascular specialist) https://web.pathway.md/studies/recCa4SgjWCCT2vda 1/2 6/28/23, 11:16 PM MOSAIC Pathway Primary outcome Mean improvement in 6-minute walking distance at 3-month follow-up 27.7 m 27.7 20.8 m 13.8 m 6.9 m Significant increase 2.3 0.0 m Motivating structured walking activity treatment Usual care Significant increase in mean improvement in 6MWD at 3-month follow-up (27.7 m vs. 2.3 m; MD 16.7, 95% CI 4.2 to 29.2) Secondary outcomes Significant increase in mean improvement in Walking Estimated Limitation Calculated by History score at 6 months (MD 7.4, 95% CI 2.5 to 12.3) Significant increase in mean improvement in attitude component of the theory of planned behavior questionnaire score at 6 months (0.7 vs. -0.7; MD 1.4, 95% CI 0.3 to 2.5) Conclusion In adults with PAD and intermittent claudication, motivating structured walking activity treatment was superior to usual care with respect to mean improvement in 6MWD at 3-month follow-up. Reference Lindsay M Bearne, Brittannia Volkmer, Janet Peacock et al. Effect of a Home-Based, Walking Exercise Behavior Change Intervention vs Usual Care on Walking in Adults With Peripheral Artery Disease: The MOSAIC Randomized Clinical Trial. JAMA. 2022 Apr 12;327(14):1344-1355. Open reference URL https://web.pathway.md/studies/recCa4SgjWCCT2vda 2/2

6/28/23, 11:19 PM MOVe-OUT Pathway Feedback Search Clinical Topics Home Studies MOVe-OUT MOVe-OUT Disease COVID 19 infection Trial question What is the role of early treatment with molnupiravir in unvaccinated adults with COVID-19? Study design Multi-center Double blinded RCT Population Characteristics of study participants 51.0% female N = 1408 49.0% male 1408 patients (723 female, 685 male) Inclusion criteria: nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory- confirmed COVID-19 and at least one risk factor for severe COVID-19 illness Key exclusion criteria: anticipated need for hospitalization for COVID-19 within 48 hours, dialysis, pregnancy, severe neutropenia, platelet count < 100,000/mL Interventions N=709 molnupiravir (800 mg administered PO BID for 5 days) N=699 placebo (matching placebo administered PO BID for 5 days) Primary outcome Hospitalization or death at day 29 https://web.pathway.md/studies/recfO864QbVD5msRp 1/2 6/28/23, 11:19 PM MOVe-OUT Pathway 9.7 % 9.7 7.3 % 6.8 4.8 % Significant decrease 2.4 % NNT = 34 0.0 % Molnupiravir Placebo Significant decrease in hospitalization or death at day 29 (6.8% vs. 9.7%; ARD -3, 95% CI -5.9 to -0.1) Secondary outcomes Significant decrease in hospitalization or death at day 29, interim analysis (7.3% vs. 14.1%; ARD -6.8, 95% CI -11.3 to -2.4) Borderline significant decrease in death from all causes at day 29 (0.1% vs. 1.3%; RR 0.11, 95% CI 0.01 to 0.86) Borderline significant decrease in COVID-19 related hospitalization or death at day 29 (6.3% vs. 9.2%; ARD -2.8, 95% CI -5.7 to 0) Safety outcomes No significant difference in adverse events. Conclusion In nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed COVID-19 and at least one risk factor for severe COVID-19 illness, molnupiravir was superior to placebo with respect to hospitalization or death at day 29. Reference Ang lica Jayk Bernal, Monica M Gomes da Silva, Dany B Musungaie et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022 Feb 10;386(6):509-520. Open reference URL https://web.pathway.md/studies/recfO864QbVD5msRp 2/2

6/28/23, 11:19 PM MPACT Pathway Feedback Search Clinical Topics Home Studies MPACT MPACT Disease Pancreatic cancer Trial question What is the role of nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 42.0% female N = 861 58.0% male 861 patients (359 female, 502 male) Inclusion criteria: patients who had metastatic pancreatic disease with a Karnofsky performance status score 70 Key exclusion criteria: receipt of cytotoxic doses of gemcitabine or any other chemotherapy in the adjuvant setting, islet-cell neoplasms or locally advanced disease Interventions N=431 nab-paclitaxel plus gemcitabine (nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1,000 mg per square meter) on days 1, 8, and 15 every 4 weeks) N=430 gemcitabine monotherapy (1,000 mg per square meter weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles)) https://web.pathway.md/studies/recrKKROCZfx4sK0d 1/2 6/28/23, 11:19 PM MPACT Pathway Primary outcome Median overall survival 8.5 months 8.5 6.7 6.4 months 4.3 months 2.1 months Significant increase 0.0 months Nab-paclitaxel plus gemcitabine Gemcitabine monotherapy Significant increase in median overall survival (8.5 months vs. 6.7 months; HR 1.38, 95% CI 1.2 to 1.61) Secondary outcomes Significant increase in median progression-free survival (5.5 months vs. 3.7 months; HR 1.44, 95% CI 1.22 to 1.72) Significant increase in response (23% vs. 7%; RR 3.19, 95% CI 2.18 to 4.66) Significant increase in rate of disease control (48% vs. 33%; RR 1.46, 95% CI 1.23 to 1.72) Safety outcomes No significant differences in anemia, thrombocytopenia, febrile neutropenia. Significant differences in adverse events grade 3, including neutropenia (38% vs. 27%), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Conclusion In patients who had metastatic pancreatic disease with a Karnofsky performance status score 70, nab-paclitaxel plus gemcitabine was superior to gemcitabine monotherapy with respect to median overall survival. Reference Von Hoff DD, Ervin T, Arena FP et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. Open reference URL https://web.pathway.md/studies/recrKKROCZfx4sK0d 2/2

6/28/23, 11:19 PM MR CLEAN Pathway Feedback Search Clinical Topics Home Studies MR CLEAN MR CLEAN Disease Acute ischemic stroke Trial question What is the role of intraarterial treatment in patients with acute ischemic stroke? Study design Multi-center Open label RCT Population Characteristics of study participants 42.0% female N = 500 58.0% male 500 patients (208 female, 292 male) Inclusion criteria: patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation Key exclusion criteria: arterial BP > 185/110 mmHg, blood glucose < 2.7 or > 22.2 mmol/L, intravenous treatment with thrombolytic therapy Interventions N=233 intervention (intraarterial treatment within 6h of symptom onset with intraarterial thrombolysis, mechanical treatment, or both plus usual care with intravenous administration of alteplase) N=267 control (usual care alone with intravenous administration of alteplase) https://web.pathway.md/studies/rece8y0gwK1P5K5rs 1/2 6/28/23, 11:19 PM MR CLEAN Pathway Primary outcome Modified Rankin Scale scores at 90 days 4.0 4 3.0 3 2.0 1.0 Borderline significant increase 0.0 Intervention Control Borderline significant increase in mRS scores at 90 days (3 vs. 4; aOR 1.67, 95% CI 1.21 to 2.3) Secondary outcomes Borderline significant increase in mRS score of 0-2 at 90 days (32.6% vs. 19.1%; aOR 2.16, 95% CI 1.39 to 3.38) Borderline significant increase in Barthel index of 19 or 20 at day 90 (46% vs. 29.8%; aOR 2.1, 95% CI 1.4 to 3.2) Borderline significant increase in no intracranial occlusion on follow-up CT angiography (75.4% vs. 32.9%; aOR 6.88, 95% CI 4.34 to 10.94) Safety outcomes No significant difference in mortality or the occurrence of symptomatic intracerebral hemorrhage. Significant difference in clinical signs of new ischemic stroke in a different vascular territory (5.6% vs. 0.4%). Conclusion In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intervention was superior to control with respect to mRS scores at 90 days. Reference Berkhemer OA, Fransen PS, Beumer D et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015 Jan 1;372(1):11-20. Open reference URL https://web.pathway.md/studies/rece8y0gwK1P5K5rs 2/2

6/28/23, 11:19 PM MR RESCUE Pathway Feedback Search Clinical Topics Home Studies MR RESCUE MR RESCUE Disease Acute ischemic stroke Trial question What is the role of endovascular thrombectomy in patients with acute ischemic stroke? Study design Multi-center Open label RCT Population Characteristics of study participants 52.0% female N = 118 48.0% male 118 patients (61 female, 57 male) Inclusion criteria: patients within 8 hours after the onset of large-vessel, anterior-circulation strokes Key exclusion criteria: acute intracranial hemorrhage, coma, NIHSS 30, rapidly improving neurological signs, pregnancy, pre-existing medical, neurological or psychiatric disease, or contraindication to MRI Interventions N=64 mechanical embolectomy (within 8 hours after the onset of symptoms, with Merci Retriever or Penumbra System) N=54 standard care (conforming with AHA/American Stroke Association guidelines) https://web.pathway.md/studies/rectQUYWfPQIb4S9R 1/2 6/28/23, 11:19 PM MR RESCUE Pathway Primary outcome Modified Rankin Scale score, with a favorable penumbral pattern 3.9 3.9 3.4 2.9 1.9 1.0 No significant difference 0.0 Mechanical embolectomy Standard care No significant difference in mRS score, with a favorable penumbral pattern (3.9 vs. 3.4; AD 0.5, 95% CI -0.31 to 1.31) Secondary outcomes No significant difference in mRS score, with a nonpenumbral pattern (4 vs. 4.4; AD -0.4, 95% CI -1.18 to 0.38) Safety outcomes No significant difference in death from all causes at 90 days or hemorrhage. Conclusion In patients within 8 hours after the onset of large-vessel, anterior-circulation strokes, mechanical embolectomy was not superior to standard care with respect to mRS score, with a favorable penumbral pattern. Reference Kidwell CS, Jahan R, Gornbein J et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013 Mar 7;368(10):914-23. Open reference URL https://web.pathway.md/studies/rectQUYWfPQIb4S9R 2/2

6/28/23, 11:19 PM MSH Pathway Feedback Search Clinical Topics Home Studies MSH MSH Disease Sickle cell disease Trial question What is the role of hydroxyurea in adult patients with sickle cell anemia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 51.0% female N = 299 49.0% male 299 patients (151 female, 148 male) Inclusion criteria: adult patients with sickle cell anemia Key exclusion criteria: sickle cell-beta+-thalassemia and sickle cell- -thalassemia, pregnancy, narcotic addiction or regular consumption of > 30 oxycodone capsules (or the equivalent) every two weeks; indication of marrow depression; or prior hydroxyurea therapy; Interventions N=152 hydroxyurea (initial dose of 15 mg/kg body weight and adjusted according to marrow depression, platelet count, and Hgb level) N=147 placebo (Starch 1500, with the same adjustments of the dose) Primary outcome https://web.pathway.md/studies/recgPETAFbH3EUNoH 1/2 6/28/23, 11:19 PM MSH Pathway Painful crises 4.5 % 4.5 3.4 % 2.5 2.3 % Significant decrease 1.1 % NNT = 50 0.0 % Hydroxyurea Placebo Significant decrease in painful crises (2.5% vs. 4.5%; RR 0.56, 95% CI 0.23 to 0.89) Secondary outcomes Significant decrease in chest syndrome (25 vs. 51; RR 0.49, 95% CI 0.2 to 0.78) Significant decrease in underwent transfusions (48 vs. 73; RR 0.66, 95% CI 0.27 to 1.05) Conclusion In adult patients with sickle cell anemia, hydroxyurea was superior to placebo with respect to painful crises. Reference Charache S, Terrin ML, Moore RD et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995 May 18;332(20):1317-22. Open reference URL https://web.pathway.md/studies/recgPETAFbH3EUNoH 2/2

6/28/23, 11:19 PM MUST Pathway Feedback Search Clinical Topics Home Studies MUST MUST Disease Psoriatic arthritis Trial question Is ustekinumab monotherapy noninferior to ustekinumab plus methotrexate in patients with active psoriatic arthritis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 42.0% female N = 166 58.0% male 166 patients (69 female, 97 male) Inclusion criteria: adult patients with active psoriatic arthritis Key exclusion criteria: previous use of ustekinumab or any other anti-IL-23 agent; inadequate response to prior methotrexate treatment for psoriatic arthritis; previous B-cell depleting therapy; active tuberculosis Interventions N=79 ustekinumab monotherapy (open-label ustekinumab over a treatment period of 52 weeks plus methotrexate placebo 3 capsules once weekly) N=87 ustekinumab combination therapy (open-label ustekinumab over a treatment period of 52 weeks plus methotrexate 15 mg once weekly, 3 capsules) https://web.pathway.md/studies/rechktv2VQOP9AEHA 1/2 6/28/23, 11:19 PM MUST Pathway Primary outcome Mean disease activity score-28 at week 24 3.1 3.1 2.9 2.3 1.6 Difference not exceeding nonferiority margin 0.8 0.0 Ustekinumab monotherapy Ustekinumab combination therapy Difference not exceeding nonferiority margin in mean disease activity score-28 at week 24 (2.9 vs. 3.1; AD -0.2, 95% CI -0.61 to 0.21) Secondary outcomes No significant difference in mean disease activity score-28 at week 52 (2.8 vs. 3.1; AD -0.3, 95% CI -0.6 to 0) No significant difference in disease activity score-28 remission at week 28 (46% vs. 44%; AD 2%, 95% CI -16.15 to 20.15) Safety outcomes No significant difference in serious adverse events. Conclusion In adult patients with active psoriatic arthritis, ustekinumab monotherapy was noninferior to ustekinumab combination therapy with respect to mean disease activity score-28 at week 24. Reference Michaela Koehm, Tanja Rossmanith, Ann C Foldenauer et al. Methotrexate plus ustekinumab versus ustekinumab monotherapy in patients with active psoriatic arthritis (MUST): a randomised, multicentre, placebo-controlled, phase 3b, non-inferiority trial. Lancet Rheumatol. 2023 Jan;3(1):E14-E23. Open reference URL https://web.pathway.md/studies/rechktv2VQOP9AEHA 2/2

6/28/23, 11:19 PM MUSTT Pathway Feedback Search Clinical Topics Home Studies MUSTT MUSTT Disease Ventricular arrhythmias Trial question Is antiarrhythmic therapy superior to no antiarrhythmic therapy in patients with coronary artery disease, a LVEF of 40%, and asymptomatic, unsustained VT in whom sustained ventricular tachyarrhythmias were induced by programmed stimulation? Study design Multi-center Single blinded RCT Population Characteristics of study participants 10.0% female N = 704 90.0% male 704 patients (70 female, 634 male) Inclusion criteria: patients with coronary artery disease, an LVEF of 40%, and asymptomatic, unsustained VT in whom sustained ventricular tachyarrhythmias were induced by programmed stimuation Key exclusion criteria: history of syncope, or sustained VT or fibrillation > 48 hours after the onset of acute myocardial infarction; systemic disease likely to be fatal in < 2 years; and 80 years of age Interventions https://web.pathway.md/studies/recCG76B5pLwWrnHB 1/2 6/28/23, 11:19 PM MUSTT Pathway N=351 antiarrhythmic therapy (drugs and implantable defibrillators, as indicated by the results of electrophysiologic testing) N=353 no antiarrhythmic therapy (electrophysiologic testing without antiarrhythmic therapy) Primary outcome Cardiac arrest or death from arrhythmia 32.0 % 32 25 24.0 % 16.0 % Significant decrease 8.0 % NNT = 14 0.0 % Antiarrhythmic therapy No antiarrhythmic therapy Significant decrease in cardiac arrest or death from arrhythmia (25% vs. 32%; RR 0.73, 95% CI 0.53 to 0.99) Secondary outcomes No significant difference in death at 5 years (42% vs. 48%; RR 0.8, 95% CI 0.64 to 1.01) Significant decrease in cardiac arrest or death from arrhythmia (12 vs. 56; RR 0.24, 95% CI 0.13 to 0.45) Conclusion In patients with coronary artery disease, an LVEF of 40%, and asymptomatic, unsustained VT in whom sustained ventricular tachyarrhythmias were induced by programmed stimuation, antiarrhythmic therapy was superior to no antiarrhythmic therapy with respect to cardiac arrest or death from arrhythmia. Reference Buxton AE, Lee KL, Fisher JD et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med. 1999 Dec 16;341(25):1882-90. Open reference URL https://web.pathway.md/studies/recCG76B5pLwWrnHB 2/2

6/28/23, 11:22 PM NAC prevention of PGF and PT Pathway Feedback Search Clinical Topics Home Studies NAC prevention of PGF and PT NAC prevention of PGF and PT Disease Disease Acute myeloid leukemia Acute promyelocytic leukemia Trial question What is the role of N-acetyl-L-cysteine prophylaxis in patients with allogeneic HSCT? Study design Single center Open label RCT Population Characteristics of study participants 43.0% female N = 120 57.0% male 120 patients (52 female, 68 male) Inclusion criteria: high-risk patients with acute leukemia undergoing haploidentical HSCT Key exclusion criteria: hypersensitivity to N-acetyl-L-cysteine; bronchial asthma; ejection fraction < 50%, creatinine 1.5 times the ULN; TBIL or aminotransferase 2 times the ULN Interventions N=80 N-acetyl-L-cysteine prophylaxis (400 mg TID from 14 days pre-HSCT to after 2 months) N=40 nonprophylaxis (no N-acetyl-L-cysteine prophylaxis) Primary outcome Poor graft function and prolonged isolated thrombocytopenia at 60 days 22.5 % 22.5 https://web.pathway.md/studies/rec04C3PIOedSxDag 1/2 6/28/23, 11:22 PM NAC prevention of PGF and PT Pathway 5 16.9 % 11.3 % Significant decrease 7.5 5.6 % NNT = 7 0.0 % N-acetyl-L-cysteine prophylaxis Nonprophylaxis Significant decrease in poor graft function and prolonged isolated thrombocytopenia at 60 days (7.5% vs. 22.5%; HR 0.317, 95% CI 0.11 to 0.89) Safety outcomes No significant differences in infections, gastrointestinal adverse events. Conclusion In high-risk patients with acute leukemia undergoing haploidentical HSCT, N-acetyl-L-cysteine prophylaxis were superior to nonprophylaxis with respect to poor graft function and prolonged isolated thrombocytopenia at 60 days. Reference Yu Wang, Yuan Kong, Hong-Yan Zhao et al. Prophylactic NAC promoted hematopoietic reconstitution by improving endothelial cells after haploidentical HSCT: a phase 3, open-label randomized trial. BMC Med. 2022 Apr 27;20(1):140. Open reference URL https://web.pathway.md/studies/rec04C3PIOedSxDag 2/2

6/28/23, 11:22 PM NASCET Pathway Feedback Search Clinical Topics Home Studies NASCET NASCET Disease Disease Disease Acute ischemic stroke Carotid artery stenosis Transient Trial question Is carotid endarterectomy superior to medical care alone in patients with moderate carotid stenosis and TIAs or nondisabling strokes ipsilateral to the stenosis (within 180 days)? Study design Multi-center Open label RCT Population Characteristics of study participants 29.6% female N = 2267 70.4% male 2267 patients (668 female, 1558 male) Inclusion criteria: patients with moderate carotid stenosis and TIAs or nondisabling strokes ipsilateral to the stenosis (within 180 days) Key exclusion criteria: lack of angiographic visualization of the symptomatic artery, nonatherosclerotic carotid disease, cardiac lesions likely to cause cardioembolism, or a history of ipsilateral endarterectomy Interventions N=1108 surgical therapy (carotid endarterectomy plus medical treatment) N=1118 medical therapy (medical care alone with antiplatelet medications, antihypertensives and antilipidemics as indicated) https://web.pathway.md/studies/recNSHWdOhMO60CJB 1/2 6/28/23, 11:22 PM NASCET Pathway Primary outcome Any ipsilateral stroke at 5 years, in patients with stenosis of 50-69% 22.2 % 22.2 16.6 % 15.7 11.1 % Significant decrease 5.5 % NNT = 15 0.0 % Surgical therapy Medical therapy Significant decrease in any ipsilateral stroke at 5 years, in patients with stenosis of 50-69% (15.7% vs. 22.2%; RR 0.7, 95% CI 0.48 to 0.93) Secondary outcomes No significant difference in any ipsilateral stroke at 5 years, in patients with < 50% stenosis (14.9% vs. 18.7%; RR 0.8, 95% CI -0.31 to 1.91) Conclusion In patients with moderate carotid stenosis and TIAs or nondisabling strokes ipsilateral to the stenosis (within 180 days), surgical therapy was superior to medical therapy with respect to any ipsilateral stroke at 5 years, in patients with stenosis of 50-69%. Reference Barnett HJ, Taylor DW, Eliasziw M et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med. 1998 Nov 12;339(20):1415-25. Open reference URL https://web.pathway.md/studies/recNSHWdOhMO60CJB 2/2

6/28/23, 11:22 PM NAVIGATE Pathway Feedback Search Clinical Topics Home Studies NAVIGATE NAVIGATE Disease Acute ischemic stroke Trial question What is the role of rivaroxaban in secondary stroke prevention in patients with embolic stroke of undetermined source? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.4% female N = 7213 61.6% male 7213 patients (2777 female, 4432 male) Inclusion criteria: patients with embolic stroke of undetermined source; with patent foramen ovale and without PFO Key exclusion criteria: a history of AF, severely disabling stroke, the presence of or plan to insert an implantable ECG loop recorder, specific indication for chronic anticoagulation or for chronic antiplatelet therapy, or previous non-traumatic intracranial hemorrhage Interventions N=3609 rivaroxaban (15 mg tablet plus placebo-aspirin once daily) N=3604 aspirin (at a dose of 100 mg tablet plus placebo-rivaroxaban once daily) https://web.pathway.md/studies/recSD6Rqxi7X3PQ4y 1/2 6/28/23, 11:22 PM NAVIGATE Pathway Primary outcome Incidence of recurrent ischemic stroke in patients with patent foramen ovale 4.8/100 py 4.8 3.6/100 py 2.6 2.4/100 py 1.2/100 py No significant difference 0.0/100 py Rivaroxaban Aspirin No significant difference in the incidence of recurrent ischemic stroke in patients with patent foramen ovale (2.6 /100 py vs. 4.8 /100 py; HR 0.54, 95% CI 0.22 to 1.36) Secondary outcomes No significant difference in the incidence of recurrent ischemic stroke in patients without PFO (4.9 /100 py vs. 4.6 /100 py; HR 1.06, 95% CI 0.84 to 1.33) Safety outcomes No significant differences in risks of major bleeding in patients with PFO (HR 2.05, 95% CI 0.51- 8.18) and without PFO (HR 2.82, 95% CI 1.69-4.70; p interaction=0.68). Conclusion In patients with embolic stroke of undetermined source; with patent foramen ovale and without PFO, rivaroxaban was not superior to aspirin with respect to the incidence of recurrent ischemic stroke in patients with patent foramen ovale. Reference Kasner SE, Swaminathan B, Lavados P et al. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial. Lancet Neurol. 2018 Dec;17(12):1053-1060. Open reference URL https://web.pathway.md/studies/recSD6Rqxi7X3PQ4y 2/2

6/28/23, 11:22 PM NEAT-HFpEF Pathway Feedback Search Clinical Topics Home Studies NEAT HFpEF NEAT HFpEF Disease Heart failure Trial question What is the role of isosorbide mononitrate in patients with HF and a preserved ejection fraction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 57.0% female N = 110 43.0% male 110 patients (63 female, 47 male) Inclusion criteria: patients with HF and a preserved ejection fraction Key exclusion criteria: systolic BP < 110 mmHg or > 180 mmHg or a previous adverse reaction to or current use of long-term nitrate or phosphodiesterase type 5 inhibitor therapy Interventions N=51 isosorbide mononitrate (6-week dose escalation from 30 mg to 60 mg to 120 mg once daily) N=59 placebo (matching placebo once daily for 6 weeks) Primary outcome Hours of activity per day 9.31 9 3 9 01 https://web.pathway.md/studies/recQbl34lh5Ir5EkI 1/2 6/28/23, 11:22 PM NEAT-HFpEF Pathway 9 3 9.3 9.01 7.0 4.7 2.3 Significant decrease 0.0 Isosorbide mononitrate Placebo Significant decrease in hours of activity per day (9.01 vs. 9.31; difference -30, 95% CI -0.55 to -0.05) Secondary outcomes Significant decrease in activity during all dose regimens (9185 vs. 9623; difference -439, 95% CI -792 to -86) Conclusion In patients with HF and a preserved ejection fraction, isosorbide mononitrate was not superior to placebo with respect to hours of activity per day. Reference Redfield MM, Anstrom KJ, Levine JA et al. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2015 Dec 10;373(24):2314-24. Open reference URL https://web.pathway.md/studies/recQbl34lh5Ir5EkI 2/2

6/28/23, 11:22 PM NETT Pathway Feedback Search Clinical Topics Home Studies NETT NETT Disease Chronic obstructive pulmonary Trial question What is the role of lung volume-reduction surgery in patients with severe emphysema? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 1218 61.0% male 1218 patients (472 female, 746 male) Inclusion criteria: patients with severe emphysema who underwent pulmonary rehabilitation Key exclusion criteria: high risk for perioperative morbidity or mortality; disease unsuitable for lung volume reduction surgery; and medical conditions precluding the completion of trial Interventions N=608 lung volume-reduction surgery (goal to resect 20-35% of each lung, targeting the most diseased portion plus medical treatment) N=610 medical therapy (continued medical treatment without surgery) Primary outcome Improvement in exercise capacity at 24 months https://web.pathway.md/studies/reckTXBwBTHbAMZD2 1/2 6/28/23, 11:22 PM NETT Pathway 15.0 % 15 11.3 % 7.5 % Significant increase 3.8 % NNT = 8 3 0.0 % Lung volume-reduction surgery Medical therapy Significant increase in improvement in exercise capacity at 24 months (15% vs. 3%; OR 6.27, 95% CI 2.55 to 9.99) Secondary outcomes Significant increase in improvement in health-related quality of life (33% vs. 9%; OR 4.9, 95% CI 1.99 to 7.81) Significant increase in death at day 90 (7.9% vs. 1.3%; AD 6.6%, 95% CI 2.68 to 10.52) No significant difference in total deaths (25.8% vs. 26.2%; AD -0.4%, 95% CI -6.16 to 5.36) Conclusion In patients with severe emphysema who underwent pulmonary rehabilitation, lung volume-reduction surgery was superior to medical therapy with respect to improvement in exercise capacity at 24 months. Reference Fishman A, Martinez F, Naunheim K et al. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003 May 22;348(21):2059-73. Open reference URL https://web.pathway.md/studies/reckTXBwBTHbAMZD2 2/2

6/28/23, 11:22 PM NICE-SUGAR Pathway Feedback Search Clinical Topics Home Studies NICE SUGAR NICE SUGAR Disease In-hospital hyperglycemia Trial question What is the role of intensive glucose control in critically ill patients? Study design Multi-center Open label RCT Population Characteristics of study participants 36.4% female N = 6104 63.6% male 6104 patients (2207 female, 3823 male) Inclusion criteria: adult medical and surgical patients admitted to the ICU who were expected to require treatment in the ICU on 3 consecutive days Key exclusion criteria: age < 18 years, imminent death (cardiac standstill or brain death anticipated within 24 hours), ICU admission for treatment of diabetic ketoacidosis or hyperosmolar state, previous hypoglycemia without full neurological recovery, or at high risk of hypoglycemia Interventions N=3054 intensive glucose control (with a target blood glucose range of 81-108 mg/dL) N=3050 conventional glucose control (with a target of 180 mg/dL) Primary outcome https://web.pathway.md/studies/recMRdVfWm69jC8Xx 1/2 6/28/23, 11:22 PM NICE-SUGAR Pathway Death from all causes at day 90 27.5 % 27.5 24.9 20.6 % 13.8 % Significant increase 6.9 % NNH = 38 0.0 % Intensive glucose control Conventional glucose control Significant increase in death from all causes at day 90 (27.5% vs. 24.9%; OR 1.14, 95% CI 1.02 to 1.28) Secondary outcomes No significant difference in RRT (15.4% vs. 14.5%; AD 0.9%, 95% CI -9 to 2.7) No significant difference in death at day 28 (22.3% vs. 20.8%; OR 1.09, 95% CI 0.96 to 1.23) Safety outcomes Significant difference in severe hypoglycemia (6.8% vs. 0.5%). Conclusion In adult medical and surgical patients admitted to the ICU who were expected to require treatment in the ICU on 3 consecutive days, intensive glucose control was inferior to conventional glucose control with respect to death from all causes at day 90. Reference NICE-SUGAR Study Investigators, Finfer S, Chittock DR et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97. Open reference URL https://web.pathway.md/studies/recMRdVfWm69jC8Xx 2/2

6/28/23, 11:22 PM NICOVID-REA Pathway Feedback Search Clinical Topics Home Studies NICOVID REA NICOVID REA Disease COVID 19 infection Trial question What is the role of nicotine patches in patients on mechanical ventilation for severe COVID-19 pneumonia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 30.0% female N = 218 70.0% male 218 patients (66 female, 152 male) Inclusion criteria: adult patients who were non-smokers, non-vapers with proven COVID-19 pneumonia receiving invasive mechanical ventilation for < 72 hours Key exclusion criteria: age < 18 years; pregnancy; anticipated duration of mechanical ventilation 48 hours; moribund; malignancy or severe disease with life expectancy < 1 year Interventions N=106 nicotine (transdermal patches at a daily dose of 14 mg until 48 hours following successful weaning from mechanical ventilation or for a maximum of 30 days, followed by a 3-week dose tapering by 3.5 mg/week) N=112 placebo (matching placebo) https://web.pathway.md/studies/reczgpUaXDrMGGwbN 1/2 6/28/23, 11:22 PM NICOVID-REA Pathway Primary outcome Death at day 28 28.0 % 28 28 21.0 % 14.0 % 7.0 % No significant difference 0.0 % Nicotine Placebo No significant difference in death at day 28 (28% vs. 28%; OR 1.03, 95% CI 0.57 to 1.87) Secondary outcomes No significant difference in death at day 60 (38% vs. 37%; OR 1.09, 95% CI 0.62 to 1.9) No significant difference in length of stay in the ICU (17 days vs. 21 days; AD -4 days, 95% CI -8 to 2) Safety outcomes No significant difference in adverse events. Conclusion In adult patients who were non-smokers, non-vapers with proven COVID-19 pneumonia receiving invasive mechanical ventilation for < 72 hours, nicotine was not superior to placebo with respect to death at day 28. Reference Guylaine Labro, Florence Tubach, Lisa Belin et al. Nicotine patches in patients on mechanical ventilation for severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial. Intensive Care Med. 2022 Jun 9;1-12. Open reference URL https://web.pathway.md/studies/reczgpUaXDrMGGwbN 2/2

6/28/23, 11:22 PM NINDS Pathway Feedback Search Clinical Topics Home Studies NINDS NINDS Disease Acute ischemic stroke Trial question What is the role of tPA in patients with ischemic stroke? Study design Multi-center Double blinded RCT Population Characteristics of study participants 42.0% female N = 624 58.0% male 624 patients (260 female, 364 male) Inclusion criteria: patients with ischemic stroke Key exclusion criteria: receipt of anticoagulants or heparin within the 48 hours preceding the onset of stroke, PTs > 15 seconds, platelet counts < 100,000/mm , or glucose concentrations < 50 mg/dL or > 400 mg/dL Interventions N=312 tPA (alteplase at a dose of 0.9 mg/kg of body weight, maximum 90 mg) N=312 placebo (matching placebo) Primary outcome Death at 90 days https://web.pathway.md/studies/recrgZrUrrnKm83sH 1/2 6/28/23, 11:22 PM NINDS Pathway 21.0 % 21 17 15.8 % 10.5 % 5.3 % No significant difference 0.0 % Tissue plasminogen activator Placebo No significant difference in death at 90 days (17% vs. 21%; RR 0.81, 95% CI -0.71 to 2.33) Safety outcomes Significant differences in symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke (6.4% vs. 0.6%, p < 0.001). Conclusion In patients with ischemic stroke, tPA was superior to placebo with respect to death at 90 days. Reference National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995 Dec 14;333(24):1581-7. Open reference URL https://web.pathway.md/studies/recrgZrUrrnKm83sH 2/2

6/28/23, 11:22 PM Nishikimi Pathway Feedback Search Clinical Topics Home Studies Nishikimi Nishikimi Trial question What is the effect of ramelteon, a melatonin agonist, among critically ill patients in the ICU? Study design Single center Double blinded RCT Population Characteristics of study participants 35.0% female N = 88 65.0% male 88 patients (31 female, 57 male) Inclusion criteria: patients in the ICU who could take medicines PO or through a nasogastric tube during the first 48 hours of admission Key exclusion criteria: already in receipt of ramelteon or fluvoxamine maleate prior to the admission, known allergy to ramelteon, refusal to provide consent for participation in the study Interventions N=45 ramelteon (8 mg/day at 20:00 hours every day until discharge from the ICU) N=43 placebo (1 g/day of lactose powder at 20:00 hours every day until discharge from the ICU) Primary outcome Duration of intensive care unit stay 5.9 days 5.86 4.56 4.4 days 2.9 days 1.5 days Significant decrease https://web.pathway.md/studies/recRp0GetpPY9oBtU 1/2 6/28/23, 11:22 PM Nishikimi Pathway 0.0 days Ramelteon Placebo Significant decrease in duration of ICU stay (4.56 days vs. 5.86 days; AD -1.3 days, 95% CI -2.46 to -0.14) Secondary outcomes Significant increase in occurrence rate of delirium (24.4% vs. 46.5%; OR 2.69, 95% CI 1.09 to 6.65) Significant decrease in duration of delirium (0.78 days vs. 1.4 days; AD -0.62 days, 95% CI -1.24 to 0) No significant difference in death at discharge (6.7% vs. 7.5%; RR 0.89, 95% CI -1273.77 to 1275.55) Safety outcomes No significant difference in mean hours of sleep. Significant differences in awakenings per night (0.80 times per night vs. 1.31 times per night), nights without awakenings (51% vs. 30%). Conclusion In patients in the ICU who could take medicines PO or through a nasogastric tube during the first 48 hours of admission, ramelteon was superior to placebo with respect to duration of ICU stay. Reference Mitsuaki Nishikimi, Atsushi Numaguchi, Kunihiko Takahashi et al. Effect of Administration of Ramelteon, a Melatonin Receptor Agonist, on the Duration of Stay in the ICU: A Single-Center Randomized Placebo-Controlled Trial. Crit Care Med. 2018 Jul;46(7):1099-1105. Open reference URL https://web.pathway.md/studies/recRp0GetpPY9oBtU 2/2

6/28/23, 11:22 PM Nitrofurantoin vs. fosfomycin in UTI Pathway Feedback Search Clinical Topics Home Studies Nitrofurantoin vs. fosfomycin in UTI Nitrofurantoin vs. fosfomycin in UTI Disease Disease Acute cystitis Acute pyelonephritis Trial question What is the effect of 5-day nitrofurantoin in female patients with uncomplicated UTI? Study design Multi-center Open label RCT Population 513 female patients Inclusion criteria: female patients with uncomplicated UTI Key exclusion criteria: pregnancy and lactation, suspected upper UTI, antibiotic use or any symptoms consistent with UTI in the preceding 4 weeks, indwelling catheter, immunosuppression, ongoing chemotherapy or radiation therapy Interventions N=255 oral nitrofurantoin (100 mg PO TID for 5 days) N=258 oral fosfomycin (single 3 g oral dose) Primary outcome Clinical resolution at 28 days after therapy completion 70.0 % 70 58 52.5 % 35.0 % Significant increase 17.5 % NNH = 8 0.0 % https://web.pathway.md/studies/reclvcrMFLsfzg2UC 1/2 6/28/23, 11:22 PM Nitrofurantoin vs. fosfomycin in UTI Pathway Oral nitrofurantoin Oral fosfomycin Significant increase in clinical resolution at 28 days after therapy completion (70% vs. 58%; ARD 12, 95% CI 4 to 21) Secondary outcomes Significant increase in microbiologic resolution (74% vs. 63%; ARD 11, 95% CI 1 to 20) Significant increase in clinical response at 14 days (75% vs. 66%; ARR 9, 95% CI 1 to 17) Safety outcomes No significant differences in adverse events, including nausea (3% vs. 2%) and diarrhea (1% vs. 1%). Conclusion In female patients with uncomplicated UTI, oral nitrofurantoin was superior to oral fosfomycin with respect to clinical resolution at 28 days after therapy completion. Reference Huttner A, Kowalczyk A, Turjeman A et al. Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial. JAMA. 2018 May 1;319(17):1781-1789. Open reference URL https://web.pathway.md/studies/reclvcrMFLsfzg2UC 2/2

6/28/23, 11:22 PM NIV in COPD with chronic hypercapnia Pathway Feedback Search Clinical Topics Home Studies NIV in COPD with chronic hypercapnia NIV in COPD with chronic hypercapnia Disease Disease Chronic obstructive pulmonary Dyspnea in palliative care Trial question What is the effect of home noninvasive ventilation plus oxygen therapy in patients with persistent hypercapnia after an acute COPD exacerbation? Study design Multi-center Open label RCT Population Characteristics of study participants 53.0% female N = 116 47.0% male 116 patients (61 female, 55 male) Inclusion criteria: patients with persistent hypercapnia (arterial partial pressure of CO2 > 53 mmHg) who had an acute COPD exacerbation Key exclusion criteria: obesity (BMI > 35), obstructive sleep apnea syndrome, or other causes of respiratory failure Interventions N=57 home noninvasive ventilation plus oxygen therapy (ventilator setting are inspiratory positive airway pressure of 24 cmH O, an EPAP of 4 cmH O, and a backup rate of 14 breaths/minute plus median oxygen flow rate of 1.0 L/min) N=59 home oxygen therapy alone (median oxygen flow rate, 1.0 L/min) https://web.pathway.md/studies/recLh4IxpvcVeFQoN 1/2 6/28/23, 11:22 PM NIV in COPD with chronic hypercapnia Pathway Primary outcome Readmission or death at 12 months 80.4 % 80.4 63.4 60.3 % 40.2 % 20.1 % No significant difference 0.0 % Home noninvasive ventilation plus oxygen therapy Home oxygen therapy alone No significant difference in readmission or death at 12 months (63.4% vs. 80.4%; ARR 17, 95% CI 0.1 to 34) Conclusion In patients with persistent hypercapnia (arterial partial pressure of CO2 > 53 mmHg) who had an acute COPD exacerbation, home noninvasive ventilation plus oxygen therapy was superior to home oxygen therapy alone with respect to readmission or death at 12 months. Reference Murphy PB, Rehal S, Arbane G et al. Effect of Home Noninvasive Ventilation With Oxygen Therapy vs Oxygen Therapy Alone on Hospital Readmission or Death After an Acute COPD Exacerbation: A Randomized Clinical Trial. JAMA. 2017 Jun 6;317(21):2177-2186. Open reference URL https://web.pathway.md/studies/recLh4IxpvcVeFQoN 2/2

6/28/23, 11:22 PM NIVAS Pathway Feedback Search Clinical Topics Home Studies NIVAS NIVAS Disease Noninvasive ventilation Reference Jaber S, Lescot T, Futier E et al. Effect of Noninvasive Ventilation on Tracheal Reintubation Among Patients With Hypoxemic Respiratory Failure Following Abdominal Surgery: A Randomized Clinical Trial. JAMA. 2016 Apr 5;315(13):1345-53. Open reference URL https://web.pathway.md/studies/recTMI6AjdQmYk6Qw 1/1

6/28/23, 11:22 PM NLST Pathway Feedback Search Clinical Topics Home Studies NLST NLST Disease Disease Non-small cell lung cancer Small cell lung cancer Trial question What is the role of low-dose computed tomographic screening in patients who are at high risk for lung cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 53454 59.0% male 53454 patients (21922 female, 31532 male) Inclusion criteria: patients who are at high risk for lung cancer Key exclusion criteria: previous diagnosis of lung cancer, chest CT within 18 months before enrollment, hemoptysis, or unexplained weight loss > 6.8 kg in the preceding year Interventions N=26722 screening using low-dose CT (use of multidetector scanners with a minimum of four channels, at an average effective dose of 1.5 mSv) N=26732 screening using CXRs (single-view posteroanterior chest radiography at an average effective dose of 8 mSv) https://web.pathway.md/studies/recmpSAUOL19xwZrN 1/2 6/28/23, 11:22 PM NLST Pathway Primary outcome Death from any cause 0.1 % 0.08 0.07 0.1 % 0.0 % Significant decrease 0.0 % NNT = 10000 0.0 % Screening using low-dose CT Screening using chest X-rays Significant decrease in death from any cause (0.07% vs. 0.08%; RR 0.93, 95% CI 0.86 to 0.99) Secondary outcomes Significant decrease in the incidence of lung cancer-specific death (247 per 100,000 person-year vs. 309 per 100,000 person-year; RR 0.8, 95% CI 0.73 to 0.93) Borderline significant increase in the incidence of lung cancer (645 /100K py vs. 572 /100K py; RR 1.13, 95% CI 1.03 to 1.23) Conclusion In patients who are at high risk for lung cancer, screening using low-dose CT was superior to screening using CXRs with respect to death from any cause. Reference National Lung Screening Trial Research Team, Aberle DR, Adams AM et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5):395- 409. Open reference URL https://web.pathway.md/studies/recmpSAUOL19xwZrN 2/2