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6/28/23, 12:24 AM CURE Pathway Feedback Search Clinical Topics Home Studies CURE CURE Disease Non-ST-elevation myocardial inf Trial question What is the role of clopidogrel in patients with acute coronary syndromes without ST-segment elevation receiving aspirin? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.0% female N = 12562 62.0% male 12562 patients (4836 female, 7726 male) Inclusion criteria: patients with acute coronary syndromes without ST-segment elevation receiving aspirin Key exclusion criteria: contraindications to antithrombotic or antiplatelet therapy, high risk for bleeding or severe HF, receipt of OACs, and coronary revascularization in the previous 3 months Interventions N=6259 clopidogrel (300 mg immediately, followed by 75 mg once daily) N=6303 placebo (matching placebo daily) Primary outcome Death from cardiovascular causes, nonfatal MI, or stroke 11.4 % 11.4 https://web.pathway.md/studies/recsg6ycpT06ZqaJG 1/2 6/28/23, 12:24 AM CURE Pathway 9.3 8.6 % 5.7 % Significant decrease 2.9 % NNT = 48 0.0 % Clopidogrel Placebo Significant decrease in death from cardiovascular causes, nonfatal MI, or stroke (9.3% vs. 11.4%; RR 0.8, 95% CI 0.72 to 0.9) Secondary outcomes Significant decrease in refractory ischemia, death from cardiovascular causes, nonfatal MI, or stroke (16.5% vs. 18.8%; RR 0.86, 95% CI 0.79 to 0.94) Significant increase in major bleeding (3.7% vs. 2.7%; RR 1.38, 95% CI 1.13 to 1.67) Safety outcomes No significant differences in life-threatening bleeding (2.2% vs. 1.8%, p=0.13) or hemorrhagic stroke (0.1% vs. 0.1%). Significant differences in major bleeding (3.7% vs. 2.7%, p = 0.001; RR 1.38). Conclusion In patients with acute coronary syndromes without ST-segment elevation receiving aspirin, clopidogrel was superior to placebo with respect to death from cardiovascular causes, nonfatal MI, or stroke. Reference Yusuf S, Zhao F, Mehta SR et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 Aug 16;345(7):494-502. Open reference URL https://web.pathway.md/studies/recsg6ycpT06ZqaJG 2/2

6/28/23, 12:29 AM CvLPRIT Pathway Feedback Search Clinical Topics Home Studies CvLPRIT CvLPRIT Disease Disease Coronary artery disease ST-elevation myocardial infarction Trial question What is the role of complete revascularization in patients presenting for primary PCI with multivessel disease? Study design Multi-center Open label RCT Population Characteristics of study participants 19.0% female N = 296 81.0% male 296 patients (56 female, 240 male) Inclusion criteria: patients found to have multivessel disease while undergoing primary PCI for ST-segment elevation myocardial infarction Key exclusion criteria: age < 18 years; clear indication for, or contraindication to, multi vessel P-PCI; previous Q wave myocardial infarction; patients with prior CABG; cardiogenic shock; VSD or moderate/severe MR; CKD; suspected or confirmed thrombosis of a previously stented artery Interventions N=150 complete percutaneous coronary revascularization (including all non-infarct-related arteries) N=146 IRA-only percutaneous coronary revascularization (infarct related artery only) Primary outcome https://web.pathway.md/studies/recqIXBtnnEB9qUWL 1/2 6/28/23, 12:29 AM CvLPRIT Pathway Rate of all-cause death, recurrent myocardial infarction, heart failure, and ischemia-driven revascularization within 12 months 21.2 % 21.2 15.9 % 10.6 % 10 Significant decrease 5.3 % NNT = 9 0.0 % Complete percutaneous coronary revascularization IRA-only percutaneous coronary revascularization Significant decrease in the rate of all-cause death, recurrent myocardial infarction, HF, and ischemia-driven revascularization within 12 months (10% vs. 21.2%; HR 0.45, 95% CI 0.24 to 0.84) Secondary outcomes No significant difference in death from any cause at 12 months (1.3% vs. 4.1%; HR 0.32, 95% CI 0.06 to 1.6) No significant difference in recurrent MI at 12 months (1.3% vs. 2.7%; HR 0.48, 95% CI 0.09 to 2.62) No significant difference in repeat revascularization at 12 months (4.7% vs. 8.2%; HR 0.55, 95% CI 0.22 to 1.39) Safety outcomes No significant differences in stroke, major bleeding, or contrast-induced nephropathy. Conclusion In patients found to have multivessel disease while undergoing primary PCI for ST-segment elevation myocardial infarction, complete percutaneous coronary revascularization was superior to IRA-only percutaneous coronary revascularization with respect to the rate of all-cause death, recurrent myocardial infarction, HF, and ischemia-driven revascularization within 12 months. Reference Gershlick AH, Khan JN, Kelly DJ et al. Randomized trial of complete versus lesion-only revascularization in patients undergoing primary percutaneous coronary intervention for STEMI and multivessel disease: the CvLPRIT trial. J Am Coll Cardiol. 2015 Mar 17;65(10):963-72. Open reference URL https://web.pathway.md/studies/recqIXBtnnEB9qUWL 2/2

6/28/23, 12:25 AM CYCLOPS Pathway Feedback Search Clinical Topics Home Studies CYCLOPS CYCLOPS Disease Disease Disease Eosinophilic granulomatosis wit Granulomatosis with polyangiitis Micros Trial question What is the role of pulse cyclophosphamide regimen in patients with newly diagnosed generalized ANCA-associated vasculitis with renal involvement? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 149 59.0% male 149 patients (61 female, 88 male) Inclusion criteria: patients who had newly diagnosed generalized ANCA-associated vasculitis with renal involvement but not immediately life-threatening disease Key exclusion criteria: coexistence of other multisystem autoimmune disease, hepatitis B or C virus or HIV infection, serum creatinine level > 500 mol/L, previous cancer; pregnancy; or age < 18 or > 80 years Interventions N=76 pulse cyclophosphamide (intravenous 15 mg/kg every 2-3 weeks plus prednisolone) N=73 daily oral cyclophosphamide (2 mg/kg per day plus prednisolone) Primary outcome Remission at 9 months 88.1 % 88.1 87.7 https://web.pathway.md/studies/recYrc41EklXCHgbE 1/2 6/28/23, 12:25 AM CYCLOPS Pathway 66.1 % 44.0 % 22.0 % No significant difference 0.0 % Pulse cyclophosphamide Daily oral cyclophosphamide No significant difference in remission at 9 months (88.1% vs. 87.7%; RR 1, 95% CI -2.52 to 4.52) Secondary outcomes No significant difference in relapse (13 vs. 6; HR 2.01, 95% CI 0.77 to 5.3) Significant decrease in absolute cumulative cyclophosphamide dose (8.2 g vs. 15.9 g; HR 0.41, 95% CI 0.23 to 0.71) Safety outcomes Significant differences in leukopenia (26% vs. 45%, p = 0.016). Conclusion In patients who had newly diagnosed generalized ANCA-associated vasculitis with renal involvement but not immediately life-threatening disease, pulse cyclophosphamide was not superior to daily oral cyclophosphamide with respect to remission at 9 months. Reference de Groot K, Harper L, Jayne DR et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009 May 19;150(10):670-80. Open reference URL https://web.pathway.md/studies/recYrc41EklXCHgbE 2/2

6/28/23, 12:29 AM Cytisine for Smoking Cessation Pathway Feedback Search Clinical Topics Home Studies Cytisine for Smoking Cessation Cytisine for Smoking Cessation Disease Tobacco use Trial question What is the effect of cytisine for smoking cessation? Study design Single center Open label RCT Population Characteristics of study participants 57.0% female N = 1310 43.0% male 1310 patients (744 female, 566 male) Inclusion criteria: adult daily smokers who were motivated to quit and called the national quitline Key exclusion criteria: pregnant or breast-feeding, taking smoking-cessation medication, self- reported pheochromocytoma, systolic BP above 150 mmHg, a diastolic BP above 100 mmHg, or both, or schizophrenia Interventions N=655 cytisine (from day 1, 6 tablets/day through day 25, 2 tablets/day) N=655 nicotine-replacement therapy (nicotine patches (in doses of 7 mg, 14 mg, or 21 mg) and for gum (2 mg or 4 mg) or lozenges (1 mg or 2 mg) or both gum and lozenges for 25 days) Primary outcome Self-reported continuous abstinence at 1 month 40.0 % 40 https://web.pathway.md/studies/recpwJGRlQ1MflY2V 1/2 6/28/23, 12:29 AM Cytisine for Smoking Cessation Pathway 31 30.0 % 20.0 % Significant increase 10.0 % NNH = 11 0.0 % Cytisine Nicotine-replacement therapy Significant increase in self-reported continuous abstinence at 1 month (40% vs. 31%; RR 1.3, 95% CI 1.1 to 1.5) Secondary outcomes Significant increase in continuous abstinence at 6 months (22% vs. 15%; RR 1.4, 95% CI 1.1 to 1.8) Safety outcomes Significant differences in self-reported adverse events (31% vs. 20%, p < 0.001), primarily nausea and vomiting and sleep disorders. Conclusion In adult daily smokers who were motivated to quit and called the national quitline, cytisine was superior to nicotine-replacement therapy with respect to a self-reported continuous abstinence at 1 month. Reference Walker N, Howe C, Glover M et al. Cytisine versus nicotine for smoking cessation. N Engl J Med. 2014 Dec 18;371(25):2353-62. Open reference URL https://web.pathway.md/studies/recpwJGRlQ1MflY2V 2/2

6/28/23, 12:25 AM CYTO-PV Pathway Feedback Search Clinical Topics Home Studies CYTO PV CYTO PV Disease Disease Polycythemia Polycythemia vera Trial question What is the role of hematocrit target < 45% in patients with polycythemia vera? Study design Multi-center Open label RCT Population Characteristics of study participants 38.0% female N = 365 62.0% male 365 patients (138 female, 227 male) Inclusion criteria: adults patients with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both Key exclusion criteria: hypersensitivity or contraindication to study treatments, significant liver or renal disease, history of active substance or alcohol abuse within the last year, pregnant or lactating women, presence of any life-threatening condition or of any disease that is likely to significantly shorten life expectancy Interventions N=182 low-hematocrit targeted therapy (more aggressive therapy for a hematocrit target of < 45%) N=183 high-hematocrit targeted therapy (less aggressive therapy for a hematocrit target of 45- 50%) Primary outcome https://web.pathway.md/studies/recdR27drgn8VVG2A 1/2 6/28/23, 12:25 AM CYTO-PV Pathway Death from cardiovascular causes or major thrombotic events 9.8 % 9.8 7.4 % 4.9 % Significant decrease 2.7 2.5 % NNT = 14 0.0 % Low-hematocrit targeted therapy High-hematocrit targeted therapy Significant decrease in death from cardiovascular causes or major thrombotic events (2.7% vs. 9.8%; HR 0.26, 95% CI 0.1 to 0.69) Secondary outcomes Significant decrease in total cardiovascular events (4.4% vs. 10.9%; HR 0.37, 95% CI 0.16 to 0.84) Safety outcomes No significant difference in rate of adverse events. Conclusion In adults patients with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both, low-hematocrit targeted therapy was superior to high-hematocrit targeted therapy with respect to death from cardiovascular causes or major thrombotic events. Reference Marchioli R, Finazzi G, Specchia G et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013 Jan 3;368(1):22-33. Open reference URL https://web.pathway.md/studies/recdR27drgn8VVG2A 2/2

6/28/23, 1:19 AM Daily ICU Sedation Holidays Pathway Feedback Search Clinical Topics Home Studies Daily ICU Sedation Holidays Daily ICU Sedation Holidays Disease Hypercapnic respiratory failure Trial question What is the effect of daily interruption of sedative infusions in 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 receiving mechanical ventilation and continuous infusions of sedative drugs in 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 (interruptions of the sedative infusions until the patients were awake, on a daily basis) N=60 control (continuous infusions, interrupted only at the discretion of the clinicians in the ICU) https://web.pathway.md/studies/recnZEBGxcq7Iv2AI 1/2 6/28/23, 1:19 AM Daily ICU Sedation Holidays Pathway Primary outcome Percentage of days during which patients were awake while receiving a sedative infusion 85.5 % 85.5 64.1 % 42.8 % Significant increase 21.4 % NNH = 1 9 0.0 % Intervention Control Significant increase in the percentage of days during which patients were awake while receiving a sedative infusion (85.5% vs. 9%; AD 76.5%, 95% CI 31.11 to 121.89) Secondary outcomes No significant difference in death in the hospital (36% vs. 46.7%; RR 0.77, 95% CI -0.53 to 2.07) Safety outcomes No significant difference in adverse events including removal of endotracheal tube by the patient. Significant differences in diagnostic testing to assess changes in mental status (9% vs. 27%), non-awake during ICU stay (10.3% vs. 25%). Conclusion In adult patients receiving mechanical ventilation and continuous infusions of sedative drugs in medical ICU, intervention was superior to control with respect to the percentage of days during which patients were awake while receiving a sedative infusion. 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/recnZEBGxcq7Iv2AI 2/2

6/28/23, 1:14 AM DANAMI-3 PRIMULTI Pathway Feedback Search Clinical Topics Home Studies DANAMI 3 PRIMULTI DANAMI 3 PRIMULTI Disease Disease Coronary artery disease ST-elevation myocardial infarction Trial question What is the role of fractional flow reserve-guided complete revascularization in patients with acute ST-segment elevation myocardial infarction and multivessel coronary disease? Study design Multi-center Open label RCT Population Characteristics of study participants 19.0% female N = 627 81.0% male 627 patients (121 female, 506 male) Inclusion criteria: patients with acute ST-segment elevation myocardial infarction (STEMI) who had 1 clinically significant coronary stenosis in addition to the lesion in the infarct-related artery Key exclusion criteria: intolerance of contrast media or of relevant anticoagulant or antithrombotic drugs, unconsciousness or cardiogenic shock, stent thrombosis, indication for CABG, or increased bleeding risk Interventions N=314 complete revascularization (guided by fractional flow reserve after primary PCI) N=313 no further invasive treatment (PCI of infarct-related artery only) https://web.pathway.md/studies/recUAchxUTPV1dgNL 1/2 6/28/23, 1:14 AM DANAMI-3 PRIMULTI Pathway Primary outcome All-cause death, nonfatal reinfarction, and ischemia-driven revascularization of lesions in noninfarct- related arteries 22.0 % 22 16.5 % 13 11.0 % Significant decrease 5.5 % NNT = 11 0.0 % Complete revascularization No further invasive treatment Significant decrease in all-cause death, nonfatal reinfarction, and ischemia-driven revascularization of lesions in noninfarct-related arteries (13% vs. 22%; HR 0.56, 95% CI 0.38 to 0.83) Secondary outcomes Significant decrease in nonurgent PCI (3% vs. 9%; HR 0.29, 95% CI 0.13 to 0.63) Conclusion In patients with acute ST-segment elevation myocardial infarction (STEMI) who had 1 clinically significant coronary stenosis in addition to the lesion in the infarct-related artery, complete revascularization was superior to no further invasive treatment with respect to a all-cause death, nonfatal reinfarction, and ischemia-driven revascularization of lesions in noninfarct-related arteries. Reference Engstrom T, Kelbaek H, Helqvist S et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3-PRIMULTI): an open-label, randomised controlled trial. Lancet. 2015 Aug 15;386(9994):665-71. Open reference URL https://web.pathway.md/studies/recUAchxUTPV1dgNL 2/2

6/28/23, 1:14 AM DANISH Pathway Feedback Search Clinical Topics Home Studies DANISH DANISH Disease Disease Heart failure Ventricular arrhythmias Trial question What is the role of prophylactic ICD in patients with symptomatic systolic HF not caused by coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 28.0% female N = 1116 72.0% male 1116 patients (307 female, 809 male) Inclusion criteria: patients with symptomatic systolic HF (LVEF 35%) not caused by coronary artery disease Key exclusion criteria: permanent AF with a resting HR > 100 beats/min or renal failure that was being treated with dialysis Interventions N=556 ICD (ICD or a CRT pacemaker or CRT defibrillator) N=560 control (usual clinical care) Primary outcome https://web.pathway.md/studies/recNwOrWTIay47g9I 1/2 6/28/23, 1:14 AM DANISH Pathway Rate of all-cause death at a median follow-up of 67.6 months 23.4 % 23.4 21.6 17.5 % 11.7 % 5.8 % No significant difference 0.0 % Implantable cardioverter-defibrillator Control No significant difference in the rate of all-cause death at a median follow-up of 67.6 months (21.6% vs. 23.4%; HR 0.87, 95% CI 0.68 to 1.12) Secondary outcomes Significant decrease in sudden cardiac death (4.3% vs. 8.2%; HR 0.5, 95% CI 0.31 to 0.82) Safety outcomes No significant differences in device infections (4.9% vs. 3.6%, p=0.29). Significant differences in risk of device infection, among patients who were not receiving CRT (5.1% vs. 0.8%, p = 0.006; HR 6.35, 95% CI 1.38-58.87). Conclusion In patients with symptomatic systolic HF (LVEF 35%) not caused by coronary artery disease, ICD was not superior to control with respect to the rate of all-cause death at a median follow-up of 67.6 months. Reference Kober L, Thune JJ, Nielsen JC et al. Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure. N Engl J Med. 2016 Sep 29;375(13):1221-30. Open reference URL https://web.pathway.md/studies/recNwOrWTIay47g9I 2/2

6/28/23, 1:14 AM DANMASK-19 Pathway Feedback Search Clinical Topics Home Studies DANMASK 19 DANMASK 19 Disease COVID 19 infection Trial question What is the effect of adding a mask recommendation to other public health measures to prevent SARS-CoV-2 infection? Study design Multi-center Open label RCT Population Characteristics of study participants 52.0% female N = 6024 48.0% male 6024 patients (3116 female, 2908 male) Inclusion criteria: adults spending > 3 hours/day outside the home without occupational mask use Key exclusion criteria: previously tested positive for corona-virus, wearing facial mask for work Interventions N=2392 face mask (mask wearers) N=2470 control (non-mask wearers) Primary outcome Severe acute respiratory syndrome coronavirus 2 infection at 1 month 2.1 % 2.1 https://web.pathway.md/studies/reczXwjy7VXIH6wXY 1/2 6/28/23, 1:14 AM DANMASK-19 Pathway 1.8 1.6 % 1.1 % 0.5 % No significant difference 0.0 % Face mask Control No significant difference in SARS-CoV-2 infection at 1 month (1.8% vs. 2.1%; OR 0.82, 95% CI 0.54 to 1.23) Secondary outcomes No significant difference in PCR positivity for other respiratory viruses (0.5% vs. 0.6%; OR 0.84, 95% CI 0.35 to 2.04) No significant difference in positivity for any virus including SARS-CoV-2 infection (0.5% vs. 0.8%; OR 0.58, 95% CI 0.25 to 1.31) No significant difference in health care-diagnosed COVID-19 (0.2% vs. 0.4%; OR 0.52, 95% CI 0.18 to 1.53) Conclusion In adults spending > 3 hours/day outside the home without occupational mask use, face mask was not superior to control with respect to SARS-CoV-2 infection at 1 month. Reference Henning Bundgaard, Johan Skov Bundgaard, Daniel Emil Tadeusz Raaschou-Pedersen et al. Effectiveness of Adding a Mask Recommendation to Other Public Health Measures to Prevent SARS-CoV-2 Infection in Danish Mask Wearers : A Randomized Controlled Trial. Ann Intern Med. 2020 Nov 18;M20-6817. Open reference URL https://web.pathway.md/studies/reczXwjy7VXIH6wXY 2/2

6/28/23, 1:15 AM DAPA-CKD (post-hoc analysis) Pathway Feedback Search Clinical Topics Home Studies DAPA CKD (post-hoc analysis) DAPA CKD (post-hoc analysis) Disease Chronic kidney disease Trial question What is the role of dapagliflozin in patients with CKD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 33.0% female N = 4292 67.0% male 4292 patients (1419 female, 2873 male) Inclusion criteria: patients with CKD with and without anemia Key exclusion criteria: T1DM, polycystic kidney disease, lupus nephritis, or antineutrophil cytoplasmic antibody-associated vasculitis Interventions N=2147 dapagliflozin (at a dose of 10 mg/day) N=2145 placebo (matching placebo daily) Primary outcome https://web.pathway.md/studies/recdBri1niwtd7DYo 1/2 6/28/23, 1:15 AM DAPA-CKD (post-hoc analysis) Pathway Significant increase in improvement in hematocrit during follow-up (2% vs. -0.3%; AD 2.3%, 95% CI 2.1 to 2.5) Secondary outcomes Borderline significant increase in correction of anemia in patients with anemia (53.3% vs. 29.4%; HR 2.29, 95% CI 1.96 to 2.68) Borderline significant decrease in incident anemia in patients without anemia (10.4% vs. 23.7%; HR 0.39, 95% CI 0.31 to 0.48) Borderline significant increase in the percentage of patients achieving 3% improvement in hematocrit (69% vs. 37%; HR 2.57, 95% CI 2.35 to 2.81) Safety outcomes No significant difference in adverse events. Significant difference in anemia-related adverse events (2.2% vs. 3.8%). Conclusion In patients with CKD with and without anemia, dapagliflozin was superior to placebo with respect to improvement in hematocrit during follow-up. Reference Akihiko Koshino, M.D., Meir Schechter et al. Dapagliflozin and Anemia in Patients with Chronic Kidney Disease. NEJM Evid. 2023;2(6). Open reference URL https://web.pathway.md/studies/recdBri1niwtd7DYo 2/2

6/28/23, 1:15 AM DAPA-CKD Pathway Feedback Search Clinical Topics Home Studies DAPA CKD DAPA CKD Disease Chronic kidney disease Trial question What is the role of dapagliflozin in patients with CKD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 33.0% female N = 4304 67.0% male 4304 patients (1425 female, 2879 male) Inclusion criteria: adult patients with CKD Key exclusion criteria: documented diagnosis of T1DM; polycystic kidney disease; lupus nephritis, or ANCA-associated vasculitis; receipt of immunotherapy for kidney disease within 6 months Interventions N=2152 dapagliflozin (10 mg once daily) N=2152 placebo (matching placebo once daily) Primary outcome Composite outcome of sustained decline in estimated glomerular filtration rate of 50%, end-stage kidney disease, or death from renal or cardiovascular causes https://web.pathway.md/studies/recaZd1qTKPQkTkMy 1/2 6/28/23, 1:15 AM DAPA-CKD Pathway 14.5 % 14.5 10.9 % 9.2 7.3 % Significant decrease 3.6 % NNT = 19 0.0 % Dapagliflozin Placebo Significant decrease in composite outcome of sustained decline in the eGFR of 50%, end-stage kidney disease, or death from renal or cardiovascular causes (9.2% vs. 14.5%; HR 0.61, 95% CI 0.51 to 0.72) Secondary outcomes Significant decrease in composite outcome of sustained decline in the eGFR of 50%, end-stage kidney disease, or death from renal causes (6.6% vs. 11.3%; HR 0.56, 95% CI 0.45 to 0.68) Significant decrease in composite outcome of death from cardiovascular causes or hospitalization for HF (4.6% vs. 6.4%; HR 0.71, 95% CI 0.55 to 0.92) Significant decrease in death from any cause (4.7% vs. 6.8%; HR 0.69, 95% CI 0.53 to 0.88) Safety outcomes No significant differences in renal-related adverse event, amputation, fracture. Significant difference in serious adverse event (29.5% vs. 33.9%). Conclusion In adult patients with CKD, dapagliflozin was superior to placebo with respect to the composite outcome of sustained decline in the eGFR of 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Reference Hiddo J L Heerspink, Bergur V Stef nsson, Ricardo Correa-Rotter et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. Open reference URL https://web.pathway.md/studies/recaZd1qTKPQkTkMy 2/2

6/28/23, 1:15 AM DAPA-HF Pathway Feedback Search Clinical Topics Home Studies DAPA HF DAPA HF Disease Heart failure Trial question What is the role of dapagliflozin among patients with HFrEF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 23.0% female N = 4744 77.0% male 4744 patients (1109 female, 3635 male) Inclusion criteria: adult patients with NYHA class II, III, or IV HF and an ejection fraction < 40% Key exclusion criteria: recent treatment with or unacceptable side effects associated with a sodium-glucose cotransporter 2 inhibitor, T1DM mellitus, symptoms of hypotension or a systolic BP < 95 mmHg Interventions N=2373 dapagliflozin (at a dose of 10 mg once daily, per oral use) N=2371 placebo (matching placebo daily) Primary outcome Worsening heart failure or cardiovascular death https://web.pathway.md/studies/recqOXHSgWAbkdUQE 1/2 6/28/23, 1:15 AM DAPA-HF Pathway 21.2 % 21.2 16.3 15.9 % 10.6 % Significant decrease 5.3 % NNT = 20 0.0 % Dapagliflozin Placebo Significant decrease in worsening HF or cardiovascular death (16.3% vs. 21.2%; HR 0.74, 95% CI 0.65 to 0.85) Secondary outcomes Significant decrease in hospitalization for HF or death from cardiovascular causes (16.1% vs. 20.9%; HR 0.75, 95% CI 0.65 to 0.85) Borderline significant decrease in a first worsening cardiovascular event (10% vs. 13.7%; HR 0.7, 95% CI 0.59 to 0.83) Borderline significant decrease in death from any cause (11.6% vs. 13.9%; HR 0.83, 95% CI 0.71 to 0.97) Safety outcomes No significant differences in adverse events including volume depletion, hypoglycemia, renal dysfunction. Significant difference in serious renal adverse events (1.6% vs. 2.7%). Conclusion In adult patients with NYHA class II, III, or IV HF and an ejection fraction < 40%, dapagliflozin was superior to placebo with respect to worsening HF or cardiovascular death. Reference John J V McMurray, Scott D Solomon, Silvio E Inzucchi et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008. Open reference URL https://web.pathway.md/studies/recqOXHSgWAbkdUQE 2/2

6/28/23, 1:15 AM DAPT Pathway Feedback Search Clinical Topics Home Studies DAPT DAPT Disease Disease Disease Coronary artery disease Non-ST-elevation myocardial inf ST-elevat Trial question What is the role of dual antiplatelet therapy beyond 12 months in patients who had undergone a coronary stent procedure in which drug-eluting stent was placed? Study design Multi-center Double blinded RCT Population Characteristics of study participants 25.0% female N = 9961 75.0% male 9961 patients (2526 female, 7435 male) Inclusion criteria: patients who underwent a coronary stent procedure in which a drug-eluting stent was placed and who were treated with a thienopyridine drug (clopidogrel or prasugrel) and aspirin for 12 months Key exclusion criteria: pregnant women, concurrent medical condition with a life expectancy of < 3 years, index procedure stent placement with stent diameter < 2.25 mm or > 4.0 mm, long-term warfarin therapy, hypersensitivity or allergy to one of the study drugs Interventions N=5020 continued thienopyridine (continued clopidogrel or prasugrel plus aspirin for 18 months) N=4941 placebo (aspirin therapy alone for 18 months) https://web.pathway.md/studies/recPhyczxUeHQHD4Y 1/2 6/28/23, 1:15 AM DAPT Pathway Primary outcome Stent thrombosis 1.4 % 1.4 1.0 % 0.7 % Significant decrease 0.4 0.3 % NNT = 100 0.0 % Continued thienopyridine Placebo Significant decrease in stent thrombosis (0.4% vs. 1.4%; HR 0.29, 95% CI 0.17 to 0.48) Secondary outcomes Significant decrease in major adverse cardiovascular and cerebrovascular events (4.3% vs. 5.9%; HR 0.71, 95% CI 0.59 to 0.85) Significant decrease in myocardial infarction (2.1% vs. 4.1%; HR 0.47, 95% CI 0.37 to 0.61) Borderline significant increase in death from any cause (2% vs. 1.5%; HR 1.36, 95% CI 1 to 1.85) Safety outcomes Significant differences in moderate or severe bleeding (2.5% vs. 1.6%, p = 0.001). Conclusion In patients who underwent a coronary stent procedure in which a drug-eluting stent was placed and who were treated with a thienopyridine drug (clopidogrel or prasugrel) and aspirin for 12 months, continued thienopyridine was superior to placebo with respect to stent thrombosis. Reference Mauri L, Kereiakes DJ, Yeh RW et al. Twelve or 30 months of dual antiplatelet therapy after drug- eluting stents. N Engl J Med. 2014 Dec 4;371(23):2155-66. Open reference URL https://web.pathway.md/studies/recPhyczxUeHQHD4Y 2/2

6/28/23, 1:15 AM DAVID Pathway Feedback Search Clinical Topics Home Studies DAVID DAVID Disease Ventricular arrhythmias Trial question What is the role of dual-chamber pacing in patients with an indication for ICD? Study design Multi-center Single blinded RCT Population Characteristics of study participants 17.2% female N = 506 82.8% male 506 patients (88 female, 416 male) Inclusion criteria: patients with an indication for ICD Key exclusion criteria: permanent pacemaker, preexisting endocardial pacing leads, symptomatic bradycardia or second- or third-degree AV block, frequent or uncontrolled atrial tachyarrhythmia, or awaiting cardiac transplantation Interventions N=250 DDDR-70 pacing (dual-chamber rate-responsive pacing at 70/min) N=256 VVI-40 pacing (implantable cardioverter defibrillators programmed to ventricular backup pacing at 40/min) Primary outcome https://web.pathway.md/studies/recOFaaC3VUVBKuJt 1/2 6/28/23, 1:15 AM DAVID Pathway Survival free of death or hospitalization for new or worsened congestive heart failure at 1 year 83.9 % 83.9 73.3 62.9 % 42.0 % Significant increase 21.0 % NNT = 9 0.0 % DDDR-70 pacing VVI-40 pacing Significant increase in survival free of death or hospitalization for new or worsened congestive HF at 1 year (73.3% vs. 83.9%; RH 1.61, 95% CI 1.06 to 2.44) Secondary outcomes No significant difference in hospitalization for new or worsened congestive HF (22.6% vs. 13.3%; RH 1.54, 95% CI 0.97 to 2.46) No significant difference in death at 1 year (10.1% vs. 6.5%; RH 1.61, 95% CI 0.84 to 3.09) Safety outcomes No significant difference in severe adverse events within 30 days. Significant difference in early death (2.2% vs. 0.8%). Conclusion In patients with an indication for ICD, DDDR-70 pacing was inferior to VVI-40 pacing with respect to survival free of death or hospitalization for new or worsened congestive HF at 1 year. Reference Wilkoff BL, Cook JR, Epstein AE et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA. 2002 Dec 25;288(24):3115-23. Open reference URL https://web.pathway.md/studies/recOFaaC3VUVBKuJt 2/2

6/28/23, 1:15 AM DAWN Pathway Feedback Search Clinical Topics Home Studies DAWN DAWN Disease Disease Acute ischemic stroke Carotid artery stenosis Trial question What is the role of thrombectomy among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct? Study design Multi-center Open label RCT Population Characteristics of study participants 55.0% female N = 206 45.0% male 206 patients (113 female, 93 male) Inclusion criteria: patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume Key exclusion criteria: history of severe head injury within past 90 days with residual neurological deficit, pre-existing neurological or psychiatric disease that would confound the neurological or functional evaluations, known hemorrhagic diathesis, coagulation factor deficiency, severe sustained hypertension Interventions N=107 thrombectomy (thrombectomy with the use of the Trevo device plus standard medical care) https://web.pathway.md/studies/recAT7BnPyZqA3BTg 1/2 6/28/23, 1:15 AM DAWN Pathway N=99 control (standard medical care alone) Primary outcome Score on utility-weighted modified Rankin scale at 90 days 5.5 5.5 4.1 3.4 2.8 1.4 Significant increase 0.0 Thrombectomy Control Significant increase in score on utility-weighted mRS at 90 days (5.5 vs. 3.4; AD 2, 95% CI 1.1 to 3) Secondary outcomes Significant increase in functional independence at 90 days (49% vs. 13%; AD 33%, 95% CI 21 to 44) Significant increase in early response (48% vs. 19%; RR 3, 95% CI 2 to 4) Significant increase in recanalization at 24 hours (77% vs. 39%; RR 2, 95% CI 2 to 4) Safety outcomes No significant differences in symptomatic intracranial hemorrhage, death from any cause or stroke-related death at 90 days. Significant difference in neurological deterioration (14% vs. 26%). Conclusion In patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, thrombectomy was superior to control with respect to score on utility-weighted mRS at 90 days. Reference Raul G Nogueira, Ashutosh P Jadhav, Diogo C Haussen et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct. N Engl J Med. 2018 Jan 4;378(1):11-21. Open reference URL https://web.pathway.md/studies/recAT7BnPyZqA3BTg 2/2

6/28/23, 1:19 AM De-escalating Vital Sign Checks Pathway Feedback Search Clinical Topics Home Studies De-escalating Vital Sign Checks De-escalating Vital Sign Checks Disease ICU delirium Trial question Can a real-time predictive algorithm reduce delirium and help physicians identify patients who can safely forgo their vital signs checks? Study design Single center Open label RCT Population Characteristics of study participants 42.0% female N = 1930 58.0% male 1930 patients (818 female, 1112 male) Inclusion criteria: hospitalized adults who were not in the ICU Key exclusion criteria: admission to the ICU Interventions N=966 clinical decision support notification (informs the physician that the patient is predicted to have normal nighttime vital signs and offers sleep-promoting vitals order) N=964 usual care (the physician does not receive a clinical decision support notification about vital sign prediction) Primary outcome https://web.pathway.md/studies/rec7eKWW5dXteYUdd 1/2 6/28/23, 1:19 AM De-escalating Vital Sign Checks Pathway Delirium 13.0 % 13 11 9.8 % 6.5 % 3.3 % No significant difference 0.0 % Clinical decision support notification Usual care No significant difference in delirium (11% vs. 13%; RR 0.85, 95% CI -0.81 to 2.51) Secondary outcomes Significant decrease in the number of nighttime vital sign checks (0.97 vs. 1.41; RR 0.69, 95% CI 0.28 to 1.1) No significant difference in ICU transfers (5% vs. 5%; RR 1, 95% CI -16.93 to 18.93) Borderline significant decrease in code blue alarms (0.2% vs. 0.9%; RR 0.22, 95% CI -0.02 to 0.46) Conclusion In hospitalized adults who were not in the ICU, clinical decision support notification was not superior to usual care with respect to delirium. Reference Nader Najafi, Andrew Robinson, Mark J Pletcher et al. Effectiveness of an Analytics-Based Intervention for Reducing Sleep Interruption in Hospitalized Patients: A Randomized Clinical Trial. JAMA Intern Med. 2022 Feb 1;182(2):172-177. Open reference URL https://web.pathway.md/studies/rec7eKWW5dXteYUdd 2/2

6/28/23, 1:15 AM DECAAF II Pathway Feedback Search Clinical Topics Home Studies DECAAF II DECAAF II Disease Atrial fibrillation Trial question Is MRI-guided fibrosis ablation superior to conventional catheter ablation in patients with persistent AF? Study design Multi-center Single blinded RCT Population Characteristics of study participants 21.0% female N = 843 79.0% male 843 patients (178 female, 665 male) Inclusion criteria: patients with persistent AF Key exclusion criteria: previous LA ablation or valvular cardiac surgery; contraindication to gadolinium and/or MRI; contraindication to -blockers Interventions N=421 MRI-guided fibrosis ablation (pulmonary vein isolation followed by ablation of all fibrotic areas observed on MRI) N=422 pulmonary vein isolation alone (electrical isolation of all pulmonary veins) Primary outcome https://web.pathway.md/studies/rec4zIbsfe6FaUQVO 1/2 6/28/23, 1:15 AM DECAAF II Pathway Atrial arrhythmia recurrence 46.1 % 46.1 43 34.6 % 23.1 % 11.5 % No significant difference 0.0 % MRI-guided fibrosis ablation Pulmonary vein isolation alone No significant difference in atrial arrhythmia recurrence (43% vs. 46.1%; HR 0.95, 95% CI 0.77 to 1.17) Secondary outcomes No significant difference in composite of atrial arrhythmia recurrence, repeat ablation or new atrial arrhythmia medication (45% vs. 48%; HR 0.95, 95% CI 0.78 to 1.16) No significant difference in repeat ablation (14% vs. 17.6%; HR 0.8, 95% CI 0.56 to 1.12) No significant difference in composite of atrial arrhythmia recurrence, repeat ablation, new atrial arrhythmia medication or cardioversion (45.9% vs. 48.5%; HR 0.96, 96% CI 0.79 to 1.17) Safety outcomes Significant differences in 1 event of death, stroke, pulmonary vein stenosis, HF, or bleeding within 30 days postablation (2.2% vs. 0%). Conclusion In patients with persistent AF, MRI-guided fibrosis ablation was not superior to pulmonary vein isolation alone with respect to atrial arrhythmia recurrence. Reference Nassir F Marrouche, Oussama Wazni, Christopher McGann et al. Effect of MRI-Guided Fibrosis Ablation vs Conventional Catheter Ablation on Atrial Arrhythmia Recurrence in Patients With Persistent Atrial Fibrillation: The DECAAF II Randomized Clinical Trial. JAMA. 2022 Jun 21;327(23):2296-2305. Open reference URL https://web.pathway.md/studies/rec4zIbsfe6FaUQVO 2/2

6/28/23, 1:20 AM Deceased ODI to Protect KGF (hypothermia vs. hypothermia plus machine perfusion) Pathway Feedback Search Clinical Topics Deceased ODI to Protect KGF (hypothermia vs. hypothermia plus machine perfusion) Home Studies Deceased ODI to Protect KGF (hypothermia vs. hypothermia plus machine perfusion) Trial question Is hypothermia alone superior to a combination of hypothermia and machine perfusion of the kidney in brain-dead organ donors? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.0% female N = 838 62.0% male 838 patients (317 female, 521 male) Inclusion criteria: adult brain-dead kidney donors Key exclusion criteria: donation after cardiac death; end-stage kidney disease; or a history of dialysis during terminal hospitalization Interventions N=359 hypothermia (therapeutic hypothermia at 34-35 degree Celsius) N=479 combination therapy (combination of therapeutic hypothermia and machine perfusion) Primary outcome Delayed graft function in kidney transplant recipients 30.0 % 30 22.5 % 22 15.0 % 7.5 % https://web.pathway.md/studies/rec36Zt0cjsEXcYnI 1/2 6/28/23, 1:20 AM 5 % Deceased ODI to Protect KGF (hypothermia vs. hypothermia plus machine perfusion) Pathway Borderline significant increase 0.0 % Hypothermia Combination therapy Borderline significant increase in delayed graft function in kidney transplant recipients (30% vs. 22%; RR 1.57, 95% CI 1.26 to 1.96) Conclusion In adult brain-dead kidney donors, hypothermia was not superior to combination therapy with respect to delayed graft function in kidney transplant recipients. Reference Darren Malinoski, Christina Saunders, Sharon Swain et al. Hypothermia or Machine Perfusion in Kidney Donors. N Engl J Med. 2023 Feb 2;388(5):418-426. Open reference URL https://web.pathway.md/studies/rec36Zt0cjsEXcYnI 2/2

6/28/23, 1:20 AM Deceased ODI to Protect KGF (hypothermia vs. machine perfusion) Pathway Feedback Search Clinical Topics Home Studies Deceased ODI to Protect KGF (hypothermia vs. machine perfusion) Deceased ODI to Protect KGF (hypothermia vs. machine perfusion) Trial question Is therapeutic hypothermia noninferior to machine perfusion of the kidney in brain-dead organ donors? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.0% female N = 869 62.0% male 869 patients (328 female, 542 male) Inclusion criteria: adult brain-dead kidney donors Key exclusion criteria: donation after cardiac death; end-stage kidney disease; or a history of dialysis during terminal hospitalization Interventions N=359 hypothermia (therapeutic hypothermia at 34-35 C) N=510 machine perfusion (ex situ kidney hypothermic machine perfusion) Primary outcome Delayed graft function in kidney transplant recipients 30.0 % 30 22.5 % 19 15.0 % 7.5 % https://web.pathway.md/studies/recGN4tRyGHttShWn 1/2 6/28/23, 1:20 AM Deceased ODI to Protect KGF (hypothermia vs. machine perfusion) Pathway Difference exceeding nonferiority margin 0.0 % Hypothermia Machine perfusion Difference exceeding nonferiority margin in delayed graft function in kidney transplant recipients (30% vs. 19%; RR 1.72, 95% CI 1.35 to 2.17) Conclusion In adult brain-dead kidney donors, hypothermia was not noninferior to machine perfusion with respect to delayed graft function in kidney transplant recipients. Reference Darren Malinoski, Christina Saunders, Sharon Swain et al. Hypothermia or Machine Perfusion in Kidney Donors. N Engl J Med. 2023 Feb 2;388(5):418-426. Open reference URL https://web.pathway.md/studies/recGN4tRyGHttShWn 2/2

6/28/23, 1:20 AM Deceased ODI to Protect KGF (machine perfusion vs. machine perfusion plus hypothermia) Pathway Feedback Search Clinical Topics Deceased ODI to Protect KGF (machine perfusion vs. machine perfusion plus hypothermia) Home Studies Deceased ODI to Protect KGF (machine perfusion vs. machine perfusion plus hypothermia) Trial question Is combination of hypothermia and machine perfusion superior to machine perfusion alone of the kidney in brain-dead organ donors? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.6% female N = 989 62.4% male 989 patients (371 female, 619 male) Inclusion criteria: adult brain-dead kidney donors Key exclusion criteria: donation after cardiac death; end-stage kidney disease; or a history of dialysis during terminal hospitalization Interventions N=479 combination therapy (combination of therapeutic hypothermia and machine perfusion) N=510 machine perfusion (ex situ kidney hypothermic machine perfusion) Primary outcome Delayed graft function in kidney transplant recipients 22.0 % 22 19 16.5 % 11.0 % 5.5 % https://web.pathway.md/studies/rec3XoqQdCRAJODAL 1/2 6/28/23, 1:20 AM Deceased ODI to Protect KGF (machine perfusion vs. machine perfusion plus hypothermia) Pathway No significant difference 0.0 % Combination therapy Machine perfusion No significant difference in delayed graft function in kidney transplant recipients (22% vs. 19%; RR 1.09, 95% CI 0.85 to 1.4) Conclusion In adult brain-dead kidney donors, combination therapy was not superior to machine perfusion with respect to delayed graft function in kidney transplant recipients. Reference Darren Malinoski, Christina Saunders, Sharon Swain et al. Hypothermia or Machine Perfusion in Kidney Donors. N Engl J Med. 2023 Feb 2;388(5):418-426. Open reference URL https://web.pathway.md/studies/rec3XoqQdCRAJODAL 2/2

6/28/23, 1:15 AM DECLARE-TIMI 58 (post-hoc analysis) Pathway Feedback Search Clinical Topics Home Studies DECLARE TIMI 58 (post-hoc analysis) DECLARE TIMI 58 (post-hoc analysis) Disease Diabetes mellitus type 2 Trial question What is the effect of dapagliflozin on hospitalizations in adults with T2DM? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 17160 63.0% male 17160 patients (6422 female, 10738 male) Inclusion criteria: adults 40 years with T2DM and either risk factors for or established ASCVD Key exclusion criteria: diagnosis of T1DM mellitus; chronic cystitis; recurrent UTIs; pregnancy Interventions N=8582 dapagliflozin (at an oral dose of 10 mg once daily) N=8578 placebo (matching placebo once daily) Primary outcome First non-elective hospitalization for any cause 35.4 % 35.4 32.4 https://web.pathway.md/studies/recvVphFoWgv4nfHo 1/2 6/28/23, 1:15 AM DECLARE-TIMI 58 (post-hoc analysis) Pathway 26.5 % 17.7 % 8.8 % Borderline significant decrease 0.0 % Dapagliflozin Placebo Borderline significant decrease in first non-elective hospitalization for any cause (32.4% vs. 35.4%; HR 0.89, 95% CI 0.85 to 0.94) Conclusion In adults 40 years with T2DM and either risk factors for or established ASCVD, dapagliflozin was superior to placebo with respect to first non-elective hospitalization for any cause. Reference Meir Schechter, Stephen D Wiviott, Itamar Raz et al. Effects of dapagliflozin on hospitalisations in people with type 2 diabetes: post-hoc analyses of the DECLARE-TIMI 58 trial. Lancet Diabetes Endocrinol. 2023 Apr;11(4):233-241. Open reference URL https://web.pathway.md/studies/recvVphFoWgv4nfHo 2/2

6/28/23, 1:15 AM DEFINITE Pathway Feedback Search Clinical Topics Home Studies DEFINITE DEFINITE Disease Disease Disease Dilated cardiomyopathy Heart failure Ventricula Trial question What is the role of prophylactic implantation of an ICD in patients with nonischemic dilated cardiomyopathy? Study design Multi-center Open label RCT Population Characteristics of study participants 29.0% female N = 458 71.0% male 458 patients (132 female, 326 male) Inclusion criteria: patients with nonischemic dilated cardiomyopathy, an LVEF < 36%, and premature ventricular complexes or nonsustained VT Key exclusion criteria: NYHA class IV congestive HF, had permanent pacemakers, in whom cardiac transplantation appeared to be imminent, familial cardiomyopathy associated with sudden death, and acute myocarditis or congenital heart disease Interventions N=229 implantation of a cardioverter-defibrillator (plus standard medical therapy) N=229 standard medical therapy alone (ACE inhibitors and -blockers, in addition to digoxin and diuretics if necessary) https://web.pathway.md/studies/recPMBpEiRRDrkRef 1/2 6/28/23, 1:15 AM DEFINITE Pathway Primary outcome Sudden death from arrhythmia 14.0 14 10.5 7.0 3.5 3 Significant decrease 0.0 Implantation of a cardioverter-defibrillator Standard medical therapy alone Significant decrease in sudden death from arrhythmia (3 vs. 14; HR 0.2, 95% CI 0.06 to 0.71) Secondary outcomes No significant difference in death (28 vs. 40; HR 0.65, 95% CI 0.4 to 1.06) Conclusion In patients with nonischemic dilated cardiomyopathy, an LVEF < 36%, and premature ventricular complexes or nonsustained VT, implantation of a cardioverter-defibrillator was superior to standard medical therapy alone with respect to sudden death from arrhythmia. Reference Kadish A, Dyer A, Daubert JP et al. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med. 2004 May 20;350(21):2151-8. Open reference URL https://web.pathway.md/studies/recPMBpEiRRDrkRef 2/2

6/28/23, 1:15 AM DEFUSE 3 Pathway Feedback Search Clinical Topics Home Studies DEFUSE 3 DEFUSE 3 Disease Disease Disease Acute ischemic stroke Carotid artery stenosis Transient Trial question What is the role of endovascular thrombectomy among patients with proximal middle cerebral artery or internal carotid artery occlusion and a region of tissue that was ischemic but not yet infarcted? Study design Multi-center Open label RCT Population Characteristics of study participants 51.0% female N = 182 49.0% male 182 patients (92 female, 90 male) Inclusion criteria: patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted Key exclusion criteria: terminal illness, current anticoagulant use, history of diabetes or prior stroke, known hereditary or acquired hemorrhagic diathesis, severe sustained hypertension, presumed septic embolus, suspicion of bacterial endocarditis Interventions N=92 endovascular therapy (thrombectomy plus standard medical therapy) N=90 medical therapy (standard medical therapy alone) https://web.pathway.md/studies/rec8xTlbcO8elTKo0 1/2 6/28/23, 1:15 AM DEFUSE 3 Pathway Primary outcome Median score on modified Rankin scale at 90 days 4.0 4 3.0 3 2.0 1.0 Significant increase 0.0 Endovascular therapy Medical therapy Significant increase in median score on mRS at 90 days (3 vs. 4; OR 2.77, 95% CI 1.63 to 4.7) Secondary outcomes Significant increase in functional independence at 90 days (45% vs. 17%; RR 2.67, 95% CI 1.6 to 4.48) No significant difference in death at 90 days (14% vs. 26%; RR 0.55, 95% CI 0.3 to 1.02) Significant increase in complete recanalization at 24 hours (78% vs. 18%; RR 4.31, 95% CI 2.65 to 7.01) Safety outcomes No significant differences in serious adverse events, symptomatic intracranial hemorrhage, early neurologic deterioration, parenchymal hematoma type 2. Significant difference in reperfusion > 90% at 24 hours (79% vs. 18%). Conclusion In patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted, endovascular therapy was superior to medical therapy with respect to median score on mRS at 90 days. Reference Gregory W Albers, Michael P Marks, Stephanie Kemp et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018 Feb 22;378(8):708-718. Open reference URL https://web.pathway.md/studies/rec8xTlbcO8elTKo0 2/2

6/28/23, 1:16 AM DELIVER Pathway Feedback Search Clinical Topics Home Studies DELIVER DELIVER Disease Heart failure Trial question What is the role of dapagliflozin in patients with HF and a mildly reduced or preserved ejection fraction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 44.0% female N = 6263 56.0% male 6263 patients (2747 female, 3516 male) Inclusion criteria: patients with HF and a LVEF > 40% Key exclusion criteria: T1DM mellitus; receipt of sodium-glucose cotransporter 2 inhibitor within 4 weeks of randomization; or previous intolerance to sodium-glucose cotransporter 2 inhibitor; impaired kidney function Interventions N=3131 dapagliflozin (at a dose of 10 mg/day plus usual therapy) N=3132 placebo (matching placebo plus usual therapy) Primary outcome https://web.pathway.md/studies/rechUMdTpDYP4WFnn 1/2 6/28/23, 1:16 AM DELIVER Pathway Worsening heart failure or cardiovascular death 19.5 % 19.5 16.4 14.6 % 9.8 % Significant decrease 4.9 % NNT = 32 0.0 % Dapagliflozin Placebo Significant decrease in worsening HF or cardiovascular death (16.4% vs. 19.5%; HR 0.82, 95% CI 0.73 to 0.92) Secondary outcomes Significant decrease in the incidence of worsening HF events and cardiovascular deaths (11.8 events/100 person-year vs. 15.3 events/100 person-year; RR 0.77, 95% CI 0.67 to 0.89) No significant difference in death from any cause (15.9% vs. 16.8%; HR 0.94, 95% CI 0.83 to 1.07) No significant difference in cardiovascular death (7.4% vs. 8.3%; HR 0.88, 95% CI 0.74 to 1.05) Safety outcomes No significant difference in adverse events and serious adverse events. Conclusion In patients with HF and a LVEF > 40%, dapagliflozin was superior to placebo with respect to worsening HF or cardiovascular death. Reference Scott D Solomon, John J V McMurray, Brian Claggett et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022 Sep 22;387(12):1089-1098. Open reference URL https://web.pathway.md/studies/rechUMdTpDYP4WFnn 2/2

6/28/23, 1:16 AM DESTINY-Breast04 Pathway Feedback Search Clinical Topics Home Studies DESTINY Breast04 DESTINY Breast04 Trial question What is the role of trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer? Study design Multi-center Open label RCT Population 557 female patients Inclusion criteria: patients with HER2-low, unresectable or metastatic breast cancer Key exclusion criteria: history of noninfectious ILD treated with glucocorticoids; suspected ILD on imaging; previous treatment with anti-HER2 Interventions N=373 trastuzumab deruxtecan (intravenous administration of 100 mg in 5 mL solution) N=184 physician's choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel, or nab- paclitaxel) Primary outcome Progression-free survival among patients with hormone receptor-positive disease 10.1 months 10.1 7.6 months 5.4 5.0 months 2.5 months Significant increase 0.0 months Trastuzumab deruxtecan Physician's choice of chemotherapy Significant increase in progression-free survival among patients with hormone receptor-positive disease (10.1 months vs. 5.4 months; HR 1.96, 96% CI 1.56 to 2.5) Secondary outcomes https://web.pathway.md/studies/rectQ7L8t5vgjhemq 1/2 6/28/23, 1:16 AM DESTINY-Breast04 Pathway Significant increase in progression-free survival among all patients (9.9 months vs. 5.1 months; HR 2, 95% CI 1.58 to 2.5) Significant increase in overall survival in the hormone receptor-positive cohort (23.9 months vs. 17.5 months; AD 6.4 months, 95% CI 2.18 to 10.62) Significant increase in overall survival in all patients (23.4 months vs. 16.8 months; AD 6.6 months, 95% CI 2.68 to 10.52) Safety outcomes No significant difference in serious adverse events and adverse events grade 3. Conclusion In patients with HER2-low, unresectable or metastatic breast cancer, trastuzumab deruxtecan was superior to physician's choice of chemotherapy with respect to a progression-free survival among patients with hormone receptor-positive disease. Reference Shanu Modi, William Jacot, Toshinari Yamashita et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Open reference URL https://web.pathway.md/studies/rectQ7L8t5vgjhemq 2/2

6/28/23, 1:16 AM DETO2X-AMI Pathway Feedback Search Clinical Topics Home Studies DETO2X AMI DETO2X AMI Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the effect of routine oxygen therapy in patients with suspected acute myocardial infarction who do not have hypoxemia at baseline? Study design Multi-center Open label RCT Population Characteristics of study participants 31.0% female N = 6629 69.0% male 6629 patients (2023 female, 4606 male) Inclusion criteria: patients with suspected acute myocardial infarction and an oxygen saturation of 90% on pulse oximetry Key exclusion criteria: patients receiving ongoing oxygen therapy, presenting with cardiac arrest or had a cardiac arrest between presentation and enrollment Interventions N=3311 oxygen therapy (supplemental oxygen at 6 L/min for 6-12 hours through an open face mask) N=3318 no supplemental oxygen https://web.pathway.md/studies/rec2LwjWH5KrZfWZR 1/2 6/28/23, 1:16 AM DETO2X-AMI Pathway Primary outcome All-cause death at 1 year 5.1 % 5.1 5 3.8 % 2.5 % 1.3 % No significant difference 0.0 % Oxygen therapy No supplemental oxygen No significant difference in all-cause death at 1 year (5% vs. 5.1%; HR 0.97, 95% CI 0.79 to 1.21) Secondary outcomes No significant difference in the rate of rehospitalization with myocardial infarction within 1 year (3.8% vs. 3.3%; HR 1.13, 95% CI 0.88 to 1.46) Conclusion In patients with suspected acute myocardial infarction and an oxygen saturation of 90% on pulse oximetry, oxygen therapy was not superior to no supplemental oxygen with respect to a all-cause death at 1 year. Reference Hofmann R, James SK, Jernberg T et al. Oxygen Therapy in Suspected Acute Myocardial Infarction. N Engl J Med. 2017 Sep 28;377(13):1240-1249. Open reference URL https://web.pathway.md/studies/rec2LwjWH5KrZfWZR 2/2

6/28/23, 1:16 AM DEVOTE Pathway Feedback Search Clinical Topics Home Studies DEVOTE DEVOTE Disease Diabetes mellitus type 2 Trial question Is degludec noninferior to glargine among patients with T2DM who are at high risk for cardiovascular events? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 7637 63.0% male 7637 patients (2859 female, 4778 male) Inclusion criteria: patients with T2DM at high risk of cardiovascular events on standard care being treated with at least one oral or injectable antihypertensive agent Key exclusion criteria: acute coronary or cerebrovascular event in the previous 60 days, planned coronary, carotid or peripheral artery revascularization, chronic HF NYHA class IV, end-stage liver disease, known or suspected hypersensitivity to trial products or related products, pregnant or breast-feeding women, current or past (within 5 years) malignant neoplasms (except basal cell and SCC) Interventions N=3818 insulin degludec (10 ml vial containing 100 U/mL once daily between dinner and bedtime) https://web.pathway.md/studies/recqDHL5LWOzi1Dyx 1/2 6/28/23, 1:16 AM DEVOTE Pathway N=3819 insulin glargine (10 ml vial containing 100 U/mL once daily between dinner and bedtime) Primary outcome Major cardiovascular events 9.3 % 9.3 8.5 7.0 % 4.7 % Difference not exceeding nonferiority margin 2.3 % 0.0 % Insulin degludec Insulin glargine Difference not exceeding nonferiority margin in major cardiovascular events (8.5% vs. 9.3%; HR 0.91, 95% CI 0.78 to 1.06) Secondary outcomes Significant decrease in severe hypoglycemia (3.7 vs. 6.25; RR 0.6, 95% CI 0.48 to 0.76) Safety outcomes No significant difference in rates of adverse events. Conclusion In patients with T2DM at high risk of cardiovascular events on standard care being treated with at least one oral or injectable antihypertensive agent, insulin degludec was noninferior to insulin glargine with respect to major cardiovascular events. Reference Marso SP, McGuire DK, Zinman B et al. Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes. N Engl J Med. 2017 Aug 24;377(8):723-732. Open reference URL https://web.pathway.md/studies/recqDHL5LWOzi1Dyx 2/2

6/28/23, 1:20 AM Dexmedetomidine in DCD kidney transplant Pathway Feedback Search Clinical Topics Home Studies Dexmedetomidine in DCD kidney transplant Dexmedetomidine in DCD kidney transplant Trial question What is the role of dexmedetomidine in patients scheduled for a donation-after-cardiac-death kidney transplant? Study design Single center Double blinded RCT Population Characteristics of study participants 42.0% female N = 111 58.0% male 111 patients (47 female, 64 male) Inclusion criteria: adult patients scheduled for a donation-after-cardiac death kidney transplant Key exclusion criteria: sick sinus syndrome; AV block; LVEF < 30%; multiorgan transplant Interventions N=56 dexmedetomidine (24-hour perioperative intravenous infusion of 0.4 g/kg/hour intraoperatively and 0.1 g/kg/hour postoperatively) N=55 placebo (24-hour normal saline infusion with matching infusion rates) Primary outcome Rate of need for dialysis in the first posttransplant week 34.5 % 34.5 25.9 % 17.9 17.3 % Significant decrease 8.6 % https://web.pathway.md/studies/recRYpbmiLm1m83c8 1/2 6/28/23, 1:20 AM Dexmedetomidine in DCD kidney transplant Pathway NNT = 6 0.0 % Dexmedetomidine Placebo Significant decrease in the rate of need for dialysis in the first posttransplant week (17.9% vs. 34.5%; OR 0.41, 95% CI 0.17 to 0.98) Secondary outcomes Significant decrease in repeated dialysis in the hospital (12.5% vs. 30.9%; OR 0.32, 95% CI 0.13 to 0.88) No significant difference in mean serum creatinine level at 30 day posttransplant (1.42 mg/dL vs. 1.57 mg/dL; MD -0.15, 95% CI -0.6 to 0.29) No significant difference in mean eGFR at 30 day posttransplant (65.1 mL/min/1.73 m vs. 63.3 mL/min/1.73 m ; MD 1.82, 95% CI -7.89 to 11.52) Conclusion In adult patients scheduled for a donation-after-cardiac death kidney transplant, dexmedetomidine was superior to placebo with respect to the rate of need for dialysis in the first posttransplant week. Reference Xi-Sheng Shan, Lin-Kun Hu, Yiqing Wang et al. Effect of Perioperative Dexmedetomidine on Delayed Graft Function Following a Donation-After-Cardiac-Death Kidney Transplant: A Randomized Clinical Trial. JAMA Netw Open. 2022 Jun 1;5(6):e2215217. Open reference URL https://web.pathway.md/studies/recRYpbmiLm1m83c8 2/2

6/28/23, 1:20 AM DiDi Pathway Feedback Search Clinical Topics Home Studies DiDi DiDi Disease Dilated cardiomyopathy Trial question What is the role of diltiazem in patients with idiopathic dilated cardiomyopathy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 24.0% female N = 186 76.0% male 186 patients (45 female, 141 male) Inclusion criteria: patients with idiopathic dilated cardiomyopathy diagnosed by coronary angiography, catheterization of left side of heart, and LVEF < 0.50 Key exclusion criteria: hypertension; valvular or congenital heart disease; myocarditis; coronary artery disease; insulin-dependent diabetes mellitus Interventions N=92 diltiazem (at a dose of 60-90 mg TID) N=94 placebo (matching placebo) Primary outcome Transplant listing-free survival https://web.pathway.md/studies/reckQ9fVXSD4JlSj6 1/2 6/28/23, 1:20 AM DiDi Pathway 85.2 % 85.2 80.4 63.9 % 42.6 % 21.3 % No significant difference 0.0 % Diltiazem Placebo No significant difference in transplant listing-free survival (85.2% vs. 80.4%; AD 4.8%, 95% CI -7.27 to 16.87) Secondary outcomes Significant increase in cardiac index at rest in 2 years (0.37 L/min vs. 0.33 L/min; AD 0.04 L/min, 95% CI 0.01 to 0.07) Significant increase in cardiac index at workload in 2 years (0.57 L/min vs. 0.33 L/min; AD 0.24 L/min, 95% CI 0.09 to 0.39) Significant decrease in HR (-7.7 L/min vs. -1.6 L/min; ARD -6.1, 95% CI -9.72 to -2.48) Safety outcomes No significant difference in adverse reactions. Significant difference in PQ interval (0.015 s vs. -0.003 s). Conclusion In patients with idiopathic dilated cardiomyopathy diagnosed by coronary angiography, catheterization of left side of heart, and LVEF < 0.50, diltiazem was not superior to placebo with respect to transplant listing-free survival. Reference H R Figulla, F Gietzen, U Zeymer et al. Diltiazem improves cardiac function and exercise capacity in patients with idiopathic dilated cardiomyopathy. Results of the Diltiazem in Dilated Cardiomyopathy Trial. Circulation. 1996 Aug 1;94(3):346-52. Open reference URL https://web.pathway.md/studies/reckQ9fVXSD4JlSj6 2/2

6/28/23, 1:16 AM DIG Pathway Feedback Search Clinical Topics Home Studies DIG DIG Disease Heart failure Trial question What is the role of digoxin in patients with a LVEF 0.45 being treated with diuretics and ACE inhibitors? Study design Multi-center Double blinded RCT Population Characteristics of study participants 22.0% female N = 6800 78.0% male 6800 patients (1520 female, 5280 male) Inclusion criteria: patients with an LVEF 0.45 being treated with diuretics and ACE inhibitors Key exclusion criteria: age < 21 years, myocardial infarction or cardiac surgery within 4 weeks, unstable or refractory angina < 1 month, acute myocarditis, hypertrophic cardiomyopathy, cor pulmonale, or complex congenital heart disease Interventions N=3397 digoxin (0.25 mg/day) N=3403 placebo (matching placebo per day) Primary outcome https://web.pathway.md/studies/recthrjzIBRHXPKKG 1/2 6/28/23, 1:16 AM DIG Pathway Death from all causes 35.1 % 35.1 34.8 26.3 % 17.6 % 8.8 % No significant difference 0.0 % Digoxin Placebo No significant difference in death from all causes (34.8% vs. 35.1%; RR 0.99, 99% CI 0.91 to 1.07) Secondary outcomes Significant decrease in hospitalization for worsening HF (26.8% vs. 34.7%; RR 0.72, 95% CI 0.66 to 0.79) No significant difference in death attributed to worsening HF (11.6% vs. 13.2%; RR 0.88, 95% CI 0.77 to 1.01) No significant difference in death from cardiovascular causes (29.9% vs. 29.5%; RR 1.01, 95% CI 0.93 to 1.1) Safety outcomes No significant difference in VF or tachycardia. Significant differences in digoxin toxicity (11.9% vs. 7.9%), supraventricular arrhythmia (2.5% vs. 1.2%) and second or third degree AV block (1.2% vs. 0.4%). Conclusion In patients with an LVEF 0.45 being treated with diuretics and ACE inhibitors, digoxin was not superior to placebo with respect to death from all causes. Reference Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997 Feb 20;336(8):525-33. Open reference URL https://web.pathway.md/studies/recthrjzIBRHXPKKG 2/2

6/28/23, 1:16 AM DINAMIT Pathway Feedback Search Clinical Topics Home Studies DINAMIT DINAMIT Disease Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Ventricula Trial question What is the role of ICD therapy in patients with acute myocardial infarction who had reduced LV function and impaired cardiac autonomic function? Study design Multi-center Open label RCT Population Characteristics of study participants 24.0% female N = 674 76.0% male 674 patients (160 female, 514 male) Inclusion criteria: patients with acute myocardial infarction who had reduced LV function and impaired cardiac autonomic function Key exclusion criteria: congestive HF; noncardiac disease that limited life expectancy; name on a waiting list for a heart transplant; current, ongoing ICD therapy; prior implantation of a permanent pacemaker; requirement for an ICD Interventions N=332 implantation of a cardioverter-defibrillator (plus standard medical therapy) N=342 standard medical therapy alone (no ICD) https://web.pathway.md/studies/recJR0dgj6DtshZOz 1/2 6/28/23, 1:16 AM DINAMIT Pathway Primary outcome Incidence of death from any cause 7.5 % / y 7.5 6.9 5.6 % / y 3.8 % / y 1.9 % / y No significant difference 0.0 % / y Implantation of a cardioverter-defibrillator Standard medical therapy alone No significant difference in the incidence of death from any cause (7.5% / y vs. 6.9% / y; HR 1.08, 95% CI 0.76 to 1.55) Secondary outcomes Significant decrease in the incidence of death due to arrhythmia (1.5% / y vs. 3.5% / y; HR 0.42, 95% CI 0.22 to 0.83) Significant increase in the incidence of death from nonarrhythmic causes (6.1% / y vs. 3.5% / y; HR 1.75, 95% CI 1.11 to 2.76) Conclusion In patients with acute myocardial infarction who had reduced LV function and impaired cardiac autonomic function, implantation of a cardioverter-defibrillator was not superior to standard medical therapy alone with respect to the incidence of death from any cause. Reference Hohnloser SH, Kuck KH, Dorian P et al. Prophylactic use of an implantable cardioverter-defibrillator after acute myocardial infarction. N Engl J Med. 2004 Dec 9;351(24):2481-8. Open reference URL https://web.pathway.md/studies/recJR0dgj6DtshZOz 2/2

6/28/23, 1:16 AM DINAMO-study Pathway Feedback Search Clinical Topics Home Studies DINAMO-study DINAMO-study Disease Acute diverticulitis Trial question Is nonantibiotic outpatient treatment noninferior to antibiotic treatment in patients with mild acute diverticulitis? Study design Multi-center Open label RCT Population Characteristics of study participants 53.0% female N = 480 47.0% male 480 patients (256 female, 224 male) Inclusion criteria: adult patients consulting the emergency department with symptoms of acute diverticulitis Key exclusion criteria: age < 18 years or > 80 years; allergy to any of the study drugs; modified Neff grade I or upper acute diverticulitis; acute diverticulitis episode in the last 3 months; antibiotic treatment for any reason in the last 2 weeks; presence of significant comorbidities Interventions N=242 non-antibiotic (anti-inflammatory and symptomatic treatment with 600 mg/8 hour ibuprofen alternating with 1 g/8 hour acetaminophen) https://web.pathway.md/studies/recum7QuE10UtWf51 1/2 6/28/23, 1:16 AM DINAMO-study Pathway N=238 antibiotic (875 mg/125 mg/8 hour amoxicillin-clavulanate apart from anti-inflammatory and symptomatic treatment) Primary outcome Hospital admission 5.8 % 5.8 4.3 % 3.3 2.9 % Difference not exceeding nonferiority margin 1.4 % 0.0 % Non-antibiotic Antibiotic Difference not exceeding nonferiority margin in hospital admission (3.3% vs. 5.8%; ARD -2.58, 95% CI -1.17 to 6.32) Secondary outcomes No significant difference in emergency department revisits (7% vs. 6.7%; AD 0.3%, 95% CI -4.83 to 4.22) No significant difference in the percentage of patients with poor pain control at 2 days (2.3% vs. 5.7%; ARD -3.39, 95% CI -0.18 to 6.96) Conclusion In adult patients consulting the emergency department with symptoms of acute diverticulitis, non- antibiotic was noninferior to antibiotic with respect to hospital admission. Reference Laura Mora-L pez, Neus Ruiz-Edo, Oscar Estrada-Ferrer et al. Efficacy and Safety of Nonantibiotic Outpatient Treatment in Mild Acute Diverticulitis (DINAMO-study): A Multicentre, Randomised, Open-label, Noninferiority Trial. Ann Surg. 2021 Nov 1;274(5):e435-e442. Open reference URL https://web.pathway.md/studies/recum7QuE10UtWf51 2/2

6/28/23, 1:16 AM DIRECT-MT Pathway Feedback Search Clinical Topics Home Studies DIRECT MT DIRECT MT Disease Acute ischemic stroke Trial question Is endovascular thrombectomy alone noninferior to endovascular thrombectomy preceded by intravenous alteplase in patients with acute ischemic stroke? Study design Multi-center Open label RCT Population Characteristics of study participants 44.0% female N = 656 56.0% male 656 patients (286 female, 370 male) Inclusion criteria: patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation Key exclusion criteria: disability before the stroke or any contraindication to intravenous alteplase according to the AHA (AHA)-American Stroke Association (ASA) guidelines Interventions N=327 thrombectomy-alone (endovascular thrombectomy) N=329 combination-therapy (endovascular thrombectomy preceded by intravenous alteplase at a dose of 0.9 mg/kg of body weight administered within 4.5 hours of symptom onset) https://web.pathway.md/studies/rec89GdFUyw6FMVa5 1/2 6/28/23, 1:16 AM DIRECT-MT Pathway Primary outcome Modified Rankin Scale score at 90 days 3.0 3 3 2.3 1.5 Difference not exceeding nonferiority margin 0.8 0.0 Thrombectomy-alone Combination-therapy Difference not exceeding nonferiority margin in mRS score at 90 days (3 vs. 3; aOR 1.07, 95% CI 0.81 to 1.4) Secondary outcomes No significant difference in death at 90 days (17.7% vs. 18.8%; RR 0.94, 95% CI 0.68 to 1.3) Borderline significant decrease in successful reperfusion before thrombectomy (2.4% vs. 7%; OR 0.33, 95% CI 0.14 to 0.74) No significant difference in overall successful reperfusion (79.4% vs. 84.5%; OR 0.7, 95% CI 0.47 to 1.06) Safety outcomes No significant differences in serious adverse events, procedural complications, asymptomatic and symptomatic intracranial hemorrhage. Conclusion In patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation, thrombectomy-alone was noninferior to combination-therapy with respect to mRS score at 90 days. Reference Pengfei Yang, Yongwei Zhang, Lei Zhang et al. Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke. N Engl J Med. 2020 May 21;382(21):1981-1993. Open reference URL https://web.pathway.md/studies/rec89GdFUyw6FMVa5 2/2

6/28/23, 1:17 AM DISCHARGE Pathway Feedback Search Clinical Topics Home Studies DISCHARGE DISCHARGE Disease Disease Chest pain Coronary artery disease Trial question Is CT superior to invasive coronary angiography in guideline-directed management of stable chest pain? Study design Multi-center Open label RCT Population Characteristics of study participants 56.0% female N = 3561 44.0% male 3561 patients (2002 female, 1559 male) Inclusion criteria: patients with stable chest pain who had an intermediate pretest probability of obstructive coronary artery disease and were referred for invasive coronary angiography Key exclusion criteria: receipt of hemodialysis; absence of sinus rhythm; pregnancy Interventions N=1808 CT (clinical management decisions based on coronary CT angiography) N=1753 invasive coronary angiography (clinical management decisions based on invasive coronary angiography) Primary outcome https://web.pathway.md/studies/reckhNqoWaOSMrz7Y 1/2 6/28/23, 1:17 AM DISCHARGE Pathway Rate of composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke over 3.5 years 3.0 % 3 2.3 % 2.1 1.5 % 0.8 % No significant difference 0.0 % Computed tomography Invasive coronary angiography No significant difference in the rate of composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke over 3.5 years (2.1% vs. 3%; HR 0.7, 95% CI 0.46 to 1.07) Secondary outcomes Borderline significant decrease in major procedure-related complications (0.5% vs. 1.9%; HR 0.26, 95% CI 0.13 to 0.55) No significant difference in the rate of angina during at the last 4 weeks of follow-up (8.8% vs. 7.5%; OR 1.17, 95% CI 0.92 to 1.48) No significant difference in European quality of life-5 dimensions visual-analog scale score (71.8 vs. 71.1; MD 0.31, 95% CI -0.76 to 1.38) Conclusion In patients with stable chest pain who had an intermediate pretest probability of obstructive coronary artery disease and were referred for invasive coronary angiography, CT was not superior to invasive coronary angiography with respect to the rate of composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke over 3.5 years. Reference DISCHARGE Trial Group, P l Maurovich-Horvat, Maria Bosserdt et al. CT or Invasive Coronary Angiography in Stable Chest Pain. N Engl J Med. 2022 Apr 28;386(17):1591-1602. Open reference URL https://web.pathway.md/studies/reckhNqoWaOSMrz7Y 2/2

6/28/23, 1:21 AM Diuretic Comparison Project Pathway Feedback Search Clinical Topics Home Studies Diuretic Comparison Project Diuretic Comparison Project Disease Hypertension Trial question Is chlorthalidone superior to hydrochlorothiazide for the prevention of cardiovascular events in patients with hypertension? Study design Multi-center Open label RCT Population Characteristics of study participants 3.0% female N = 13523 97.0% male 13523 patients (431 female, 13092 male) Inclusion criteria: adult patients 65 years of age receiving hydrochlorothiazide at a dose of 25-50 mg/day Key exclusion criteria: receipt of blood-pressure medication containing hydrochlorothiazide combined with other agents Interventions N=6756 chlorthalidone (at a daily dose of 12.5-25 mg) N=6767 hydrochlorothiazide (at a daily dose of 25-50 mg) Primary outcome https://web.pathway.md/studies/recd7zuj6v0ZbxVVw 1/2 6/28/23, 1:21 AM Diuretic Comparison Project Pathway Composite outcome of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death 10.4 % 10.4 10 7.8 % 5.2 % 2.6 % No significant difference 0.0 % Chlorthalidone Hydrochlorothiazide No significant difference in composite outcome of nonfatal myocardial infarction, stroke, HF resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer- related death (10.4% vs. 10%; HR 1.04, 95% CI 0.94 to 1.16) Secondary outcomes No significant difference in myocardial infarction (2.1% vs. 2.1%; HR 1.02, 95% CI 0.8 to 1.28) No significant difference in hospitalization due to HF (3.6% vs. 3.4%; HR 1.04, 95% CI 0.87 to 1.25) No significant difference in non-cancer-related death (5.3% vs. 5.2%; HR 1.01, 95% CI 0.88 to 1.17) Safety outcomes No significant difference in hospitalization for any cause. Significant difference in hypokalemia (6.0% vs. 4.4%). Conclusion In adult patients 65 years of age receiving hydrochlorothiazide at a dose of 25-50 mg/day, chlorthalidone was not superior to hydrochlorothiazide with respect to the composite outcome of nonfatal myocardial infarction, stroke, HF resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Reference Areef Ishani, William C Cushman, Sarah M Leatherman et al. Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events. N Engl J Med. 2022 Dec 29;387(26):2401-2410. Open reference URL https://web.pathway.md/studies/recd7zuj6v0ZbxVVw 2/2

6/28/23, 1:21 AM Diuretics in PE Pathway Feedback Search Clinical Topics Home Studies Diuretics in PE Diuretics in PE Disease Pulmonary embolism Trial question Is diuretic therapy superior to volume expansion in patients with acute intermediate high-risk PE? Study design Multi-center Open label RCT Population 60 patients Inclusion criteria: patients with intermediate high-risk PE Key exclusion criteria: thrombolysis, cardiogenic shock, severe chronic renal impairment, pregnancy Interventions N=30 diuretic therapy (furosemide at a dose of 40 mg IV) N=30 volume expansion (isotonic sodium chloride 9%) Primary outcome Time to b-type natriuretic peptide normalization 108.0 hours 108 81.0 hours 56 54.0 hours 27.0 hours No significant difference 0.0 hours https://web.pathway.md/studies/recEXLpUReoqcKaut 1/2 6/28/23, 1:21 AM Diuretics in PE Pathway Diuretic therapy Volume expansion No significant difference in time to b-type natriuretic peptide normalization (56 hours vs. 108 hours; AD -52 hours, 95% CI -104.09 to 0.09) Secondary outcomes Significant decrease in achievement of a 50% decrease in b-type natriuretic peptide from peak value (36 hours vs. 54 hours; AD -18 hours, 95% CI -29.87 to -6.13) Significant increase in b-type natriuretic peptide concentration reduction within first 12 hours (42% vs. 12%; AD 30%, 95% CI 12.2 to 47.8) Conclusion In patients with intermediate high-risk PE, diuretic therapy was superior to volume expansion with respect to time to b-type natriuretic peptide normalization. Reference Emile Ferrari, Benjamin Sartre, Mohamed Labbaoui et al. Diuretics Versus Volume Expansion in the Initial Management of Acute Intermediate High-Risk Pulmonary Embolism. Lung. 2022 Apr;200(2):179-185. Open reference URL https://web.pathway.md/studies/recEXLpUReoqcKaut 2/2

6/28/23, 1:17 AM DIVA Pathway Feedback Search Clinical Topics Home Studies DIVA DIVA Disease Coronary artery disease Trial question What is the role of drug-eluting stents in patients undergoing stenting of de-novo saphenous vein bypass graft lesions? Study design Multi-center Double blinded RCT Population 599 patients (2 female, 595 male) Inclusion criteria: patients who had at least one significant de-novo SVG lesion requiring PCI with intent to use embolic protection devices Key exclusion criteria: planned noncardiac surgery within 12 months of screening, ST-segment elevation acute myocardial infarction, target SVG that was the last remaining vessel or was a left main equivalent, previous percutaneous treatment of the target vessel within the previous 12 months, or hemorrhagic diatheses Interventions N=292 drug-eluting stents (coronary revascularization with drug-eluting stents) N=305 bare metal stents (coronary revascularization with bare metal stents) Primary outcome Myocardial infarction during follow-up 10.0 % 10 10 7.5 % 5.0 % 2 5 % https://web.pathway.md/studies/recjr2NZ687dsk2zu 1/2 6/28/23, 1:17 AM 2.5 % DIVA Pathway No significant difference 0.0 % Drug-eluting stents Bare metal stents No significant difference in myocardial infarction during follow-up (10% vs. 10%; HR 0.94, 95% CI 0.56 to 1.57) Secondary outcomes No significant difference in revascularization (19% vs. 17%; HR 1.11, 95% CI 0.76 to 1.61) Safety outcomes No significant difference in serious adverse events. Conclusion In patients who had at least one significant de-novo SVG lesion requiring PCI with intent to use embolic protection devices, drug-eluting stents were not superior to bare metal stents with respect to myocardial infarction during follow-up. Reference Brilakis ES, Edson R, Bhatt DL et al. Drug-eluting stents versus bare-metal stents in saphenous vein grafts: a double-blind, randomised trial. Lancet. 2018 May 19;391(10134):1997-2007. Open reference URL https://web.pathway.md/studies/recjr2NZ687dsk2zu 2/2

6/28/23, 1:17 AM DOLPHIN Pathway Feedback Search Clinical Topics Home Studies DOLPHIN DOLPHIN Trial question What is the role of model-informed precision dosing of -lactam antibiotics and ciprofloxacin in critically ill patients? Study design Multi-center Open label RCT Population Characteristics of study participants 38.0% female N = 388 62.0% male 388 patients (149 female, 239 male) Inclusion criteria: adult patients admitted to the ICU who were treated with antibiotics Key exclusion criteria: pregnancy; antibiotic cessation before first blood sample collection; admittance for burn wounds, or receipt of study antibiotics as part of selective decontamination of digestive tract prophylaxis Interventions N=189 model-informed precision dosing (individualized dose and interval adjustments based on monitoring serum drug levels combined with pharmacometric modeling of -lactam antibiotics and ciprofloxacin) N=199 standard dosing (antibiotic dosing based on local guidelines and freely adjusted by attending physician) Primary outcome Intensive care unit length of stay 10.0 days 10 8 7.5 days https://web.pathway.md/studies/rec1UTgJL7HwpYJGk 1/2 6/28/23, 1:17 AM DOLPHIN Pathway 5.0 days 2.5 days No significant difference 0.0 days Model-informed precision dosing Standard dosing No significant difference in ICU length of stay (10 days vs. 8 days; aIRR 1.16, 95% CI 0.96 to 1.41) Secondary outcomes No significant difference in target attainment before intervention at day 1 (55.6% vs. 60.9%; aOR 0.78, 95% CI 0.52 to 1.18) No significant difference in death in the ICU (21.7% vs. 18.1%; aOR 1.21, 95% CI 0.74 to 2.02) No significant difference in death at day 28 (26.5% vs. 24.6%; aOR 1.04, 95% CI 0.65 to 1.66) Safety outcomes No significant difference in adverse events. Conclusion In adult patients admitted to the ICU who were treated with antibiotics, model-informed precision dosing was not superior to standard dosing with respect to ICU length of stay. Reference Tim M J Ewoldt, Alan Abdulla, Wim J R Rietdijk et al. Model-informed precision dosing of beta- lactam antibiotics and ciprofloxacin in critically ill patients: a multicentre randomised clinical trial. Intensive Care Med. 2022 Dec;48(12):1760-1771. Open reference URL https://web.pathway.md/studies/rec1UTgJL7HwpYJGk 2/2

6/28/23, 1:19 AM DOREMI Pathway Feedback Search Clinical Topics Home Studies DOREMI DOREMI Disease Cardiogenic shock Trial question Is milrinone superior to dobutamine for the treatment of cardiogenic shock? Study design Single center Double blinded RCT Population Characteristics of study participants 36.0% female N = 192 64.0% male 192 patients (70 female, 122 male) Inclusion criteria: adult patients with cardiogenic shock Key exclusion criteria: pregnancy, out-of-hospital cardiac arrest, healthcare team preference for use of specific inotrope Interventions N=96 milrinone (at a dose of 0.125 g/kg/min to > 0.500 g/kg/min) N=96 dobutamine (at a dose of 2.5 g/kg/min to > 10.0 g/kg/min) Primary outcome In-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke https://web.pathway.md/studies/recTakOuM3XvgzPWQ 1/2 6/28/23, 1:19 AM DOREMI Pathway diagnosed by a neurologist, or initiation of renal replacement therapy 54.0 % 54 49 40.5 % 27.0 % No significant difference 13.5 % 0.0 % Milrinone Dobutamine No significant difference in in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, TIA or stroke diagnosed by a neurologist, or initiation of RRT (49% vs. 54%; RR 0.9, 95% CI 0.69 to 1.19) Secondary outcomes No significant difference in in-hospital death (37% vs. 43%; RR 0.85, 95% CI 0.6 to 1.21) No significant difference in resuscitated cardiac arrest (7% vs. 9%; HR 0.78, 95% CI 0.29 to 2.07) No significant difference in receipt of mechanical circulatory support (12% vs. 15%; HR 0.78, 95% CI 0.36 to 1.71) Safety outcomes No significant differences in serum lactate level, serum creatinine level, HR, arrhythmias. Conclusion In adult patients with cardiogenic shock, milrinone was not superior to dobutamine with respect to a in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, TIA or stroke diagnosed by a neurologist, or initiation of RRT. Reference Rebecca Mathew, Pietro Di Santo, Richard G Jung et al. Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock. N Engl J Med. 2021 Aug 5;385(6):516-525. Open reference URL https://web.pathway.md/studies/recTakOuM3XvgzPWQ 2/2

6/28/23, 1:21 AM DoxyPEP Pathway Feedback Search Clinical Topics Home Studies DoxyPEP DoxyPEP Disease Disease Chlamydia trachomatis infection Syphilis infection Trial question What is the role of doxycycline postexposure prophylaxis among MSM and transgender women with recent bacterial STIs? Study design Multi-center Open label RCT Population Characteristics of study participants 4.0% female N = 501 96.0% male 501 patients (19 female, 482 male) Inclusion criteria: MSM and transgender women with bacterial STIs in the previous 12 months Key exclusion criteria: tetracycline allergy; receipt of medications with drug interactions with doxycycline; plan for receipt of doxycycline for an extended period Interventions N=339 doxycycline (at a dose of 200 mg within 72 hours of condomless sex) N=162 standard care (standard of care without the use of doxycycline) Primary outcome Any sexually transmitted infections per follow-up quarter, in pre-exposure prophylaxis cohort https://web.pathway.md/studies/recy6c1gUyrRv4Txw 1/2 6/28/23, 1:21 AM DoxyPEP Pathway 31.9 % 31.9 23.9 % 15.9 % Significant decrease 10.7 8.0 % NNT = 5 0.0 % Doxycycline Standard care Significant decrease in any STIs per follow-up quarter, in pre-exposure prophylaxis cohort (10.7% vs. 31.9%; RR 0.34, 95% CI 0.24 to 0.46) Secondary outcomes Significant decrease in STIs per follow-up quarter, in persons living with human immunodeficiency virus infection cohort (11.8% vs. 30.5%; RR 0.38, 95% CI 0.24 to 0.6) Borderline significant decrease in gonorrhea infection in pre-exposure prophylaxis cohort (9.1% vs. 20.2%; RR 0.45, 95% CI 0.32 to 0.65) Borderline significant decrease in chlamydia infection in pre-exposure prophylaxis cohort (1.4% vs. 12.1%; RR 0.12, 95% CI 0.05 to 0.25) Safety outcomes No significant difference in adverse events. Conclusion In MSM and transgender women with bacterial STIs in the previous 12 months, doxycycline was superior to standard care with respect to any STIs per follow-up quarter, in pre-exposure prophylaxis cohort. Reference Anne F Luetkemeyer, Deborah Donnell, Julia C Dombrowski et al. Postexposure Doxycycline to Prevent Bacterial Sexually Transmitted Infections. N Engl J Med. 2023 Apr 6;388(14):1296-1306. Open reference URL https://web.pathway.md/studies/recy6c1gUyrRv4Txw 2/2

6/28/23, 1:19 AM DRAFFT2 Pathway Feedback Search Clinical Topics Home Studies DRAFFT2 DRAFFT2 Disease Distal radius fracture Trial question Is surgical fixation with K-wires superior to casting in patients with dorsally-displaced distal radius fracture? Study design Multi-center Open label RCT Population Characteristics of study participants 83.0% female N = 500 17.0% male 500 patients (417 female, 83 male) Inclusion criteria: adult patients with a dorsally-displaced distal radius fracture that needed manipulation Key exclusion criteria: injury > 2 weeks old; fracture extending > 3 cm from radiocarpal joint; open fracture with Gustilo and Anderson grading > 1; inability to reduce the joint surface of fracture by closed manipulation Interventions N=245 K-wire fixation (manipulation and surgical fixation with K-wires plus cast) N=255 cast (manipulation and moulded cast only) https://web.pathway.md/studies/rechT1KZdDfygzNjA 1/2 6/28/23, 1:19 AM DRAFFT2 Pathway Primary outcome Patient Rated Wrist Evaluation score at 12 months 21.2 21.2 20.7 15.9 10.6 5.3 No significant difference 0.0 K-wire fixation Cast No significant difference in Patient Rated Wrist Evaluation score at 12 months (20.7 vs. 21.2; MD -0.34, 95% CI -4.33 to 3.66) Secondary outcomes No significant difference in Patient Rated Wrist Evaluation at 6 months (27.6 vs. 28.4; MD -0.32, 95% CI -4.26 to 3.62) No significant difference in the mean score of EuroQol-5D at 12 months (0.78 vs. 0.81; AD -0.03, 95% CI -0.07 to 0.02) No significant difference in the mean score of EuroQol VAS at 12 months (80.42 vs. 81.11; AD -0.51, 95% CI -4.3 to 3.29) Safety outcomes No significant differences in blood clots, complex regional pain syndrome. Significant difference in surgery for loss of fracture reduction in the first 6 weeks (0.4% vs. 13%). Conclusion In adult patients with a dorsally-displaced distal radius fracture that needed manipulation, K-wire fixation was not superior to cast with respect to Patient Rated Wrist Evaluation score at 12 months. Reference Matthew L Costa, Juul Achten, Alexander Ooms et al. Surgical fixation with K-wires versus casting in adults with fracture of distal radius: DRAFFT2 multicentre randomised clinical trial. BMJ. 2022 Jan 19;376:e068041. Open reference URL https://web.pathway.md/studies/rechT1KZdDfygzNjA 2/2

6/28/23, 1:19 AM DRAIN Pathway Feedback Search Clinical Topics Home Studies DRAIN DRAIN Disease Heart failure Trial question What is the role of continuous infusion of furosemide in patients with acute decompensation of advanced chronic HF and high risk for diuretic resistance? Study design Single center Double blinded RCT Population Characteristics of study participants 10.0% female N = 80 90.0% male 80 patients (8 female, 72 male) Inclusion criteria: patients admitted for acute decompensation of advanced chronic HF with criteria of high risk for diuretic resistance Key exclusion criteria: reversible causes of acute HF, cardiogenic shock, chronic renal failure stage V Interventions N=40 continuous infusion (intravenous infusion of furosemide 120 mg/day or 240 mg/day continuously for up to 72 hours) N=40 bolus intermittent (intravenous furosemide bolus of 120 mg/day or 240 mg/day every 12 hours for up to 72 hours) https://web.pathway.md/studies/recRZRgWN1QPyqUX8 1/2 6/28/23, 1:19 AM DRAIN Pathway Primary outcome Freedom from congestion at 72 hours 48.0 % 48 36.0 % 25 24.0 % Significant increase 12.0 % NNT = 4 0.0 % Continuous infusion Bolus intermittent Significant increase in freedom from congestion at 72 hours (48% vs. 25%; OR 2.71, 95% CI 1.05 to 7) Secondary outcomes Significant increase in total urinary output after 72 hours (10020 ,020 ml vs. 8612 ,020 ml; OR 1.2, 95% CI 1.03 to 1.4) Significant decrease in treatment failure (15% vs. 38%; OR 0.29, 95% CI 0.1 to 0.87) No significant difference in worsening HF after 72 hours (20% vs. 30%; OR 0.59, 95% CI 0.18 to 1.83) Safety outcomes No significant differences in worsening of renal function, heart transplantation, LV assist device implantation, or in-hospital death. Significant difference in diuretic response (-1.0 vs. -0.6) and estimated right atrial pressure at echo-Doppler after 72 hours (13.5 mmHg vs. 16.4 mmHg). Conclusion In patients admitted for acute decompensation of advanced chronic HF with criteria of high risk for diuretic resistance, continuous infusion was superior to bolus intermittent with respect to freedom from congestion at 72 hours. Reference Simone Frea, Stefano Pidello, Alessandra Volpe et al. Diuretic treatment in high-risk acute decompensation of advanced chronic heart failure-bolus intermittent vs. continuous infusion of furosemide: a randomized controlled trial. Clin Res Cardiol. 2020 Apr;109(4):417-425. Open reference URL https://web.pathway.md/studies/recRZRgWN1QPyqUX8 2/2

6/28/23, 1:19 AM DREAM Pathway Feedback Search Clinical Topics Home Studies DREAM DREAM Trial question Is early surgery superior to a strategy of exercise and education in young adults with meniscal tear? Study design Multi-center Open label RCT Population Characteristics of study participants 28.0% female N = 121 72.0% male 121 patients (34 female, 87 male) Inclusion criteria: young adults with MRI-verified meniscal tears Key exclusion criteria: previous surgery on the affected knee; clinical suspicion of displaced bucket-handle tear confirmed by MRI; fracture of the affected extremity within the previous 12 months; complete rupture of 1 knee ligaments Interventions N=60 early surgery (partial meniscectomy or meniscal repair) N=61 exercise and education (12-week supervised exercise therapy and education with the option of surgery later if needed) Primary outcome Improvement in Knee Injury and Osteoarthritis Outcome Score at 12 months 19.2 19.2 16.4 14.4 9.6 4.8 https://web.pathway.md/studies/rectWKLo1sEx5NdZS 1/2 6/28/23, 1:19 AM DREAM Pathway No significant difference 0.0 Early surgery Exercise and education No significant difference in improvement in Knee Injury and OA Outcome Score at 12 months (19.2 vs. 16.4; aMD 5.4, 95% CI -0.7 to 11.4) Secondary outcomes No significant difference in improvement in pain subscale of Knee Injury and OA Outcome Score at 12 months (15.1 vs. 13.3; aMD 6, 95% CI 0.4 to 11.7) Borderline significant increase in improvement in Western Ontario Meniscal Evaluation Tool score at 12 months (24 vs. 18.8; aMD 9.4, 95% CI 1.7 to 17) Borderline significant decrease in improvement in isometric lower extremity muscle strength at 12 months (1.75 kg vs. 29.1 kg; aMD -24.4, 95% CI -39.6 to -8.7) Safety outcomes No significant difference in serious adverse events and non-serious adverse events. Conclusion In young adults with MRI-verified meniscal tears, early surgery was not superior to exercise and education with respect to improvement in Knee Injury and OA Outcome Score at 12 months. Reference S ren T. Skou, Ph.D., Per H lmich et al. Early Surgery or Exercise and Education for Meniscal Tears in Young Adults. NEJM Evid. 2022;1(2). Open reference URL https://web.pathway.md/studies/rectWKLo1sEx5NdZS 2/2

6/28/23, 1:21 AM Duct Tape for Treatment of the Common Wart Pathway Feedback Search Clinical Topics Home Studies Duct Tape for Treatment of the Common Wart Duct Tape for Treatment of the Common Wart Disease Cutaneous warts Trial question Is duct tape occlusion superior to cryotherapy in patients with warts? Study design Single center Open label RCT Population Characteristics of study participants 51.0% female N = 51 49.0% male 51 patients (26 female, 25 male) Inclusion criteria: patients (age range, 3-22 years) with warts Key exclusion criteria: immunodeficiency states; chronic skin diseases, such as eczema or psoriasis; allergy to adhesive tape; warts located on the face, periungual, perianal, or genital areas; and previous cryotherapy for the same wart Interventions N=26 local treatment with duct tape occlusion (applied directly to the wart for a maximum of 2 months) N=25 local cryotherapy (liquid nitrogen applied to each wart for 10 seconds every 2-3 weeks for a maximum of 6 treatments) https://web.pathway.md/studies/recJYzUIFFXfXG20Y 1/2 6/28/23, 1:21 AM Duct Tape for Treatment of the Common Wart Pathway Primary outcome Complete resolution of wart 85.0 % 85 63.8 % 60 42.5 % 21.3 % No significant difference 0.0 % Local treatment with duct tape occlusion Local cryotherapy No significant difference in complete resolution of wart (85% vs. 60%; AD 25%, 95% CI -0.04 to 50.04) Conclusion In patients (age range, 3-22 years) with warts, local treatment with duct tape occlusion was superior to local cryotherapy with respect to complete resolution of wart. Reference Focht DR rd, Spicer C, Fairchok MP. The efficacy of duct tape vs cryotherapy in the treatment of verruca vulgaris (the common wart). Arch Pediatr Adolesc Med. 2002 Oct;156(10):971-4. Open reference URL https://web.pathway.md/studies/recJYzUIFFXfXG20Y 2/2

6/28/23, 1:19 AM DUMAS Pathway Feedback Search Clinical Topics Home Studies DUMAS DUMAS Disease Acute ischemic stroke Trial question What is the role of dual thrombolytic therapy with mutant prourokinase and small bolus alteplase in patients with ischemic stroke? Study design Multi-center Open label RCT Population Characteristics of study participants 38.0% female N = 238 62.0% male 238 patients (91 female, 147 male) Inclusion criteria: adult patients with ischemic stroke Key exclusion criteria: eligibility for endovascular thrombectomy; prestroke disability interfering with assessment of functional outcome; pregnancy; contraindication to MRI Interventions N=121 mutant prourokinase (bolus of 5 mg intravenous alteplase and 40 mg intravenous infusion of mutant prourokinase) N=117 alteplase alone (standard treatment with 0.9 mg/kg of intravenous alteplase alone) Primary outcome https://web.pathway.md/studies/reccIhu45i5WWUWGm 1/2 6/28/23, 1:19 AM DUMAS Pathway Any intracranial hemorrhage on neuroimaging at 24 hours 13.7 % 13.7 13.2 10.3 % 6.8 % 3.4 % No significant difference 0.0 % Mutant prourokinase Alteplase alone No significant difference in any intracranial hemorrhage on neuroimaging at 24 hours (13.2% vs. 13.7%; OR 0.98, 95% CI 0.46 to 2.12) Secondary outcomes No significant difference in improvement in NIHSS score at 24 hours (63.6% vs. 70.9%; OR 0.68, 95% CI 0.39 to 1.2) No significant difference in mean ordinal mRS score at day 30 (2 vs. 2; OR 1.16, 95% CI 0.74 to 1.84) No significant difference in mean infarct volume at 24 hours (5.1 mL vs. 7 mL; AD -1.9 mL, 95% CI -3.8 to 0) Safety outcomes No significant differences in death at day 30, serious adverse events. Conclusion In adult patients with ischemic stroke, mutant prourokinase was not superior to alteplase alone with respect to any intracranial hemorrhage on neuroimaging at 24 hours. Reference Nadinda A M van der Ende, Bob Roozenbeek, Lucas E M Smagge et al. Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke. JAMA Neurol. 2023 May 22;e231262. Online ahead of print. Open reference URL https://web.pathway.md/studies/reccIhu45i5WWUWGm 2/2

6/28/23, 1:21 AM Duration of antibiotics in community-acquired pneumonia Pathway Feedback Search Clinical Topics Home Studies Duration of antibiotics in community-acquired pneumonia Duration of antibiotics in community-acquired pneumonia Disease Community-acquired pneumonia Trial question What is the role of duration of antibiotic treatment in patients with community-acquired pneumonia? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 312 63.0% male 312 patients (116 female, 196 male) Inclusion criteria: hospitalized patients with community-acquired pneumonia (CAP) Key exclusion criteria: human immunodeficiency virus infection; chronic immunosuppression; lived in a nursing home; discharge from an acute care hospital, an onsite subacute care unit, or a palliative care unit within the previous 14 days; taken antibiotics in the 30 days before admission Interventions N=162 protocolized discontinuation of antibiotics after 5 days (duration of antibiotic treatment for a minimum of 5 days) N=150 physician-guided antibiotic discontinuation (duration of antibiotic treatment determined by physicians) https://web.pathway.md/studies/recfH6vvSTTI2Dig8 1/2 6/28/23, 1:21 AM Duration of antibiotics in community-acquired pneumonia Pathway Primary outcome Clinical success at day 10 56.3 % 56.3 48.6 42.2 % 28.1 % Difference not exceeding nonferiority margin 14.1 % 0.0 % Protocolized discontinuation of antibiotics after 5 days Physician-guided antibiotic discontinuation Difference not exceeding nonferiority margin in clinical success at day 10 (56.3% vs. 48.6%; RR 1.16, 95% CI -0.53 to 2.85) Secondary outcomes No significant difference in clinical success at day 30 (91.9% vs. 88.6%; RR 1.04, 95% CI -1.03 to 3.11) No significant difference in mean CAP symptom questionnaire scores at day 5 (27.2 vs. 24.7; AD 2.5, 95% CI -0.48 to 5.48) No significant difference in mean CAP symptom questionnaire scores at day 10 (17.9 vs. 18.6; AD -0.7, 95% CI -3.99 to 2.59) Conclusion In hospitalized patients with community-acquired pneumonia (CAP), protocolized discontinuation of antibiotics after 5 days were noninferior to physician-guided antibiotic discontinuation with respect to clinical success at day 10. Reference Uranga A, Espana PP, Bilbao A et al. Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial. JAMA Intern Med. 2016 Sep 1;176(9):1257-65. Open reference URL https://web.pathway.md/studies/recfH6vvSTTI2Dig8 2/2

6/28/23, 10:12 PM Early liver transplantation for severe alcoholic hepatitis Pathway Feedback Search Clinical Topics Home Studies Early liver transplantation for severe alcoholic hepatitis Early liver transplantation for severe alcoholic hepatitis Disease Disease Disease Alcohol-related liver disease Alcoholic hepatitis Liver tr Trial question What is the role of early liver transplantation in patients with severe alcoholic hepatitis? Study design Multi-center Open label RCT Population Characteristics of study participants 42.0% female N = 52 58.0% male 52 patients (22 female, 30 male) Inclusion criteria: patients with no prior episodes of alcoholic hepatitis and had scores of 0.45 according to the Lille model Key exclusion criteria: uncontrolled infection, recent gastrointestinal bleeding, positive for hepatitis B, HCV and HIV antibodies, and severe psychiatric disorders Interventions N=26 undergoing early liver transplantation (early liver transplantation within a median of 13 days after nonresponse to medical therapy) N=26 not undergoing liver transplantation (matched patients who did not undergo transplantation) Primary outcome Cumulative survival at 6 months 77.0 % 77 https://web.pathway.md/studies/recHa3qasoSKfglXz 1/2 6/28/23, 10:12 PM Early liver transplantation for severe alcoholic hepatitis Pathway 57.8 % 38.5 % Significant increase 23 19.3 % NNT = 2 0.0 % Undergoing early liver transplantation Not undergoing liver transplantation Significant increase in cumulative survival at 6 months (77% vs. 23%; RR 3.35, 95% CI 1.36 to 5.34) Secondary outcomes Significant increase in survival at 2 year follow-up, in univariate analysis (71% vs. 23%; RR 3.09, 95% CI 1.26 to 4.92) Conclusion In patients with no prior episodes of alcoholic hepatitis and had scores of 0.45 according to the Lille model, undergoing early liver transplantation was superior to not undergoing liver transplantation with respect to cumulative survival at 6 months. Reference Mathurin P, Moreno C, Samuel D et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med. 2011 Nov 10;365(19):1790-800. Open reference URL https://web.pathway.md/studies/recHa3qasoSKfglXz 2/2

6/28/23, 10:11 PM Early Mobilization in the ICU Pathway Feedback Search Clinical Topics Home Studies Early Mobilization in the ICU Early Mobilization in the ICU Trial question What is the effect of early mobilization in ICU patients after mechanical ventilation? Study design Single center Open label RCT Population Characteristics of study participants 43.0% female N = 198 57.0% male 198 patients (85 female, 113 male) Inclusion criteria: adult patients who were functionally independent and mechanically ventilated Key exclusion criteria: rapidly changing neurological conditions; cardiac arrest as cause of respiratory failure; elevated ICP; pregnancy; terminal condition; TBI Interventions N=99 early mobilization (early physical therapy occupational therapy delivered by a team consisting of physical and occupational therapists) N=99 standard care (physical therapy occupational therapy delivered as ordered by the primary ICU team) Primary outcome Rate of cognitive impairment 1 year after hospital discharge 43.0 % 43 32.3 % 24 21.5 % Significant decrease 10.8 % NNT = 5 0.0 % https://web.pathway.md/studies/recN7G69rXEyLO2g3 1/2 6/28/23, 10:11 PM Early Mobilization in the ICU Pathway Early mobilization Standard care Significant decrease in the rate of cognitive impairment 1 year after hospital discharge (24% vs. 43%; ARD -19.2, 95% CI -32.1 to -6.3) Secondary outcomes Significant increase in Montreal Cognitive Assessment score at 1 year (26 vs. 23; AD 3, 95% CI 1 to 4) Significant decrease in cognitive impairment at hospital discharge (54% vs. 69%; ARD -15.2, 95% CI -28.6 to -1.7) Significant decrease in ICU-acquired weakness at 1 year (ARD -14.1, 95% CI -21 to -7.3) Safety outcomes Significant difference in adverse events (6% vs. 0%). Conclusion In adult patients who were functionally independent and mechanically ventilated, early mobilization was superior to standard care with respect to the rate of cognitive impairment 1 year after hospital discharge. Reference Bhakti K Patel, Krysta S Wolfe, Shruti B Patel et al. Effect of early mobilisation on long-term cognitive impairment in critical illness in the USA: a randomised controlled trial. Lancet Respir Med. 2023 Jun;11(6):563-572. Open reference URL https://web.pathway.md/studies/recN7G69rXEyLO2g3 2/2

6/28/23, 10:12 PM Early palliative care for metastatic NSLC Pathway Feedback Search Clinical Topics Home Studies Early palliative care for metastatic NSLC Early palliative care for metastatic NSLC Disease Non-small cell lung cancer Trial question What is the effect of early palliative care in patients with metastatic non-small cell lung cancer? Study design Single center Open label RCT Population Characteristics of study participants 52.0% female N = 151 48.0% male 151 patients (78 female, 73 male) Inclusion criteria: patients with newly diagnosed metastatic non-small cell lung cancer, within 8 weeks after diagnosis Key exclusion criteria: patients already receiving care from palliative care service, ECOG performance status > 2, and not able to read and respond to questions in English Interventions N=77 early palliative care (early palliative care integrated with standard oncologic care) N=74 standard oncologic care (no routine early palliative care) Primary outcome FACT-L quality of life scores at 12 weeks 98.0 98 91.5 73.5 https://web.pathway.md/studies/recWvKApMB1OxiscS 1/2 6/28/23, 10:12 PM Early palliative care for metastatic NSLC Pathway 49.0 24.5 Significant increase 0.0 Early palliative care Standard oncologic care Significant increase in FACT-L quality of life scores at 12 weeks (98 vs. 91.5; MD 6.5, 95% CI 0.5 to 12.4) Secondary outcomes Significant decrease in depression at 12 weeks, as assessed by Hospital Anxiety and Depression Scale (16% vs. 38%; RR 0.42, 95% CI 0.1 to 0.74) Significant increase in median survival (11.6 vs. 8.9; MD 2.7, 95% CI 0.42 to 4.98) Conclusion In patients with newly diagnosed metastatic non-small cell lung cancer, within 8 weeks after diagnosis, early palliative care was superior to standard oncologic care with respect to a FACT-L quality of life scores at 12 weeks. Reference Temel JS, Greer JA, Muzikansky A et al. Early palliative care for patients with metastatic non- small-cell lung cancer. N Engl J Med. 2010 Aug 19;363(8):733-42. Open reference URL https://web.pathway.md/studies/recWvKApMB1OxiscS 2/2

6/28/23, 10:11 PM Early Prone in ARDS Pathway Feedback Search Clinical Topics Home Studies Early Prone in ARDS Early Prone in ARDS Disease Acute respiratory distress syndr Trial question Is prone ventilation superior to supine ventilation in patients with severe ARDS? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 136 63.0% male 136 patients (50 female, 86 male) Inclusion criteria: intubated patients with severe ARDS Key exclusion criteria: relapse of > 48 hours since meeting inclusion criteria; systolic BP < 80 mmHg despite vasopressors; pelvic or spine fractures; cranial trauma, increased ICP; moribund Interventions N=76 prone ventilation (continuous ventilation in face down position for 20 hours/day) N=60 supine ventilation (ventilation in face up position) Primary outcome Death in intensive care unit 58.0 % 58 43.5 % 43 https://web.pathway.md/studies/recwZybDWMLSyioCX 1/2 6/28/23, 10:11 PM Early Prone in ARDS Pathway 29.0 % 14.5 % No significant difference 0.0 % Prone ventilation Supine ventilation No significant difference in death in the ICU (43% vs. 58%; RR 0.74, 95% CI -0.19 to 1.67) Secondary outcomes No significant difference in death in the hospital (50% vs. 62%; RR 0.81, 95% CI -0.48 to 2.1) No significant difference in length of stay in the ICU (20.5 days vs. 19.1 days; AD 1.4 days, 95% CI -5.41 to 8.21) No significant difference in pneumothorax (9.2% vs. 6.7%; RR 1.37, 95% CI -6.96 to 9.7) Safety outcomes No significant differences in pressure sores, conjunctival hemorrhage. Conclusion In intubated patients with severe ARDS, prone ventilation was not superior to supine ventilation with respect to death in the ICU. Reference Jordi Mancebo, Rafael Fern ndez, Lluis Blanch et al. A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med. 2006 Jun 1;173(11):1233-9. Open reference URL https://web.pathway.md/studies/recwZybDWMLSyioCX 2/2

6/28/23, 10:12 PM Early TIPS for variceal hemorrhage Pathway Feedback Search Clinical Topics Home Studies Early TIPS for variceal hemorrhage Early TIPS for variceal hemorrhage Disease Disease Disease Liver cirrhosis Portal hypertension Varicea Trial question What is the role of early use of TIPS in patients with cirrhosis who are hospitalized for acute variceal bleeding and at high risk for treatment failure? Study design Multi-center Open label RCT Population Characteristics of study participants 30.0% female N = 63 70.0% male 63 patients (19 female, 44 male) Inclusion criteria: patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy Key exclusion criteria: age > 75 years, pregnancy, HCC that did not meet the Milano criteria for transplantation, previous pharmacologic therapy combined with endoscopic treatment to prevent rebleeding, previous use of a portosystemic shunt or TIPS, bleeding from isolated gastric or ectopic varices, total portal vein thrombosis, and HF Interventions N=32 early TIPS implantation (treatment with a PTFE-covered stent within 72 hours after randomization) N=31 vasoactive drugs and endoscopic band ligation (continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation) https://web.pathway.md/studies/rec6tkFAqlPVXfJ2i 1/2 6/28/23, 10:12 PM Early TIPS for variceal hemorrhage Pathway Primary outcome Freedom from rebleeding or failure to control bleeding 97.0 % 97 72.8 % 50 48.5 % Significant increase 24.3 % NNT = 2 0.0 % Early TIPS implantation Vasoactive drugs and endoscopic band ligation Significant increase in freedom from rebleeding or failure to control bleeding (97% vs. 50%; ARR 47, 95% CI 25 to 69) Secondary outcomes Significant increase in the rate of 1-year actuarial survival (86% vs. 61%; ARR 25, 95% CI 2 to 48) Significant increase in days in the ICU (3.6 days vs. 8.6 days; AD 5 days, 95% CI 1.19 to 8.81) Safety outcomes No significant difference in serious adverse events. Conclusion In patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy, early TIPS implantation was superior to vasoactive drugs and endoscopic band ligation with respect to freedom from rebleeding or failure to control bleeding. Reference Garcia-Pagan JC, Caca K, Bureau C et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010 Jun 24;362(25):2370-9. Open reference URL https://web.pathway.md/studies/rec6tkFAqlPVXfJ2i 2/2

6/28/23, 9:49 PM EARNEST Pathway Feedback Search Clinical Topics Home Studies EARNEST EARNEST Disease Ulcerative colitis Trial question What is the role of vedolizumab in patients who developed chronic pouchitis after undergoing ileal pouch-anal anastomosis for ulcerative colitis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 31.0% female N = 102 69.0% male 102 patients (32 female, 70 male) Inclusion criteria: adult patients who developed chronic pouchitis after undergoing ileal pouch- anal anastomosis for ulcerative colitis Key exclusion criteria: Crohn's disease; irritable pouch syndrome; active or latent tuberculosis; chronic hepatitis B or chronic HCV infection Interventions N=51 vedolizumab (intravenous infusion at a dose of 300 mg on day 1 and at weeks 2, 6, 14, 22, and 30 plus ciprofloxacin from week 1 to 4) N=51 placebo (intravenous infusion of a matching placebo on day 1 and at weeks 2, 6, 14, 22, and 30 plus ciprofloxacin from week 1 to 4) Primary outcome Modified Pouchitis Disease Activity Index-defined remission at week 14 https://web.pathway.md/studies/recGWpERKKo9YzPIP 1/2 6/28/23, 9:49 PM EARNEST Pathway 31.0 % 31 23.3 % 15.5 % Significant increase 10 7.8 % NNT = 5 0.0 % Vedolizumab Placebo Significant increase in modified Pouchitis Disease Activity Index-defined remission at week 14 (31% vs. 10%; AD 21%, 95% CI 5 to 38) Secondary outcomes Borderline significant increase in modified Pouchitis Disease Activity Index-defined remission at week 34 (35% vs. 18%; AD 17%, 95% CI 0 to 35) Significant increase in modified Pouchitis Disease Activity Index-defined response at week 14 (63% vs. 33%; AD 30%, 95% CI 8 to 48) Significant increase in Pouchitis Disease Activity Index-defined remission at week 14 (35% vs. 10%; AD 25%, 95% CI 8 to 41) Safety outcomes No significant difference in serious adverse events. Conclusion In adult patients who developed chronic pouchitis after undergoing ileal pouch-anal anastomosis for ulcerative colitis, vedolizumab was superior to placebo with respect to modified Pouchitis Disease Activity Index-defined remission at week 14. Reference Simon Travis, Mark S Silverberg, Silvio Danese et al. Vedolizumab for the Treatment of Chronic Pouchitis. N Engl J Med. 2023 Mar 30;388(13):1191-1200. Open reference URL https://web.pathway.md/studies/recGWpERKKo9YzPIP 2/2

6/28/23, 9:49 PM EAST-AFNET 4 Pathway Feedback Search Clinical Topics Home Studies EAST AFNET 4 EAST AFNET 4 Disease Atrial fibrillation Trial question What is the role of early rhythm-control therapy in patients with AF? Study design Multi-center Open label RCT Population Characteristics of study participants 46.0% female N = 2789 54.0% male 2789 patients (1293 female, 1496 male) Inclusion criteria: patients who had early AF diagnosed 1 year before enrollment and cardiovascular conditions Key exclusion criteria: any disease that limits life expectancy to < 1 year, pregnancy or breastfeeding, drug abuse, prior ablation or surgical therapy of AF, previous therapy failure on amiodarone, severe mitral valve stenosis, prosthetic mitral valve Interventions N=1395 early rhythm control (treatment with antiarrhythmic drugs or AF ablation at an early time point) N=1394 usual care (following the 2010 ESC guidelines for AF treatment) Primary outcome Incidence of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome https://web.pathway.md/studies/rec05cudwNIhrzJuY 1/2 6/28/23, 9:49 PM EAST-AFNET 4 Pathway 5.0/100 py 5 3.9 3.8/100 py 2.5/100 py 1.3/100 py Significant decrease 0.0/100 py Early rhythm control Usual care Significant decrease in the incidence of death from cardiovascular causes, stroke, or hospitalization with worsening of HF or acute coronary syndrome (3.9 /100 py vs. 5 /100 py; HR 0.79, 96% CI 0.66 to 0.94) Secondary outcomes No significant difference in the incidence of mean number of nights spent in the hospital (5.8 days / y vs. 5.1 days / y; HR 1.08, 99% CI 0.92 to 1.28) No significant difference in change in European Quality of Life-5 Dimensions score at 2 years (-1 vs. -2.7; AD 1.07, 95% CI -0.68 to 2.82) Significant decrease in change in 12-Item Short-Form General Health Survey Mental score at 2 years (0.7 vs. 1.6; AD -1.2, 95% CI -2.04 to -0.37) Safety outcomes No significant difference in symptoms of LV function at 2 years and death. Significant difference in serious adverse events related to rhythm-control therapy (4.9% vs. 1.4%). Conclusion In patients who had early AF diagnosed 1 year before enrollment and cardiovascular conditions, early rhythm control was superior to usual care with respect to the incidence of death from cardiovascular causes, stroke, or hospitalization with worsening of HF or acute coronary syndrome. Reference Paulus Kirchhof, A John Camm, Andreas Goette et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020 Oct 1;383(14):1305-1316. Open reference URL https://web.pathway.md/studies/rec05cudwNIhrzJuY 2/2

6/28/23, 9:49 PM ECASS III Pathway Feedback Search Clinical Topics Home Studies ECASS III ECASS III Disease Acute ischemic stroke Trial question What is the effect of intravenous alteplase administered after 3 to 4.5 hours in patients with acute ischemic stroke? Study design Multi-center Double blinded RCT Population Characteristics of study participants 40.0% female N = 821 60.0% male 821 patients (326 female, 495 male) Inclusion criteria: patients with ischemic stroke Key exclusion criteria: intracranial hemorrhage or major ischemic infarction as detected on CT scan, seizure at the onset of stroke, stroke or serious head trauma within the previous 3 months, OAC treatment, or increased risk of bleeding Interventions N=418 alteplase (intravenous dose of 0.9 mg/kg of body weight) N=403 placebo (identical placebo IV) Primary outcome Modified Rankin Scale score of 0 or 1 52.4 % 52.4 45.2 39 3 % https://web.pathway.md/studies/recS1lrKXdXYG7A01 1/2 6/28/23, 9:49 PM 39.3 % ECASS III Pathway 26.2 % Significant increase 13.1 % NNH = 14 0.0 % Alteplase Placebo Significant increase in mRS score of 0 or 1 (52.4% vs. 45.2%; OR 1.34, 95% CI 1.02 to 1.76) Safety outcomes No significant differences in mortality (7.7% vs. 8.4%, p=0.68) and other serious adverse events. Significant differences in any intracranial hemorrhage (27.0% vs. 17.6%, p = 0.001) and symptomatic intracranial hemorrhage (2.4% vs. 0.2%, p = 0.008). Conclusion In patients with ischemic stroke, alteplase was superior to placebo with respect to mRS score of 0 or 1. Reference Hacke W, Kaste M, Bluhmki E et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008 Sep 25;359(13):1317-29. Open reference URL https://web.pathway.md/studies/recS1lrKXdXYG7A01 2/2

6/28/23, 9:49 PM ECHELON-1 Pathway Feedback Search Clinical Topics Home Studies ECHELON 1 ECHELON 1 Disease Hodgkin's lymphoma Trial question What is the role of front-line chemotherapy with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine in patients with previously untreated stage III or IV classical Hodgkin's lymphoma? Study design Multi-center Open label RCT Population Characteristics of study participants 42.0% female N = 1334 58.0% male 1334 patients (558 female, 776 male) Inclusion criteria: adult patients with previously untreated stage III or IV classical Hodgkin's lymphoma Key exclusion criteria: nodular lymphocyte predominant Hodgkin's lymphoma; cerebral/meningeal disease; sensory or motor peripheral neuropathy; prior immunosuppressive chemotherapy, therapeutic radiation, or any immunotherapy within 12 weeks of first study drug dose Interventions N=664 brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (at a dose of 1.2 mg/kg, 25 mg/m , 6 mg/m , and 375 mg/m , respectively, IV on days 1 and 15 of each 28-day cycle for up to 6 cycles) https://web.pathway.md/studies/rec64WDZTmyqJPIEv 1/2 6/28/23, 9:49 PM ECHELON-1 Pathway N=670 doxorubicin, bleomycin, vinblastine, and dacarbazine (at a dose of 25 mg/m , 10 U/m2, 6 mg/m , and 375 mg/m , respectively, IV on days 1 and 15 of each 28-day cycle for up to 6 cycles) Primary outcome Progression-free survival at 5 years 82.2 % 82.2 75.3 61.7 % 41.1 % Significant increase 20.6 % NNT = 14 0.0 % Brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine Doxorubicin, bleomycin, vinblastine, and dacarbazine Significant increase in progression-free survival at 5 years (82.2% vs. 75.3%; HR 1.47, 95% CI 1.15 to 1.89) Secondary outcomes Significant increase in progression-free survival at 5 years, among patients with positron emission tomography scan negativity rate at cycle 2 (84.9% vs. 78.9%; HR 1.51, 95% CI 1.13 to 2) No significant difference in progression-free survival at 5 years, among patients with positron emission tomography scan positivity rate at cycle 2 (60.6% vs. 45.9%; HR 1.42, 95% CI 0.79 to 2.56) Safety outcomes No significant difference in improvement or resolution of peripheral neuropathy. Conclusion In adult patients with previously untreated stage III or IV classical Hodgkin's lymphoma, brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine were superior to doxorubicin, bleomycin, vinblastine, and dacarbazine with respect to a progression-free survival at 5 years. Reference David J Straus, Monika D ugosz-Danecka, Joseph M Connors et al. Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. Lancet Haematol. 2021 Jun;8(6):e410-e421. Open reference URL https://web.pathway.md/studies/rec64WDZTmyqJPIEv 2/2

6/28/23, 9:50 PM ECHOGUIDE Pathway Feedback Search Clinical Topics Home Studies ECHOGUIDE ECHOGUIDE Disease Traumatic hemorrhage Trial question Is ultrasound guidance superior to landmark guidance in patients requiring urgent femoral arterial and venous catheterization? Study design Single center Single blinded RCT Population Characteristics of study participants 25.0% female N = 136 75.0% male 136 patients (34 female, 102 male) Inclusion criteria: patients requiring both urgent arterial and venous femoral catheterization Key exclusion criteria: age < 18 years; contraindication to femoral access; clinical indication for only one catheter Interventions N=67 US-guided catheterization (identification of femoral artery and vein using ultrasound to guide catheter insertion) N=69 landmark-guided catheterization (using anatomic landmarks by palpating the femoral pulse to guide catheter insertion) Primary outcome Occurrence of 1 mechanical complication 58.0 % 58 https://web.pathway.md/studies/recwnc69yCfjX00be 1/2 6/28/23, 9:50 PM ECHOGUIDE Pathway 43.5 % 33 29.0 % Significant decrease 14.5 % NNT = 4 0.0 % Ultrasound-guided catheterization Landmark-guided catheterization Significant decrease in occurrence of 1 mechanical complication (33% vs. 58%; OR 0.35, 95% CI 0.18 to 0.71) Secondary outcomes Significant increase in successful catheterization (96% vs. 74%; OR 7.5, 95% CI 2.1 to 27) No significant difference in cannulation time (103 seconds vs. 121 seconds; AD -18 seconds, 95% CI -39.46 to 3.46) Significant decrease in the number of punctures (2 vs. 3; AD -1, 95% CI -1.84 to -0.16) Safety outcomes No significant differences in bleeding, late hematomas. Significant differences in immediate complications (27% vs. 51%), late complications (10% vs. 23%). Conclusion In patients requiring both urgent arterial and venous femoral catheterization, US-guided catheterization was superior to landmark-guided catheterization with respect to occurrence of 1 mechanical complication. Reference Stephen Lazaar, Am lie Mazaud, Claire Delsuc et al. Ultrasound guidance for urgent arterial and venous catheterisation: randomised controlled study. Br J Anaesth. 2021 Dec;127(6):871-878. Open reference URL https://web.pathway.md/studies/recwnc69yCfjX00be 2/2

6/28/23, 9:50 PM ECLA PHRI COLCOVID Pathway Feedback Search Clinical Topics Home Studies ECLA PHRI COLCOVID ECLA PHRI COLCOVID Disease COVID 19 infection Trial question What is the role of colchicine in hospitalized patients with COVID-19 pneumonia? Study design Multi-center Open label RCT Population Characteristics of study participants 35.0% female N = 1279 65.0% male 1279 patients (449 female, 830 male) Inclusion criteria: adults hospitalized with COVID-19 symptoms and had severe acute respiratory syndrome Key exclusion criteria: clear indications or contraindications for colchicine; CKD; negative results on a reverse transcription-PCR test for COVID-19 Interventions N=640 colchicine (oral loading dose of 1.5 mg followed by 0.5 mg after 2 hours and 0.5 mg 2 times for 14 days or until discharge) N=639 usual care (local standard of care) Primary outcome Mechanical ventilation or death at day 28 28.8 % 28.8 25 https://web.pathway.md/studies/reca9yL6A6GsTRupr 1/2 6/28/23, 9:50 PM ECLA PHRI COLCOVID Pathway 21.6 % 14.4 % 7.2 % No significant difference 0.0 % Colchicine Usual care No significant difference in mechanical ventilation or death at day 28 (25% vs. 28.8%; HR 0.83, 95% CI 0.67 to 1.02) Secondary outcomes No significant difference in death at day 28 (20.5% vs. 22.2%; HR 0.88, 95% CI 0.7 to 1.12) Significant decrease in new intubation or death from respiratory failure at day 28 (22.3% vs. 27.1%; HR 0.79, 95% CI 0.63 to 0.99) No significant difference in death from respiratory failure at day 28 (16.9% vs. 19.6%; HR 0.83, 95% CI 0.64 to 1.07) Safety outcomes No significant difference in other adverse events. Significant difference in severe diarrhea (11.3% vs. 4.5%). Conclusion In adults hospitalized with COVID-19 symptoms and had severe acute respiratory syndrome, colchicine was not superior to usual care with respect to mechanical ventilation or death at day 28. Reference Rafael Diaz, Andr s Orlandini, Noelia Castellana et al. Effect of Colchicine vs Usual Care Alone on Intubation and 28-Day Mortality in Patients Hospitalized With COVID-19: A Randomized Clinical Trial. JAMA Netw Open. 2021 Dec 1;4(12):e2141328. Open reference URL https://web.pathway.md/studies/reca9yL6A6GsTRupr 2/2

6/28/23, 9:50 PM ECOSPOR III Pathway Feedback Search Clinical Topics Home Studies ECOSPOR III ECOSPOR III Disease Clostridioides difficile infection Trial question What is the role of SER-109 microbiome therapy in patients with recurrent C. difficile infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 60.0% female N = 182 40.0% male 182 patients (109 female, 73 male) Inclusion criteria: patients who had 3 episodes of C. difficile infection Key exclusion criteria: pregnancy; toxic megacolon; small bowel ileus; major gastrointestinal surgery; active IBD; history of fecal microbiota transplantation within 3 months; significant comorbidities Interventions N=89 SER-109 (four daily capsules of SER-109, which contains purified Firmicutes bacterial spores, for 3 days after standard antibiotic treatment) N=93 placebo (matching placebo for 3 days after standard antibiotic treatment) Primary outcome Recurrence of Clostridioides difficile infection 40.0 % 40 https://web.pathway.md/studies/rec9mPp84LIQzBrph 1/2 6/28/23, 9:50 PM ECOSPOR III Pathway 30.0 % 20.0 % Significant decrease 12 10.0 % NNT = 4 0.0 % SER-109 Placebo Significant decrease in recurrence of C. difficile infection (12% vs. 40%; RR 0.32, 95% CI 0.18 to 0.58) Secondary outcomes Borderline significant decrease in recurrence of C. difficile infection in patients aged < 65 years (7% vs. 31%; RR 0.24, 95% CI 0.07 to 0.78) Borderline significant decrease in the rate of recurrence of C. difficile infection in patients aged 65 years (17% vs. 46%; RR 0.36, 95% CI 0.18 to 0.72) Borderline significant decrease in recurrence of C. difficile infection in recipients of vancomycin (16% vs. 38%; RR 0.41, 95% CI 0.22 to 0.79) Safety outcomes No significant difference in adverse events. Conclusion In patients who had 3 episodes of C. difficile infection, SER-109 was superior to placebo with respect to recurrence of C. difficile infection. Reference Paul Feuerstadt, Thomas J Louie, Bret Lashner et al. SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection. N Engl J Med. 2022 Jan 20;386(3):220-229. Open reference URL https://web.pathway.md/studies/rec9mPp84LIQzBrph 2/2

6/28/23, 9:50 PM ECST Pathway Feedback Search Clinical Topics Home Studies ECST ECST Disease Disease Disease Acute ischemic stroke Carotid artery stenosis Transie Trial question What is the role of carotid endarterectomy in adult patients with carotid stenosis who experienced at least one ischemic vascular event in the distribution of one or both carotid arteries in the previous 6 months? Study design Multi-center Single blinded RCT Population Characteristics of study participants 28.0% female N = 3024 72.0% male 3024 patients (850 female, 2168 male) Inclusion criteria: adult patients with carotid stenosis with 1 ischemic vascular event in the distribution of one or both carotid arteries in the previous 6 months Key exclusion criteria: doctors reasonably certain surgery is indicated or not indicated, embolism from the heart to the brain or eye, or more severe disease of the distal than of the proximal ICA Interventions N=1811 carotid endarterectomy (within 1 year of randomization) N=1213 no routine surgical intervention (surgery to be avoided for as long as possible) Primary outcome Major stroke or death at 3 years, in patients with stenosis > 80% https://web.pathway.md/studies/recphn8udemEv8wp2 1/2 6/28/23, 9:50 PM ECST Pathway 26.5 % 26.5 19.9 % 14.9 13.3 % Significant increase 6.6 % NNH = 9 0.0 % Carotid endarterectomy No routine surgical intervention Significant increase in major stroke or death at 3 years, in patients with stenosis > 80% (14.9% vs. 26.5%; ARD 11.6, 95% CI 4.72 to 18.48) Conclusion In adult patients with carotid stenosis with 1 ischemic vascular event in the distribution of one or both carotid arteries in the previous 6 months, carotid endarterectomy was superior to no routine surgical intervention with respect to major stroke or death at 3 years, in patients with stenosis > 80%. Reference European Carotid Surgery Trialists' Collaborative Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998 May 9;351(9113):1379-87. Open reference URL https://web.pathway.md/studies/recphn8udemEv8wp2 2/2

6/28/23, 9:50 PM EDIC Pathway Feedback Search Clinical Topics Home Studies EDIC EDIC Disease Diabetes mellitus type 1 Reference Nathan DM, Cleary PA, Backlund JY et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005 Dec 22;353(25):2643-53. Open reference URL https://web.pathway.md/studies/recWvTMbVaRrOCarx 1/1

6/28/23, 10:12 PM Effect of Propranolol in TBI Pathway Feedback Search Clinical Topics Home Studies Effect of Propranolol in TBI Effect of Propranolol in TBI Disease Traumatic brain injury Trial question What is the effect of propranolol in patients with severe TBI? Study design Single center Open label RCT Population Characteristics of study participants 14.0% female N = 219 86.0% male 219 patients (30 female, 189 male) Inclusion criteria: adult patients with a severe TBI, intracranial Abbreviated Injury Scale 3 Key exclusion criteria: pre-injury -blocker therapy, persistent shock at 24 h after admission, and transfer from another hospital Interventions N=99 -blocker therapy positive (20 mg propranolol PO every 12 hours up to 10 days or until discharge) N=120 -blocker therapy negative (no propranolol) Primary outcome Death in hospital 16.7 % 16.7 12.5 % https://web.pathway.md/studies/recq4EM27gwfXHw6B 1/2 6/28/23, 10:12 PM Effect of Propranolol in TBI Pathway 8.3 % 8.1 4.2 % No significant difference 0.0 % Beta-blocker therapy positive Beta-blocker therapy negative No significant difference in death in the hospital (8.1% vs. 16.7%; aIRR 0.6, 95% CI 0.3 to 1.4) Secondary outcomes Significant decrease in death in the hospital in patients with isolated TBI (4.4% vs. 18.6%; aIRR 0.32, 95% CI 0.1 to 0.9) Significant increase in the rate of functional outcome at 6-month follow up Glasgow Outcome Scale-Extended 5 in patients with isolated TBI (92.3% vs. 79.1%; aIRR 1.2, 95% CI 1 to 1.3) No significant difference in the rate of functional outcome at 6-month follow up Glasgow Outcome Scale-Extended 5 (86.5% vs. 77.5%; aIRR 1.1, 95% CI 0.9 to 1.2) Safety outcomes No significant difference in good functional outcome at discharge in patients with severe TBI and isolated severe TBI. Conclusion In adult patients with a severe TBI, intracranial Abbreviated Injury Scale 3, -blocker therapy positive was not superior to -blocker therapy negative with respect to death in the hospital. Reference Hosseinali Khalili, Rebecka Ahl, Shahram Paydar et al. Beta-Blocker Therapy in Severe Traumatic Brain Injury: A Prospective Randomized Controlled Trial. World J Surg. 2020 Jun;44(6):1844-1853. Open reference URL https://web.pathway.md/studies/recq4EM27gwfXHw6B 2/2

6/28/23, 10:12 PM Effect of Screen Time on Recovery from Concussion Pathway Feedback Search Clinical Topics Home Studies Effect of Screen Time on Recovery from Concussion Effect of Screen Time on Recovery from Concussion Disease Concussion Trial question What is the effect of screen time on patients who sustain a concussion? Study design Multi-center Open label RCT Population Characteristics of study participants 49.0% female N = 125 51.0% male 125 patients (61 female, 64 male) Inclusion criteria: patients aged 12 to 25 years presenting to the emergency department within 24 hours of sustaining a concussion Key exclusion criteria: intoxication, glasgow coma scale score < 15 points, intracranial abnormalities identified on imaging, preexisting intellectual disability, severe psychiatric illness, severe neurological conditions, substantial previous neurological surgery Interventions N=66 screen time permitted (screen time permission for 48 hours after injury) N=59 screen time abstinent (abstinence of screen time for 48 hours after injury) Primary outcome Median time until concussion recovery 8.0 days 8 https://web.pathway.md/studies/recFjj3Og0mhf1EMp 1/2 6/28/23, 10:12 PM Effect of Screen Time on Recovery from Concussion Pathway 6.0 days 4.0 days 3.5 2.0 days Significant increase 0.0 days Screen time permitted Screen time abstinent Significant increase in median time until concussion recovery (8 days vs. 3.5 days; AD 4.5 days, 95% CI 0.43 to 8.57) Secondary outcomes No significant difference in sleep duration on first 3 days (29 hours vs. 29 hours; RR 1, 95% CI 0 to 2) Conclusion In patients aged 12 to 25 years presenting to the emergency department within 24 hours of sustaining a concussion, screen time permitted was inferior to screen time abstinent with respect to median time until concussion recovery. Reference Theodore Macnow, Tess Curran, Courtney Tolliday et al. Effect of Screen Time on Recovery From Concussion: A Randomized Clinical Trial. JAMA Pediatr. 2021 Nov 1;175(11):1124-1131. Open reference URL https://web.pathway.md/studies/recFjj3Og0mhf1EMp 2/2

6/28/23, 10:13 PM Effect of Vitamin D on psoriasis severity Pathway Feedback Search Clinical Topics Home Studies Effect of Vitamin D on psoriasis severity Effect of Vitamin D on psoriasis severity Disease Psoriasis Trial question What is the effect of vitamin D supplementation on psoriasis severity in patients with lower-range serum 25-hydroxyvitamin D levels? Study design Single center Double blinded RCT Population Characteristics of study participants 38.0% female N = 122 62.0% male 122 patients (46 female, 76 male) Inclusion criteria: adults with active plaque psoriasis and 25-hydroxyvitamin D levels < 24 ng/mL Key exclusion criteria: nut allergy; primary hyperparathyroidism; granulomatous diseases; pregnancy; clinical signs of proximal myopathy Interventions N=60 vitamin D (cholecalciferol oral capsules, 100,000 IU loading dose, followed by 20,000 IU per week for 4 months) N=62 placebo (matching placebo oral capsules for 4 months) Primary outcome Reduction in psoriasis area severity index score 0.4 0.41 https://web.pathway.md/studies/reczogDJDo1RbJ6CY 1/2 6/28/23, 10:13 PM Effect of Vitamin D on psoriasis severity Pathway 0.34 0.3 0.2 0.1 No significant difference 0.0 Vitamin D Placebo No significant difference in reduction in psoriasis area severity index score (0.34 vs. 0.41; AD -0.11, 95% CI -0.45 to 0.23) Secondary outcomes No significant difference in reduction in self-administered psoriasis area severity index (0.5 vs. -0.25; AD 0.6, 95% CI -0.55 to 1.76) No significant difference in improvement in DLQI (-0.59 vs. 0.1; AD -0.86, 95% CI -1.9 to 0.19) No significant difference in improvement in physical global assessment score of 1 (8.5% vs. 11.5%; OR 0.66, 95% CI 0.27 to 1.63) Conclusion In adults with active plaque psoriasis and 25-hydroxyvitamin D levels < 24 ng/mL, vitamin D was not superior to placebo with respect to reduction in psoriasis area severity index score. Reference Marita Jenssen, Anne-Sofie Furberg, Rolf Jorde et al. Effect of Vitamin D Supplementation on Psoriasis Severity in Patients With Lower-Range Serum 25-Hydroxyvitamin D Levels: A Randomized Clinical Trial. JAMA Dermatol. 2023 Mar 29;e230357. Open reference URL https://web.pathway.md/studies/reczogDJDo1RbJ6CY 2/2

6/28/23, 9:51 PM EFFECTS Pathway Feedback Search Clinical Topics Home Studies EFFECTS EFFECTS Disease Disease Acute ischemic stroke Intracerebral hemorrhage Trial question What is the role of fluoxetine in patients with acute stroke? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.0% female N = 1500 62.0% male 1500 patients (575 female, 925 male) Inclusion criteria: adult patients with a clinical diagnosis of ischemic or intracerebral hemorrhage in the previous 2-15 days Key exclusion criteria: primary subarachnoid hemorrhage; epileptic seizures; unavailable for follow-up for next 12 months; previous drug overdose or attempted suicide; ongoing depression Interventions N=750 fluoxetine (an oral dose of 20 mg/day for 6 months) N=750 placebo (matching placebo for 6 months) Primary outcome Physical function as measured by stroke impact scale score 77.4 77.4 76.7 58 1 https://web.pathway.md/studies/recI0fnac7i4Tt6vg 1/2 6/28/23, 9:51 PM EFFECTS Pathway 58.1 38.7 19.4 No significant difference 0.0 Fluoxetine Placebo No significant difference in physical function as measured by the stroke impact scale score (76.7 vs. 77.4; AD -0.7, 95% CI -6.06 to 4.66) Secondary outcomes Significant decrease in memory as measured by the stroke impact scale score (89.3 vs. 92.9; AD -3.6, 95% CI -6.19 to -1.01) Safety outcomes No significant differences in death, new stroke, thrombotic events, bleeding events. Significant differences in new depression (7% vs. 11%), bone fractures (4% vs. 2%), hyponatremia (1% vs. <1%) at 6 months. Conclusion In adult patients with a clinical diagnosis of ischemic or intracerebral hemorrhage in the previous 2-15 days, fluoxetine was not superior to placebo with respect to physical function as measured by the stroke impact scale score. Reference EFFECTS Trial Collaboration. Safety and efficacy of fluoxetine on functional recovery after acute stroke (EFFECTS): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2020 Aug;19(8):661-669. Open reference URL https://web.pathway.md/studies/recI0fnac7i4Tt6vg 2/2

6/28/23, 9:51 PM EINSTEIN-PE Pathway Feedback Search Clinical Topics Home Studies EINSTEIN PE EINSTEIN PE Disease Disease Deep vein thrombosis Pulmonary embolism Trial question Is rivaroxaban noninferior to standard therapy for the treatment of symptomatic PE? Study design Multi-center Open label RCT Population Characteristics of study participants 47.0% female N = 4832 53.0% male 4832 patients (2276 female, 2556 male) Inclusion criteria: patients who had acute symptomatic PE with or without deep vein thrombosis Key exclusion criteria: thrombectomy, vena cava filter placed, contraindication listed in the local labeling of enoxaparin, warfarin, or acenocoumarol, a CrCl < 30 mL/min, acute hepatitis, chronic active hepatitis, or cirrhosis, bacterial endocarditis, active bleeding or a high risk of bleeding Interventions N=2419 rivaroxaban (15 mg BID for 3 weeks, followed by 20 mg once daily) N=2413 vitamin K antagonists (enoxaparin followed by an adjusted-dose vitamin K antagonist) Primary outcome Symptomatic recurrent venous thromboembolism 2.1 % 2.1 https://web.pathway.md/studies/rec3a5FqyimsctZQW 1/2 6/28/23, 9:51 PM EINSTEIN-PE Pathway 1.8 1.6 % 1.1 % Difference not exceeding nonferiority margin 0.5 % 0.0 % Rivaroxaban Vitamin K antagonists Difference not exceeding nonferiority margin in symptomatic recurrent VTE (2.1% vs. 1.8%; HR 1.12, 95% CI 0.75 to 1.68) Secondary outcomes No significant difference in net clinical benefit; VTE plus major bleeding (3.4% vs. 4%; HR 0.85, 95% CI 0.63 to 1.14) Safety outcomes No significant differences in major or clinically relevant nonmajor bleeding (10.3% vs. 11.4%, p=0.23; HR 0.90, 95% CI 0.76-1.07) and other adverse events. Significant differences in major bleeding (1.1% vs. 2.2%, p = 0.003; HR 0.49, 95% CI 0.31- 0.79). Conclusion In patients who had acute symptomatic PE with or without deep vein thrombosis, rivaroxaban was noninferior to vitamin K antagonists with respect to symptomatic recurrent VTE. Reference EINSTEIN-PE Investigators, Buller HR, Prins MH et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. Open reference URL https://web.pathway.md/studies/rec3a5FqyimsctZQW 2/2

6/28/23, 9:52 PM ELAIN FOLLOW-UP Pathway Feedback Search Clinical Topics Home Studies ELAIN FOLLOW UP ELAIN FOLLOW UP Disease Acute kidney injury Trial question Is early initiation of RRT superior to late initiation of RRT in critically ill patients with AKI? Study design Single center Open label RCT Population Characteristics of study participants 37.0% female N = 231 63.0% male 231 patients (85 female, 146 male) Inclusion criteria: critically ill patients with AKI Key exclusion criteria: pre-existing kidney disease not requiring RRT; previous RRT; acute renal injury caused by post-renal obstruction; pregnancy Interventions N=111 early RRT initiation (within 8 hours of diagnosis of stage 2 AKI) N=119 late initiation (within 12 hours of diagnosis of stage 3 AKI) Primary outcome Major adverse kidney events consisting of persistent renal dysfunction, dialysis dependence, and death at 1 year 89.1 89.1 % 66.8 % 64.9 https://web.pathway.md/studies/rec2IRD6I5i6miLTX 1/2 6/28/23, 9:52 PM ELAIN FOLLOW-UP Pathway 44.5 % Significant decrease 22.3 % NNT = 4 0.0 % Early renal replacement therapy initiation Late initiation Significant decrease in major adverse kidney events consisting of persistent renal dysfunction, dialysis dependence, and death at 1 year (64.9% vs. 89.1%; OR 0.23, 95% CI 0.11 to 0.45) Secondary outcomes Significant decrease in death from all causes at 1 year (50.2% vs. 69.8%; OR 0.62, 95% CI 0.44 to 0.87) No significant difference in the percentage of patients who require RRT at 1 year (7.3% vs. 11.1%; OR 0.62, 95% CI 0.15 to 2.69) Significant decrease in the percentage of patients with persistent renal dysfunction at 1 year (29.1% vs. 63.9%; OR 0.23, 95% CI 0.09 to 0.57) Safety outcomes No significant differences in death due to refractory septic shock, myocardial dysfunction, stroke, or bleeding. Significant difference in death due to multiple organ dysfunction syndrome (21.4% vs. 38.6%). Conclusion In critically ill patients with AKI, early RRT initiation was superior to late initiation with respect to major adverse kidney events consisting of persistent renal dysfunction, dialysis dependence, and death at 1 year. Reference Melanie Meersch, Mira K llmar, Christoph Schmidt et al. Long-Term Clinical Outcomes after Early Initiation of RRT in Critically Ill Patients with AKI. J Am Soc Nephrol. 2018 Mar;29(3):1011- 1019. Open reference URL https://web.pathway.md/studies/rec2IRD6I5i6miLTX 2/2

6/28/23, 9:52 PM ELAIN Pathway Feedback Search Clinical Topics Home Studies ELAIN ELAIN Disease Acute kidney injury Trial question What is the effect of early initiation of RRT among critically ill patients with AKI? Study design Single center Open label RCT Population Characteristics of study participants 37.0% female N = 231 63.0% male 231 patients (85 female, 146 male) Inclusion criteria: critically ill patients with AKI Key exclusion criteria: preexisting CKD; previous RRT; glomerulonephritis; interstitial nephritis; vasculitis; HUS; TTP Interventions N=112 early RRT (initiation within 8 hours of diagnosis of stage 2 AKI) N=119 delayed RRT (initiation within 12 hours of stage 3 AKI) Primary outcome Death from all causes at day 90 54.7 % 54.7 41.0 % 39.3 27 4 % https://web.pathway.md/studies/recXMSMeToWCZiXtM 1/2 6/28/23, 9:52 PM 27.4 % ELAIN Pathway Significant decrease 13.7 % NNT = 6 0.0 % Early renal replacement therapy Delayed renal replacement therapy Significant decrease in death from all causes at day 90 (39.3% vs. 54.7%; HR 0.66, 95% CI 0.45 to 0.97) Secondary outcomes Significant decrease in duration of RRT (9 days vs. 25 days; HR 0.69, 95% CI 0.48 to 1) Significant decrease in deterioration of renal function at day 90 (38.7% vs. 53.6%; OR 0.55, 95% CI 0.32 to 0.93) Significant decrease in length of hospital stay (51 days vs. 82 days; HR 0.34, 95% CI 0.22 to 0.52) Safety outcomes No significant differences in organ dysfunction, adverse events, RRT-related complications. Significant differences in interleukin-8 concentration at day 1 (65.7 pg/mL vs. 215.5 pg/mL), IL- 6 concentration at day 1 (399.4 pg/mL vs. 989.3 pg/mL). Conclusion In critically ill patients with AKI, early RRT was superior to delayed RRT with respect to death from all causes at day 90. Reference Alexander Zarbock, John A Kellum, Christoph Schmidt et al. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA. 2016 May 24-31;315(20):2190-9. Open reference URL https://web.pathway.md/studies/recXMSMeToWCZiXtM 2/2

6/28/23, 9:52 PM ELDERCARE-AF (subanalysis) Pathway Feedback Search Clinical Topics Home Studies ELDERCARE AF (subanalysis) ELDERCARE AF (subanalysis) Disease Atrial fibrillation Trial question What is the role of edoxaban in older adult patients with AF who were not considered candidates for standard-dose OACs? Study design Multi-center Double blinded RCT Population Characteristics of study participants 57.0% female N = 984 43.0% male 984 patients (565 female, 419 male) Inclusion criteria: adult patients, aged 80 years, with AF who were not considered candidates for standard-dose OACs Key exclusion criteria: moderate to severe mitral stenosis; mechanical heart valves Interventions N=492 edoxaban (at a dose of 15 mg PO once daily) N=492 placebo (matching placebo once daily) Primary outcome Stroke or systemic embolism in patients aged 90 years 10.1 % / p-y 10.1 7 6 % / p y https://web.pathway.md/studies/recg1rQ5QrcVkFHIx 1/2 6/28/23, 9:52 PM 7.6 % / p-y ELDERCARE-AF (subanalysis) Pathway 5.0 % / p-y 2.5 % / p-y 2.4 Significant decrease 0.0 % / p-y Edoxaban Placebo Significant decrease in stroke or systemic embolism in patients aged 90 years (2.4% / p-y vs. 10.1% / p-y; HR 0.23, 95% CI 0.08 to 0.68) Secondary outcomes Borderline significant decrease in stroke or systemic embolism in patients aged 85-89 years (2.8% / p-y vs. 7.3% / p-y; HR 0.42, 95% CI 0.17 to 0.99) No significant difference in net clinical outcome in patients aged 90 years (19.6% / p-y vs. 22.1% / p-y; HR 0.88, 95% CI 0.54 to 1.42) No significant difference in death from all causes in group aged 80-84 years (6.4% / p-y vs. 5% / p-y; HR 1.28, 95% CI 0.62 to 2.67) Safety outcomes No significant differences in major bleeding, major or clinically relevant nonmajor bleeding. Significant difference in clinically relevant nonmajor bleeding in group aged 85-89 years (15.0% per patient-year vs. 7.4% per patient-year). Conclusion In adult patients, aged 80 years, with AF who were not considered candidates for standard- dose OACs, edoxaban was superior to placebo with respect to stroke or systemic embolism in patients aged 90 years. Reference Masaru Kuroda, Eiji Tamiya, Takahisa Nose et al. Effect of 15-mg Edoxaban on Clinical Outcomes in 3 Age Strata in Older Patients With Atrial Fibrillation: A Prespecified Subanalysis of the ELDERCARE-AF Randomized Clinical Trial. JAMA Cardiol. 2022 Jun 1;7(6):583-590. Open reference URL https://web.pathway.md/studies/recg1rQ5QrcVkFHIx 2/2

6/28/23, 9:52 PM ELEKT-D Pathway Feedback Search Clinical Topics Home Studies ELEKT D ELEKT D Disease Major depressive disorder Trial question Is ketamine noninferior to electroconvulsive therapy in patients with nonpsychotic treatment- resistant major depression? Study design Multi-center Open label RCT Population Characteristics of study participants 51.0% female N = 403 49.0% male 403 patients (206 female, 197 male) Inclusion criteria: patients with treatment-resistant major depression without psychosis Key exclusion criteria: pregnancy or breastfeeding; contraindication to ketamine or electroconvulsive therapy; severe medical illness or severe neurological disorder; diagnosis of major depressive disorder with psychotic features Interventions N=200 ketamine (0.5 mg/kg infusion over 40 minutes twice per week) N=203 electroconvulsive therapy (therapy given three times per week) Primary outcome Response to treatment 55.4 55.4 % https://web.pathway.md/studies/recAXLBvhj2yRV9Zw 1/2 6/28/23, 9:52 PM ELEKT-D Pathway 41.2 41.5 % 27.7 % Difference not exceeding nonferiority margin 13.8 % 0.0 % Ketamine Electroconvulsive therapy Difference not exceeding nonferiority margin in response to treatment (55.4% vs. 41.2%; AD 14.2%, 95% CI 3.9 to 24.2) Secondary outcomes No significant difference in Montgomery-Asberg Depression Rating Scale-based response (50.8% vs. 41.4%; AD 9.3%, 95% CI -0.9 to 19.4) Significant increase in Global Self-Evaluation of Memory score at end-of-treatment (4.2 vs. 3.2; AD 1.1, 95% CI 0.9 to 1.2) No significant difference in improvement in 16-item Quality-of-Life Scale score (12.3 vs. 12.9; AD -0.6, 95% CI -3.4 to 2.1) Safety outcomes No significant difference in 1 adverse event. Significant difference in muscle pain or weakness (0.5% vs. 5.3%). Conclusion In patients with treatment-resistant major depression without psychosis, ketamine was noninferior to electroconvulsive therapy with respect to response to treatment. Reference Amit Anand, Sanjay J Mathew, Gerard Sanacora et al. Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. N Engl J Med. 2023 May 24. Online ahead of print. Open reference URL https://web.pathway.md/studies/recAXLBvhj2yRV9Zw 2/2

6/28/23, 9:53 PM ELIXA Pathway Feedback Search Clinical Topics Home Studies ELIXA ELIXA Disease Disease Disease Diabetes mellitus type 2 In-hospital hyperglycemia Non-ST Trial question What is the role of lixisenatide in patients with T2DM and acute coronary syndrome? Study design Multi-center Double blinded RCT Population Characteristics of study participants 31.0% female N = 6068 69.0% male 6068 patients (1861 female, 4207 male) Inclusion criteria: patients with T2DM who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days Key exclusion criteria: age < 30 years, PCI within the previous 15 days, CABG surgery for the qualifying event, planned coronary revascularization procedure within 90 days after screening, an eGFR < 30 mL/min/1.73 m of body-surface area, a glycated Hgb level < 5.5% or > 11.0% Interventions N=3034 lixisenatide (a dose of 10 g/day for first 2 weeks and increased to a maximum dose of 20 g/day) N=3034 placebo (volume matched placebo per day) Primary outcome Cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina 13.4 13.4 % 13.2 https://web.pathway.md/studies/recpAVOksmJfkJfnQ 1/2 6/28/23, 9:53 PM ELIXA Pathway 10.1 % 6.7 % 3.4 % No significant difference 0.0 % Lixisenatide Placebo No significant difference in cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina (13.4% vs. 13.2%; HR 1.02, 95% CI 0.89 to 1.17) Secondary outcomes No significant difference in hospitalization for HF (4% vs. 4.2%; HR 0.96, 96% CI 0.75 to 1.23) No significant difference in death (7% vs. 7.4%; HR 0.94, 95% CI 0.78 to 1.13) Safety outcomes No significant differences in serious adverse events or severe hypoglycemia, pancreatitis, pancreatic neoplasms, or allergic reactions. Conclusion In patients with T2DM who had had a myocardial infarction or who had been hospitalized for unstable angina within the previous 180 days, lixisenatide was not superior to placebo with respect to cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina. Reference Pfeffer MA, Claggett B, Diaz R et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015 Dec 3;373(23):2247-57. Open reference URL https://web.pathway.md/studies/recpAVOksmJfkJfnQ 2/2

6/28/23, 9:53 PM EMBRACE (ambulatory ECG monitoring) Pathway Feedback Search Clinical Topics Home Studies EMBRACE (ambulatory ECG monitoring) EMBRACE (ambulatory ECG monitoring) Disease Disease Disease Acute ischemic stroke Atrial fibrillation Transie Reference Gladstone DJ, Spring M, Dorian P et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 2014 Jun 26;370(26):2467-77. Open reference URL https://web.pathway.md/studies/recDJAUhbfkNJJn76 1/1

6/28/23, 9:53 PM EMBRACE (azithromycin) Pathway Feedback Search Clinical Topics Home Studies EMBRACE (azithromycin) EMBRACE (azithromycin) Disease Bronchiectasis Trial question What is the role of azithromycin in adult patients with non-cystic fibrosis bronchiectasis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 70.0% female N = 141 30.0% male 141 patients (98 female, 43 male) Inclusion criteria: adult patients with non-cystic fibrosis bronchiectasis with 1 pulmonary exacerbation requiring antibiotic treatment in the past year Key exclusion criteria: history of cystic fibrosis; hypogammaglobulinemia; allergic bronchopulmonary aspergillosis; a positive culture of non-tuberculous mycobacteria in the past 2 years or at screening; macrolide treatment for > 3 months in the past 6 months; or unstable arrhythmia Interventions N=71 azithromycin (500 mg thrice weekly for 6 months) N=70 placebo (matching placebo thrice weekly for 6 months) Primary outcome Event-based exacerbations 1.6/pt 1.57 https://web.pathway.md/studies/recB5CEae1n7F5GRe 1/2 6/28/23, 9:53 PM EMBRACE (azithromycin) Pathway 1.2/pt 0.8/pt 0.59 0.4/pt Significant decrease 0.0/pt Azithromycin Placebo Significant decrease in event-based exacerbations (0.59 per patient vs. 1.57 per patient; RR 0.38, 95% CI 0.26 to 0.54) Secondary outcomes No significant difference in prebronchodilator FEV in 1 second (AD 0.04 L, 95% CI -0.03 to 0.12) No significant difference in St. George's Respiratory Questionnaire total score (-5.17 units vs. -1.92 units; AD -3.25 units, 95% CI -7.21 to 0.72) No significant difference in 6-minute walk test distance (0.88 m vs. -9.63 m; AD 10.52 m, 95% CI -5.12 to 26.15) Safety outcomes No significant differences in adverse events, drug discontinuation due to gastrointestinal symptoms. Significant differences in severe adverse events (6% vs. 13%), gastrointestinal symptoms (27% vs. 13%). Conclusion In adult patients with non-cystic fibrosis bronchiectasis with 1 pulmonary exacerbation requiring antibiotic treatment in the past year, azithromycin was superior to placebo with respect to a event-based exacerbations. Reference Gladstone DJ, Spring M, Dorian P et al. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 2014 Jun 26;370(26):2467-77. Open reference URL https://web.pathway.md/studies/recB5CEae1n7F5GRe 2/2

6/28/23, 9:53 PM EMERGE Pathway Feedback Search Clinical Topics Home Studies EMERGE EMERGE Disease Cardiac arrest Trial question Is emergency coronary angiogram superior to delayed coronary angiogram in survivors of out-of- hospital cardiac arrest? Study design Multi-center Open label RCT Population Characteristics of study participants 30.0% female N = 279 70.0% male 279 patients (84 female, 195 male) Inclusion criteria: survivors of out-of-hospital cardiac arrest without ST-segment elevation on ECG Key exclusion criteria: age < 18 years; pregnancy; no ROSC; in-hospital sudden cardiac death; presence of ST-segment elevation; suspected noncardiac etiology Interventions N=138 emergency coronary angiogram (immediate coronary angiogram at the time of hospital admission) N=137 delayed coronary angiogram (coronary angiogram delayed between 48 and 96 hours after hospital admission) Primary outcome Survival with cerebral performance category of 2 at day 180 https://web.pathway.md/studies/recfrX1pOKQqdsowU 1/2 6/28/23, 9:53 PM EMERGE Pathway 34.1 % 34.1 30.7 25.6 % 17.1 % 8.5 % No significant difference 0.0 % Emergency coronary angiogram Delayed coronary angiogram No significant difference in survival with cerebral performance category of 2 at day 180 (34.1% vs. 30.7%; HR 1.15, 95% CI 0.87 to 1.54) Secondary outcomes No significant difference in survival at 180 days (36.2% vs. 33.3%; HR 1.16, 95% CI 0.87 to 1.56) No significant difference in survival with cerebral performance category of 2 at day 90 (28.4% vs. 24.6%; HR 1.16, 95% CI 0.88 to 1.56) No significant difference in shock during the first 24 hours (38.8% vs. 39.8%; HR 1.03, 95% CI 0.72 to 1.32) Safety outcomes No significant differences in VT, ventricular febrillation. Conclusion In survivors of out-of-hospital cardiac arrest without ST-segment elevation on ECG, emergency coronary angiogram was not superior to delayed coronary angiogram with respect to survival with cerebral performance category of 2 at day 180. Reference Caroline Hauw-Berlemont, Lionel Lamhaut, Jean-Luc Diehl et al. Emergency vs Delayed Coronary Angiogram in Survivors of Out-of-Hospital Cardiac Arrest Results of the Randomized, Multicentric EMERGE Trial. JAMA Cardiol. 2022 Jul 1;7(7):700-707. Open reference URL https://web.pathway.md/studies/recfrX1pOKQqdsowU 2/2

6/28/23, 9:54 PM EMILIA Pathway Feedback Search Clinical Topics Home Studies EMILIA EMILIA Trial question What is the role of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced breast cancer? Study design Multi-center Open label RCT Population 991 female patients Inclusion criteria: patients with HER2-positive advanced breast cancer who had previously been treated with trastuzumab and a taxane Key exclusion criteria: prior treatment with T-DM1, lapatinib, or capecitabine; symptomatic CNS metastases or treatment for these metastases within 2 months before randomization; symptomatic congestive HF or serious cardiac arrhythmia requiring treatment; myocardial infarction or unstable angina within 6 months before randomization Interventions N=495 T-DM1 (trastuzumab emtansine 3.6 mg/kg of body weight IV every 21 days) N=496 lapatinib plus capecitabine (oral lapatinib at a dose of 1,250 mg daily plus oral capecitabine at a dose of 1,000 mg/m of body-surface area every 12h on days 1 through 14 of each 21-day treatment cycle) Primary outcome Median progression-free survival 9.6 months 9.6 7.2 months 6.4 4.8 months 2.4 months Significant increase 0.0 months T-DM1 Lapatinib plus capecitabine Significant increase in median progression-free survival (9.6 months vs. 6.4 months; HR 1.53, 95% CI 1.29 to 1.81) Secondary outcomes https://web.pathway.md/studies/rec2g0aQ5OJIUlAxi 1/2 6/28/23, 9:54 PM EMILIA Pathway Seco da y outco es Significant increase in median overall survival (30.9 vs. 25.1; HR 1.47, 95% CI 1.17 to 1.81) Significant increase in objective response (43.6% vs. 30.8%; ARD 12.7, 95% CI 6 to 19.4) Safety outcomes Significant difference in grade 3 or 4 adverse events (41% vs. 57%). Conclusion In patients with HER2-positive advanced breast cancer who had previously been treated with trastuzumab and a taxane, T-DM1 was superior to lapatinib plus capecitabine with respect to median progression-free survival. Reference Verma S, Miles D, Gianni L et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. Open reference URL https://web.pathway.md/studies/rec2g0aQ5OJIUlAxi 2/2

6/28/23, 9:54 PM EMMA Pathway Feedback Search Clinical Topics Home Studies EMMA EMMA Trial question Is McGrath Mac videolaryngoscopy superior to direct laryngoscopy in patients undergoing elective tracheal intubation? Study design Multi-center Open label RCT Population Characteristics of study participants 50.0% female N = 2092 50.0% male 2092 patients (1053 female, 1039 male) Inclusion criteria: adult patients without predicted difficult airway requiring tracheal intubation for elective surgery Key exclusion criteria: anticipated difficult airway with an airway difficulty score > 8; ASA physical status 4 or 5; BMI 40; increased risk of pulmonary aspiration; or pregnancy Interventions N=1053 McGrath videolaryngoscopy (use of McGrath videolaryngoscope with a size 3 or 4 Macintosh-based blade) N=1039 direct laryngoscopy (use of a standard laryngoscope with a size 3 or 4 Macintosh blade) Primary outcome First-pass tracheal intubation success 94.0 % 94 82 70.5 % 47.0 % Significant increase 23.5 % NNT = 8 0 0 % https://web.pathway.md/studies/rec73SIRIV5m5KGpq 1/2 6/28/23, 9:54 PM 0.0 % EMMA Pathway McGrath videolaryngoscopy Direct laryngoscopy Significant increase in first-pass tracheal intubation success (94% vs. 82%; AD 12.1%, 95% CI 10.9 to 13.6) Secondary outcomes Significant increase in overall success rate of tracheal intubation (99% vs. 96%; AD 3%, 95% CI 1.22 to 4.78) Significant increase in time to tracheal tube placement (22 seconds vs. 20 seconds; AD 2 seconds, 95% CI 0.81 to 3.19) Significant decrease in intubation difficulty score > 5 (1% vs. 6%; ARD -5, 95% CI -7.97 to -2.03) Conclusion In adult patients without predicted difficult airway requiring tracheal intubation for elective surgery, McGrath videolaryngoscopy was superior to direct laryngoscopy with respect to a first- pass tracheal intubation success. Reference M Kriege, R R Noppens, T Turkstra et al. A multicentre randomised controlled trial of the McGrath Mac videolaryngoscope versus conventional laryngoscopy. Anaesthesia. 2023 Jun;78(6):722-729. Open reference URL https://web.pathway.md/studies/rec73SIRIV5m5KGpq 2/2

6/28/23, 9:54 PM EMPA-HEART2 CardioLink-7 Pathway Feedback Search Clinical Topics Home Studies EMPA HEART2 CardioLink-7 EMPA HEART2 CardioLink-7 Trial question What is the role of empagliflozin in patients without diabetes but with risk of adverse cardiac remodeling? Study design Multi-center Double blinded RCT Population Characteristics of study participants 17.0% female N = 169 83.0% male 169 patients (28 female, 141 male) Inclusion criteria: adult patients, aged 40-80 years, without diabetes but with risk factors for adverse cardiac remodeling Key exclusion criteria: type 1 or 2 diabetes; HbA1c 6.5%, ketoacidosis; systolic BP < 95 mmHg; planned coronary revascularization within the next 6 months or coronary revascularization within the preceding 3 months Interventions N=85 empagliflozin (at a dose of 10 mg/day for 6 months) N=84 placebo (matching placebo for 6 months) Primary outcome Reduction in left ventricular mass indexed to body surface area at 6 months 1.2 g/m 1.2 1.1 0.9 g/m 0.6 g/m 0.3 g/m No significant difference 0.0 g/m https://web.pathway.md/studies/recY6be5pYNOErkQJ 1/2 6/28/23, 9:54 PM EMPA-HEART2 CardioLink-7 Pathway Empagliflozin Placebo No significant difference in reduction in LV mass indexed to BSA at 6 months (1.2 g/m vs. 1.1 g/m ; AD 0.3 g/m , 95% CI -1.5 to 2.1) Secondary outcomes No significant difference in improvement in LVEF at 6 months (1.3% vs. -0.2%; AD 1.5%, 95% CI -0.12 to 3.12) Safety outcomes No significant difference in adverse events. Conclusion In adult patients, aged 40-80 years, without diabetes but with risk factors for adverse cardiac remodeling, empagliflozin was not superior to placebo with respect to reduction in LV mass indexed to BSA at 6 months. Reference Kim A Connelly, C David Mazer, Pankaj Puar et al. Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial. Circulation. 2023 Jan 24;147(4):284-295. Open reference URL https://web.pathway.md/studies/recY6be5pYNOErkQJ 2/2

6/28/23, 9:54 PM EMPA-KIDNEY Pathway Feedback Search Clinical Topics Home Studies EMPA KIDNEY EMPA KIDNEY Disease Chronic kidney disease Trial question What is the role of empagliflozin in patients with CKD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 33.0% female N = 6609 67.0% male 6609 patients (2192 female, 4417 male) Inclusion criteria: patients with CKD with an eGFR 20 and < 45 mL/min/1.73 m , or 45 and < 90 mL/min/1.73 m with a urinary albumin-to-creatinine ratio 200 Key exclusion criteria: polycystic kidney disease; receipt of kidney transplant Interventions N=3304 empagliflozin (at a dose of 10 mg/day) N=3305 placebo (matching placebo) Primary outcome Progression of kidney disease or death from cardiovascular causes 16.9 % 16.9 13.1 12.7 % 8 4 % https://web.pathway.md/studies/recbxMQR99r9ZzJud 1/2 6/28/23, 9:54 PM 8.4 % EMPA-KIDNEY Pathway Significant decrease 4.2 % NNT = 26 0.0 % Empagliflozin Placebo Significant decrease in progression of kidney disease or death from cardiovascular causes (13.1% vs. 16.9%; HR 0.72, 95% CI 0.64 to 0.82) Secondary outcomes No significant difference in hospitalization for HF or death from cardiovascular causes (4% vs. 4.6%; HR 0.84, 95% CI 0.67 to 1.07) Significant decrease in the incidence of hospitalization for any cause (24.8 events /100 py vs. 29.2 events /100 py; HR 0.86, 95% CI 0.78 to 0.95) No significant difference in death from any cause (4.5% vs. 5.1%; HR 0.87, 95% CI 0.7 to 1.08) Safety outcomes No significant difference in serious adverse events. Conclusion In patients with CKD with an eGFR 20 and < 45 mL/min/1.73 m , or 45 and < 90 mL/min/1.73 m with a urinary albumin-to-creatinine ratio 200, empagliflozin was superior to placebo with respect to progression of kidney disease or death from cardiovascular causes. Reference EMPA-KIDNEY Collaborative Group, William G Herrington, Natalie Staplin et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023 Jan 12;388(2):117-127. Open reference URL https://web.pathway.md/studies/recbxMQR99r9ZzJud 2/2

6/28/23, 9:55 PM EMPA-REG OUTCOME Pathway Feedback Search Clinical Topics Home Studies EMPA REG OUTCOME EMPA REG OUTCOME Disease Diabetes mellitus type 2 Trial question What is the role of empagliflozin in patients with T2DM at high cardiovascular risk? Study design Multi-center Double blinded RCT Population Characteristics of study participants 29.0% female N = 7020 71.0% male 7020 patients (2004 female, 5016 male) Inclusion criteria: patients with T2DM at high cardiovascular risk who are on standard care Key exclusion criteria: uncontrolled hyperglycemia with glucose > 240 mg/dL, indication of liver disease, planned cardiac surgery or angioplasty within 3 months, bariatric surgery within the past 2 years, blood dyscrasias, medical history of cancer and/or treatment of cancer within the last 5 years, uncontrolled endocrine disorder, or pregnant or lactating women Interventions N=4687 empagliflozin (10 mg or 25 mg once daily) N=2333 placebo (matching placebo once daily) Primary outcome Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke 12.1 % 12.1 10.5 https://web.pathway.md/studies/reca4EqrygEOvQkeU 1/2 6/28/23, 9:55 PM EMPA-REG OUTCOME Pathway 9.1 % 6.0 % Significant decrease 3.0 % NNT = 63 0.0 % Empagliflozin Placebo Significant decrease in death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (10.5% vs. 12.1%; HR 0.86, 95% CI 0.74 to 0.99) Secondary outcomes Significant decrease in cardiovascular death (3.7% vs. 5.9%; HR 0.62, 95% CI 0.49 to 0.77) Safety outcomes No significant differences in adverse events, serious adverse events and adverse events leading to discontinuation of study drug. Significant difference in genital infection (6.4% vs. 1.8%). Conclusion In patients with T2DM at high cardiovascular risk who are on standard care, empagliflozin was superior to placebo with respect to death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Reference Zinman B, Wanner C, Lachin JM et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. Open reference URL https://web.pathway.md/studies/reca4EqrygEOvQkeU 2/2

6/28/23, 9:56 PM EMPACTA Pathway Feedback Search Clinical Topics Home Studies EMPACTA EMPACTA Disease COVID 19 infection Trial question What is the role of tocilizumab in patients hospitalized with COVID-19 pneumonia not undergoing mechanical ventilation? Study design Multi-center Double blinded RCT Population Characteristics of study participants 41.2% female N = 389 58.8% male 389 patients (154 female, 223 male) Inclusion criteria: patients hospitalized with COVID-19 pneumonia who were not receiving mechanical ventilation Key exclusion criteria: receiving CPAP, bilevel positive airway pressure, or mechanical ventilation; progression of the illness to death imminent and inevitable within 24 hours; active tuberculosis or suspected active bacterial, fungal, or viral infection (other than SARS-CoV-2 infection or well-controlled human immunodeficiency virus infection) Interventions N=249 tocilizumab plus standard care (one or two doses of intravenous 8 mg/kg of body weight, to a maximum of 800 mg per dose) N=128 placebo plus standard care (matching one or two intravenous doses of placebo) Primary outcome https://web.pathway.md/studies/recraHR8fi1ToHRg7 1/2 6/28/23, 9:56 PM EMPACTA Pathway Rate of mechanical ventilation or death by day 28 19.3 % 19.3 14.5 % 12 9.7 % Significant decrease 4.8 % NNT = 14 0.0 % Tocilizumab plus standard care Placebo plus standard care Significant decrease in the rate of mechanical ventilation or death by day 28 (12% vs. 19.3%; HR 0.56, 95% CI 0.33 to 0.97) Secondary outcomes No significant difference in median time to hospital discharge or readiness for discharge over 28- day period (6 days vs. 7.5 days; HR 1.16, 95% CI 0.91 to 1.48) Safety outcomes No significant differences in overall adverse events, death, and progression of illness to category 6 on the seven-category ordinal scale. Significant difference in serious adverse events (15.2% vs. 19.7%) and serious infections (5.2% vs. 7.1%). Conclusion In patients hospitalized with COVID-19 pneumonia who were not receiving mechanical ventilation, tocilizumab plus standard care was superior to placebo plus standard care with respect to the rate of mechanical ventilation or death by day 28. Reference Carlos Salama, Jian Han, Linda Yau et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021 Jan 7;384(1):20-30. Open reference URL https://web.pathway.md/studies/recraHR8fi1ToHRg7 2/2

6/28/23, 9:56 PM EMPEROR-Preserved Pathway Feedback Search Clinical Topics Home Studies EMPEROR Preserved EMPEROR Preserved Disease Heart failure Trial question What is the role of empagliflozin in patients with HFpEF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 45.0% female N = 5988 55.0% male 5988 patients (2676 female, 3312 male) Inclusion criteria: patients with NYHA class II-IV HF and an ejection fraction > 40% Key exclusion criteria: myocardial infarction; major cardiovascular surgery, or stroke in past 90 days; heart transplant; acute decompensated HF; indication for liver disease; impaired renal function Interventions N=2997 empagliflozin (10 mg once daily plus usual therapy) N=2991 placebo (matching placebo plus usual care) Primary outcome Cardiovascular death or hospitalization for heart failure 17.1 % 17.1 13.8 12.8 % https://web.pathway.md/studies/recoc9ovpunItjZE8 1/2 6/28/23, 9:56 PM EMPEROR-Preserved Pathway 8.6 % Significant decrease 4.3 % NNT = 30 0.0 % Empagliflozin Placebo Significant decrease in cardiovascular death or hospitalization for HF (13.8% vs. 17.1%; HR 0.79, 95% CI 0.69 to 0.9) Secondary outcomes Significant decrease in hospitalization for HF (8.6% vs. 11.8%; HR 0.71, 95% CI 0.6 to 0.83) No significant difference in cardiovascular death (7.3% vs. 8.2%; HR 0.91, 95% CI 0.76 to 1.09) Significant increase in the incidence of improvement in GFR (-1.25 mL/min/1.73 m /year vs. -2.62 mL/min/1.73 m /year; HR 1.36, 95% CI 1.06 to 1.66) Safety outcomes No significant difference in serious adverse events and adverse events leading to discontinuation of trial drug. Conclusion In patients with NYHA class II-IV HF and an ejection fraction > 40%, empagliflozin was superior to placebo with respect to cardiovascular death or hospitalization for HF. Reference Stefan D Anker, Javed Butler, Gerasimos Filippatos et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451-1461. Open reference URL https://web.pathway.md/studies/recoc9ovpunItjZE8 2/2

6/28/23, 9:56 PM EMPEROR-Reduced Pathway Feedback Search Clinical Topics Home Studies EMPEROR Reduced EMPEROR Reduced Disease Heart failure Trial question What is the role of empagliflozin in patients with HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 24.0% female N = 3730 76.0% male 3730 patients (893 female, 2837 male) Inclusion criteria: adult patients with chronic HF and an ejection fraction 40% who were receiving recommended therapy Key exclusion criteria: myocardial infarction, major cardiovascular surgery or stroke in the past 90 days; heart transplant recipient; acute decompensated HF; symptomatic hypotension; indication of liver disease; impaired renal function Interventions N=1863 empagliflozin (at a dose of 10 mg once daily) N=1867 placebo (matching placebo) Primary outcome Cardiovascular death or hospitalization for worsening heart failure 24.7 24.7 % 19 4 https://web.pathway.md/studies/rec4wn5P1oc265qiW 1/2 6/28/23, 9:56 PM EMPEROR-Reduced Pathway 19.4 18.5 % 12.3 % Significant decrease 6.2 % NNT = 19 0.0 % Empagliflozin Placebo Significant decrease in cardiovascular death or hospitalization for worsening HF (19.4% vs. 24.7%; HR 0.75, 95% CI 0.65 to 0.86) Secondary outcomes Significant decrease in total hospitalizations for HF (388 events vs. 553 events; HR 0.7, 95% CI 0.58 to 0.85) Significant decrease in the incidence of eGFR decline (0.55 mL/min/1.73 m /year vs. 2.28 mL/min/1.73 m /year; AD -1.73 mL/min/1.73 m /year, 95% CI -1.1 to -2.37) No significant difference in death from any cause (13.4% vs. 14.2%; HR 0.92, 95% CI 0.77 to 1.1) Safety outcomes No significant difference in adverse effects. Significant difference in serious renal outcome (1.6% vs. 3.1%). Conclusion In adult patients with chronic HF and an ejection fraction 40% who were receiving recommended therapy, empagliflozin was superior to placebo with respect to cardiovascular death or hospitalization for worsening HF. Reference Milton Packer, Stefan D Anker, Javed Butler et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020 Oct 8;383(15):1413-1424. Open reference URL https://web.pathway.md/studies/rec4wn5P1oc265qiW 2/2

6/28/23, 9:57 PM EMPHASIS-HF Pathway Feedback Search Clinical Topics Home Studies EMPHASIS HF EMPHASIS HF Disease Heart failure Trial question What is the role of eplerenone in patients with chronic systolic HF and mild symptoms? Study design Multi-center Double blinded RCT Population Characteristics of study participants 22.0% female N = 2737 78.0% male 2737 patients (610 female, 2127 male) Inclusion criteria: patients with NYHA class II HF and an ejection fraction of no more than 35% Key exclusion criteria: acute myocardial infarction, NYHA class III or IV HF, serum potassium level > 5.0 mmol/L, an eGFR < 30 mL/min/1.73 m of body-surface area, or need for a potassium-sparing diuretic Interventions N=1364 eplerenone (up to 50 mg daily plus recommended therapy) N=1373 placebo (matching placebo plus recommended therapy) Primary outcome Death from cardiovascular causes or hospitalization for heart failure 25.9 25.9 % 19.4 % 18.3 https://web.pathway.md/studies/reca83x7Cz4fXJGcx 1/2 6/28/23, 9:57 PM EMPHASIS-HF Pathway 12.9 % Significant decrease 6.5 % NNT = 13 0.0 % Eplerenone Placebo Significant decrease in death from cardiovascular causes or hospitalization for HF (18.3% vs. 25.9%; HR 0.63, 95% CI 0.54 to 0.74) Secondary outcomes Significant decrease in death from any cause (12.5% vs. 15.5%; HR 0.76, 95% CI 0.62 to 0.93) Significant decrease in death due to cardiovascular causes (10.8% vs. 13.5%; HR 0.76, 95% CI 0.61 to 0.94) Significant decrease in hospitalizations for HF (12% vs. 18.4%; HR 0.58, 95% CI 0.47 to 0.7) Safety outcomes Significant differences in adverse event leading to discontinuation of study drug (13.8% vs. 16.2%, p = 0.09) and hyperkalemia > 5.5 mmol/L (11.8% vs. 7.2%,p < 0.001). Conclusion In patients with NYHA class II HF and an ejection fraction of no more than 35%, eplerenone was superior to placebo with respect to death from cardiovascular causes or hospitalization for HF. Reference Zannad F, McMurray JJ, Krum H et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 6;364(1):11-21. Open reference URL https://web.pathway.md/studies/reca83x7Cz4fXJGcx 2/2

6/28/23, 9:57 PM EMPULSE Pathway Feedback Search Clinical Topics Home Studies EMPULSE EMPULSE Disease Heart failure Trial question What is the role of empagliflozin in patients hospitalized for acute HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 34.0% female N = 530 66.0% male 530 patients (179 female, 351 male) Inclusion criteria: patients with a primary diagnosis of acute de novo or decompensated chronic HF regardless of LVEF Key exclusion criteria: cardiogenic shock; PE; current hospitalization for acute HF primarily triggered by PE, cerebrovascular accident, or acute myocardial infarction Interventions N=265 empagliflozin (at a dose of 10 mg/day) N=265 placebo (matching placebo) Primary outcome Clinical benefit at day 90 53.9 % 53.89 40.4 % 39.71 https://web.pathway.md/studies/recvh6mbcKUlUutnH 1/2 6/28/23, 9:57 PM EMPULSE Pathway 26.9 % Significant increase 13.5 % NNH = 7 0.0 % Empagliflozin Placebo Significant increase in clinical benefit at day 90 (53.89% vs. 39.71%; AD 14%, 95% CI 4.14 to 23.86) Secondary outcomes No significant difference in cardiovascular death or hospitalization for HF (12.8% vs. 18.5%; HR 0.69, 95% CI 0.45 to 1.08) No significant difference in improvement of 10 points in Kansas City Cardiomyopathy Questionnaire-total symptom score at day 90 (83.1% vs. 76.3%; OR 1.522, 95% CI 0.93 to 2.5) Significant increase in improvement in Kansas City Cardiomyopathy Questionnaire-total symptom score at day 90 (36.19 vs. 31.73; AD 4.45, 95% CI 0.32 to 8.59) Safety outcomes No significant difference in serious adverse events. Conclusion In patients with a primary diagnosis of acute de novo or decompensated chronic HF regardless of LVEF, empagliflozin was superior to placebo with respect to clinical benefit at day 90. Reference Adriaan A Voors, Christiane E Angermann, John R Teerlink et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022 Mar;28(3):568-574. Open reference URL https://web.pathway.md/studies/recvh6mbcKUlUutnH 2/2

6/28/23, 9:57 PM ENGAGE AF-TIMI 48 Pathway Feedback Search Clinical Topics Home Studies ENGAGE AF TIMI 48 ENGAGE AF TIMI 48 Disease Disease Disease Acute ischemic stroke Atrial fibrillation Transie Reference Giugliano RP, Ruff CT, Braunwald E et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. Open reference URL https://web.pathway.md/studies/rectZnNDexgxjZUQd 1/1

6/28/23, 9:57 PM ENTRUST-AF PCI Pathway Feedback Search Clinical Topics Home Studies ENTRUST AF PCI ENTRUST AF PCI Disease Atrial fibrillation Trial question Is edoxaban-based regimen noninferior to vitamin K antagonist-based antithrombotic regimen in patients with AF? Study design Multi-center Open label RCT Population Characteristics of study participants 26.0% female N = 1506 74.0% male 1506 patients (386 female, 1120 male) Inclusion criteria: adult patients with AF after successful coronary stenting requiring oral anticoagulation Key exclusion criteria: mechanical heart valves; moderate-to-severe mitral stenosis; end-stage renal disease; and other major comorbidities Interventions N=751 edoxaban regimen (at a dose of 60 mg daily plus P2Y12 inhibitor for 12 months) N=755 Vitamin K antagonist regimen (Vitamin K antagonist plus P2Y12 inhibitor and aspirin 100 mg/day for 1-12 months) Primary outcome Rate of major or clinically relevant non-major bleeding within 12 months 20.0 % 20 https://web.pathway.md/studies/reczxAqYegWtl1rR3 1/2 6/28/23, 9:57 PM ENTRUST-AF PCI Pathway 17 15.0 % 10.0 % Difference not exceeding nonferiority margin 5.0 % 0.0 % Edoxaban regimen Vitamin K antagonist regimen Difference not exceeding nonferiority margin in the rate of major or clinically relevant non-major bleeding within 12 months (17% vs. 20%; HR 0.83, 95% CI 0.65 to 1.05) Secondary outcomes No significant difference in composite outcome of cardiovascular death, stroke, systemic embolic events, myocardial infarction, and definite stent thrombosis (7% vs. 6%; HR 1.06, 95% CI 0.71 to 1.69) No significant difference in major bleeding (6% vs. 6%; HR 0.95, 95% CI 0.63 to 1.42) Conclusion In adult patients with AF after successful coronary stenting requiring oral anticoagulation, edoxaban regimen was noninferior to Vitamin K antagonist regimen with respect to the rate of major or clinically relevant non-major bleeding within 12 months. Reference Pascal Vranckx, Marco Valgimigli, Lars Eckardt et al. Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial. Lancet. 2019 Oct 12;394(10206):1335-1343. Open reference URL https://web.pathway.md/studies/reczxAqYegWtl1rR3 2/2

6/28/23, 9:57 PM EOLIA Pathway Feedback Search Clinical Topics Home Studies EOLIA EOLIA Disease Acute respiratory distress syndr Trial question What is the role of ECMO in patients with severe ARDS? Study design Multi-center Open label RCT Population Characteristics of study participants 29.0% female N = 249 71.0% male 249 patients (72 female, 177 male) Inclusion criteria: patients with very severe ARDS, as indicated by one of three criteria - a ratio of partial pressure of arterial oxygen to the FiO2 < 50 mmHg for > 3 hours; a ratio of partial pressure of arterial oxygen to the FiO2 < 80 mmHg for > 6 hours; or an arterial blood pH < 7.25 with a partial pressure of arterial CO2 of at least 60 mmHg for > 6 hours Key exclusion criteria: age < 18 years; receipt of mechanical ventilation for 7 days; pregnancy; long-term chronic respiratory insufficiency treated with oxygen therapy or noninvasive ventilation; cardiac failure resulting in venoarterial ECMO; a history of heparin- induced thrombocytopenia; cancer with a life expectancy < 5 years; a moribund condition Interventions N=124 ECMO (percutaneous venovenous cannulation within 2 hours of randomization) N=125 control (continued conventional treatment) Primary outcome https://web.pathway.md/studies/reci6YNhAbxGHOxeP 1/2 6/28/23, 9:57 PM EOLIA Pathway Death at 60 days 46.0 % 46 35 34.5 % 23.0 % 11.5 % No significant difference 0.0 % Extracorporeal membrane oxygenation Control No significant difference in death at 60 days (35% vs. 46%; RR 0.76, 95% CI 0.55 to 1.04) Secondary outcomes Significant decrease in treatment failure at 60 days (35% vs. 58%; RR 0.62, 95% CI 0.47 to 0.82) Borderline significant increase in days free of RRT (50 days vs. 32 days; AD 18 days, 95% CI 0 to 51) No significant difference in days free from mechanical ventilation (23 days vs. 3 days; AD 20 days, 95% CI -5 to 32) Safety outcomes No significant differences in hemorrhagic stroke, pneumothorax, ventilator-associated pneumonia, massive bleeding. Significant differences in severe thrombocytopenia (27% vs. 16%), bleeding events leading to packed red-cell transfusion (46% vs. 28%), ischemic stroke (0% vs. 5%). Conclusion In patients with very severe ARDS, as indicated by one of three criteria - a ratio of partial pressure of arterial oxygen to the FiO2 < 50 mmHg for > 3 hours; a ratio of partial pressure of arterial oxygen to the FiO2 < 80 mmHg for > 6 hours; or an arterial blood pH < 7.25 with a partial pressure of arterial CO2 of at least 60 mmHg for > 6 hours, ECMO was not superior to control with respect to death at 60 days. Reference Alain Combes, David Hajage, Gilles Capellier et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018 May 24;378(21):1965-1975. Open reference URL https://web.pathway.md/studies/reci6YNhAbxGHOxeP 2/2

6/28/23, 10:00 PM EPaNIC Pathway Feedback Search Clinical Topics Home Studies EPaNIC EPaNIC Disease Parenteral nutrition Trial question What is the role of late initiation of parenteral nutrition in critically ill patients to supplement insufficient enteral nutrition? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 4640 64.0% male 4640 patients (1668 female, 2972 male) Inclusion criteria: adults in the ICU who had a score of 3 on nutritional risk screening Key exclusion criteria: age < 18 years, moribund, do-not-resuscitate code, short bowel syndrome, home ventilation, diabetic coma, pregnancy/lactation, receipt of oral nutrition, BMI < 17, nutritional risk screening score < 3 Interventions N=2328 late parenteral initiation (parenteral nutrition not initiated before day 8) N=2312 early parenteral initiation (parenteral nutrition initiated within 48 hours after ICU admission) Primary outcome Duration of stay in intensive care unit 4.0 days 4 https://web.pathway.md/studies/recZDKo2Mpc51CaKO 1/2 6/28/23, 10:00 PM EPaNIC Pathway 3.0 days 3 2.0 days 1.0 days Significant increase 0.0 days Late parenteral initiation Early parenteral initiation Significant increase in duration of stay in the ICU (3 days vs. 4 days; HR 1.06, 95% CI 1 to 1.13) Secondary outcomes Significant decrease in new infection (22.8% vs. 26.2%; RR 0.87, 95% CI 0.23 to 1.51) Significant increase in duration of hospital stay (14 days vs. 16 days; HR 1.06, 95% CI 1 to 1.13) No significant difference in mechanical ventilation duration (2 days vs. 2 days; HR 1.06, 95% CI 0.99 to 1.12) Safety outcomes No significant differences in death in the ICU and hospital, nutrition-related complication. Significant differences in discharged live from ICU within 8 days (75.2% vs. 71.7%), hypoglycemia during intervention (3.5% vs. 1.9%). Conclusion In adults in the ICU who had a score of 3 on nutritional risk screening, late parenteral initiation was superior to early parenteral initiation with respect to duration of stay in the ICU. Reference Michael P Casaer, Dieter Mesotten, Greet Hermans et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011 Aug 11;365(6):506-17. Open reference URL https://web.pathway.md/studies/recZDKo2Mpc51CaKO 2/2

6/28/23, 9:58 PM EPCAT I Pathway Feedback Search Clinical Topics Home Studies EPCAT I EPCAT I Disease Disease Hip fracture Hip osteoarthritis Trial question Is aspirin noninferior to dalteparin for extended VTE prophylaxis after total hip arthroplasty? Study design Multi-center Double blinded RCT Population Characteristics of study participants 43.4% female N = 786 56.6% male 786 patients (341 female, 444 male) Inclusion criteria: patients undergoing elective unilateral total hip arthroplasty who had an initial dalteparin prophylaxis for 10 days Key exclusion criteria: hip fracture in the previous 3 months, metastatic cancer, life expectancy < 6 months, major bleeding, active peptic ulcer disease or gastritis that precluded aspirin use, aspirin allergy, heparin-induced thrombocytopenia or heparin allergy Interventions N=386 aspirin (81 mg once daily for 28 days) N=400 dalteparin (5,000 U once daily for 28 days) Primary outcome Symptomatic venous thromboembolism 1.3 % 1.3 https://web.pathway.md/studies/recsOhcN1htgqSy4E 1/2 6/28/23, 9:58 PM EPCAT I Pathway 1.0 % 0.7 % Difference not exceeding nonferiority margin 0.3 % 0.3 0.0 % Aspirin Dalteparin Difference not exceeding nonferiority margin in symptomatic VTE (0.3% vs. 1.3%; AD 1%, 95% CI -0.5 to 2.5) Secondary outcomes No significant difference in major bleeding (AD 0.25%, 95% CI -4.9 to 1) No significant difference in VTE or clinically relevant bleeding (0.8% vs. 2.5%; AD 1.7%, 95% CI -0.3 to 3.8) No significant difference in clinically significant nonmajor bleeding (0.5% vs. 1%; AD 0.48%, 95% CI -1 to 2) Safety outcomes No significant differences in wound infections, arterial vascular events, deaths. Conclusion In patients undergoing elective unilateral total hip arthroplasty who had an initial dalteparin prophylaxis for 10 days, aspirin was noninferior to dalteparin with respect to symptomatic VTE. Reference Anderson DR, Dunbar MJ, Bohm ER et al. Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. Ann Intern Med. 2013 Jun 4;158(11):800-6. Open reference URL https://web.pathway.md/studies/recsOhcN1htgqSy4E 2/2

6/28/23, 9:58 PM EPCAT II Pathway Feedback Search Clinical Topics Home Studies EPCAT II EPCAT II Disease Disease Disease Hip fracture Knee osteoarthritis Periope Trial question Is aspirin noninferior to rivaroxaban for the prevention of VTE in patients undergoing total hip arthroplasty or total knee arthroplasty? Study design Multi-center Double blinded RCT Population Characteristics of study participants 52.0% female N = 3424 48.0% male 3424 patients (1787 female, 1637 male) Inclusion criteria: patients who underwent total hip arthroplasty or total knee arthroplasty and received once-daily oral rivaroxaban 10 mg until postoperative day 5 Key exclusion criteria: hip or lower limb fracture during the previous 3 months and metastatic cancer Interventions N=1707 aspirin (81 mg daily for additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty) N=1717 rivaroxaban (continued 10 mg for an additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty) Primary outcome Venous thromboembolism https://web.pathway.md/studies/rec9Hz4k4zZFRIWq5 1/2 6/28/23, 9:58 PM EPCAT II Pathway 0.7 % 0.7 0.64 0.5 % 0.3 % Difference not exceeding nonferiority margin 0.2 % 0.0 % Aspirin Rivaroxaban Difference not exceeding nonferiority margin in VTE (0.64% vs. 0.7%; AD 0.06%, 95% CI -0.55 to 0.66) Secondary outcomes No significant difference in major bleeding (0.47% vs. 0.29%; AD 0.18%, 95% CI -0.65 to 0.29) No significant difference in major bleeding and clinically relevant nonmajor bleeding (1.29% vs. 0.99%; AD 0.3%, 95% CI -1.07 to 0.47) Safety outcomes No significant differences in major bleeding complications, deep vein thrombosis in the calf. Conclusion In patients who underwent total hip arthroplasty or total knee arthroplasty and received once- daily oral rivaroxaban 10 mg until postoperative day 5, aspirin was noninferior to rivaroxaban with respect to VTE. Reference Anderson DR, Dunbar M, Murnaghan J et al. Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty. N Engl J Med. 2018 Feb 22;378(8):699-707. Open reference URL https://web.pathway.md/studies/rec9Hz4k4zZFRIWq5 2/2

6/28/23, 9:58 PM EPHESUS Pathway Feedback Search Clinical Topics Home Studies EPHESUS EPHESUS Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the role of eplerenone in patients with acute myocardial infarction complicated by LV dysfunction and HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 29.0% female N = 6632 71.0% male 6632 patients (1918 female, 4714 male) Inclusion criteria: patients with acute myocardial infarction complicated by LV dysfunction and HF Key exclusion criteria: use of potassium-sparing diuretics, a serum creatinine concentration > 2.5 mg/dL, and a serum potassium concentration > 5.0 mmol/L before randomization Interventions N=3319 eplerenone (25 mg per day initially, titrated to a maximum of 50 mg per day) N=3313 placebo (matching placebo) Primary outcome Cardiovascular death or hospitalization for cardiovascular events 30.0 % 30 26.7 22 5 % https://web.pathway.md/studies/recGOrkaW6SuoQYv4 1/2 6/28/23, 9:58 PM 22.5 % EPHESUS Pathway 15.0 % Significant decrease 7.5 % NNT = 30 0.0 % Eplerenone Placebo Significant decrease in cardiovascular death or hospitalization for cardiovascular events (26.7% vs. 30%; RR 0.87, 95% CI 0.79 to 0.95) Secondary outcomes Significant decrease in death from any cause or hospitalization (52% vs. 55%; RR 0.92, 95% CI 0.86 to 0.98) Safety outcomes Significant differences in serious hyperkalemia (5.5% vs. 3.9%, p = 0.002) and hypokalemia (8.4% vs. 13.1%, p < 0.001). Conclusion In patients with acute myocardial infarction complicated by LV dysfunction and HF, eplerenone was superior to placebo with respect to cardiovascular death or hospitalization for cardiovascular events. Reference Pitt B, Remme W, Zannad F et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003 Apr 3;348(14):1309- 21. Open reference URL https://web.pathway.md/studies/recGOrkaW6SuoQYv4 2/2

6/28/23, 9:58 PM EPVent2 Pathway Feedback Search Clinical Topics Home Studies EPVent2 EPVent2 Disease Acute respiratory distress syndr Trial question What is the effect of titrating PEEP with an esophageal pressure-guided strategy among patients with moderate-to-severe ARDS? Study design Multi-center Open label RCT Population Characteristics of study participants 46.0% female N = 200 54.0% male 200 patients (92 female, 108 male) Inclusion criteria: mechanically ventilated patients aged 16 years and older with moderate-to- severe ARDS Key exclusion criteria: contraindication to esophageal instrumentation, high PEEP, severe coagulopathy, history of lung or liver transplantation, elevated ICP, neuromuscular disease, severe chronic liver disease Interventions N=102 esophageal-pressure guided mechanical ventilation (PEEP titration guided by esophageal pressure adjusted as needed to maintain end-expiratory PL between 0 to 6 cmH O) N=98 high PEEP mechanical ventilation (PEEP adjusted to maintain the lowest PEEP-FiO2 combination possible on the empirical table while maintaining oxygenation goals) P i t https://web.pathway.md/studies/recKrP7ijSghUV6w0 1/2 6/28/23, 9:58 PM EPVent2 Pathway Primary outcome Rate of death and days free from mechanical ventilation among survivors through day 28 50.4 % 50.4 49.6 37.8 % 25.2 % 12.6 % No significant difference 0.0 % Esophageal-pressure guided mechanical ventilation High PEEP mechanical ventilation No significant difference in the rate of death and days free from mechanical ventilation among survivors through day 28 (49.6% vs. 50.4%; ARD -0.8, 95% CI -15.14 to 13.54) Secondary outcomes No significant difference in the rate of death through day 28 (32.4% vs. 30.6%; AD 1.7%, 95% CI -11.1 to 14.6) Safety outcomes No significant differences in shock-free days, pneumothorax, barotrauma. Significant difference in rescue therapy (3.9% vs. 12.2%). Conclusion In mechanically ventilated patients aged 16 years and older with moderate-to-severe ARDS, esophageal-pressure guided mechanical ventilation was not superior to high PEEP mechanical ventilation with respect to the rate of death and days free from mechanical ventilation among survivors through day 28. Reference Jeremy R Beitler, Todd Sarge, Valerie M Banner-Goodspeed et al. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2019 Mar 5;321(9):846-857. Open reference URL https://web.pathway.md/studies/recKrP7ijSghUV6w0 2/2

6/28/23, 10:00 PM ERSPC Pathway Feedback Search Clinical Topics Home Studies ERSPC ERSPC Disease Prostate cancer Trial question What is the role of PSA testing in men for prostate cancer screening? Study design Multi-center Open label RCT Population 162243 male patients Inclusion criteria: men between the ages of 55 and 69 years Key exclusion criteria: diagnosis of prostate cancer Interventions N=72890 prostate cancer screening (PSA screening at an average of once every 4 years) N=89353 no screening (did not receive PSA screening) Primary outcome Death from prostate cancer 0.4 % 0.36 0.29 0.3 % 0.2 % Significant decrease 0.1 % NNT = 1429 0.0 % Prostate cancer screening No screening Significant decrease in death from prostate cancer (0.29% vs. 0.36%; aRR 0.8, 95% CI 0.65 to 0.98) Conclusion https://web.pathway.md/studies/recnOU5pM0aagYlhx 1/2 6/28/23, 10:00 PM ERSPC Pathway In men between the ages of 55 and 69 years, prostate cancer screening was superior to no screening with respect to death from prostate cancer. Reference Schroder FH, Hugosson J, Roobol MJ et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009 Mar 26;360(13):1320-8. Open reference URL https://web.pathway.md/studies/recnOU5pM0aagYlhx 2/2

6/28/23, 10:00 PM ESCAPe Pathway Feedback Search Clinical Topics Home Studies ESCAPe ESCAPe Disease Community-acquired pneumonia Trial question What is the role of prolonged low-dose methylprednisolone in patients with severe community- acquired pneumonia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 4.0% female N = 584 96.0% male 584 patients (21 female, 562 male) Inclusion criteria: adult patients with severe community-acquired pneumonia presenting in hospital within 72-96 hours Key exclusion criteria: vasopressor-dependent shock requiring multiple or high-dose vasopressors; major gastrointestinal bleeding; postoperative pneumonia; cystic fibrosis; active tuberculosis; fungal infection Interventions N=297 methylprednisolone (intravenous 40 mg loading bolus, followed by 40 mg/day through day 7 and progressive tapering during the 20-day treatment course) N=287 placebo (matching placebo for 20 days) Primary outcome Death from all causes at day 60 https://web.pathway.md/studies/rec0QZekarcSJ01Zj 1/2 6/28/23, 10:00 PM ESCAPe Pathway 18.0 % 18 16 13.5 % 9.0 % 4.5 % No significant difference 0.0 % Methylprednisolone Placebo No significant difference in death from all causes at day 60 (16% vs. 18%; aOR 0.9, 95% CI 0.57 to 1.4) Secondary outcomes No significant difference in death in the hospital (12% vs. 10%; AD 2%, 95% CI -3 to 7) Safety outcomes No significant difference in serious adverse events. Conclusion In adult patients with severe community-acquired pneumonia presenting in hospital within 72-96 hours, methylprednisolone was not superior to placebo with respect to death from all causes at day 60. Reference G Umberto Meduri, Mei-Chiung Shih, Lisa Bridges et al. Low-dose methylprednisolone treatment in critically ill patients with severe community-acquired pneumonia. Intensive Care Med. 2022 Aug;48(8):1009-102. Open reference URL https://web.pathway.md/studies/rec0QZekarcSJ01Zj 2/2

6/28/23, 10:00 PM ESCAPE Pathway Feedback Search Clinical Topics Home Studies ESCAPE ESCAPE Disease Heart failure Trial question What is the role of pulmonary artery catheter in patients hospitalized with severe symptomatic and recurrent HF? Study design Multi-center Open label RCT Population Characteristics of study participants 26.0% female N = 433 74.0% male 433 patients (113 female, 320 male) Inclusion criteria: patients hospitalized with severe symptomatic and recurrent HF Key exclusion criteria: creatinine level > 3.5 mg/dL, or prior use of dobutamine or dopamine > 3 g/kg/min, or any prior use of milrinone during the current hospitalization Interventions N=215 pulmonary artery catheter-guided resuscitation (therapy guided by clinical assessment and pulmonary artery catheters) N=218 resuscitation based on clinical assessment (therapy guided by clinical assessment alone) Primary outcome Time alive out of hospital at 6 months 135 135.0 days 133 https://web.pathway.md/studies/recVPyJHvjyQWuL7g 1/2 6/28/23, 10:00 PM ESCAPE Pathway y 101.3 days 67.5 days 33.8 days No significant difference 0.0 days Pulmonary artery catheter-guided resuscitation Resuscitation based on clinical assessment No significant difference in time alive out of hospital at 6 months (133 days vs. 135 days; HR 1, 95% CI 0.82 to 1.21) Secondary outcomes No significant difference in death (10% vs. 9%; OR 1.26, 95% CI 0.78 to 2.03) No significant difference in the number of days hospitalized (8.7 vs. 8.3; HR 1.04, 95% CI 0.86 to 1.27) No significant difference in in-hospital death or death at 30 days (4.7% vs. 5%; OR 0.97, 95% CI 0.38 to 2.22) Safety outcomes Significant differences in in-hospital adverse events (21.9% vs. 11.5%, p = 0.04). Conclusion In patients hospitalized with severe symptomatic and recurrent HF, pulmonary artery catheter- guided resuscitation was not superior to resuscitation based on clinical assessment with respect to time alive out of hospital at 6 months. Reference Binanay C, Califf RM, Hasselblad V et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA. 2005 Oct 5;294(13):1625-33. Open reference URL https://web.pathway.md/studies/recVPyJHvjyQWuL7g 2/2

6/28/23, 10:01 PM ESPRIT Pathway Feedback Search Clinical Topics Home Studies ESPRIT ESPRIT Disease Disease Acute ischemic stroke Transient ischemic attack Trial question Is combination of aspirin and dipyridamole superior to aspirin in patients with a recent history of TIA or minor stroke of presumed arterial origin? Study design Multi-center Open label RCT Population Characteristics of study participants 34.3% female N = 2763 65.7% male 2763 patients (950 female, 1789 male) Inclusion criteria: patients within 6 months of a TIA or minor ischemic stroke of presumed arterial origin Key exclusion criteria: possible cardiac source of embolism, any blood coagulation disorder, any contraindication for aspirin or dipyridamole, and a limited life expectancy Interventions N=1363 aspirin and dipyridamole (aspirin dose of 30-325 mg/day and dipyridamole dose of 400 mg daily) N=1376 aspirin alone (at a dose of 30-325 mg/day) Primary outcome Death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, or major bleeding 16.0 % 16 https://web.pathway.md/studies/recM11rZK4cqmMcZT 1/2 6/28/23, 10:01 PM ESPRIT Pathway 13 12.0 % 8.0 % 4.0 % Borderline significant decrease 0.0 % Aspirin and dipyridamole Aspirin alone Borderline significant decrease in death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, or major bleeding (13% vs. 16%; HR 0.8, 95% CI 0.66 to 0.98) Secondary outcomes No significant difference in death from any cause (7% vs. 8%; HR 0.88, 95% CI 0.67 to 1.17) No significant difference in vascular death (3.2% vs. 4.4%; HR 0.75, 95% CI 0.51 to 1.1) No significant difference in major bleeding complications (2.6% vs. 3.9%; HR 0.67, 95% CI 0.44 to 1.03) Safety outcomes No significant difference in all major ischemic events. Significant difference in discontinuation of trial medication (34.5% vs. 13.4%). Conclusion In patients within 6 months of a TIA or minor ischemic stroke of presumed arterial origin, aspirin and dipyridamole were superior to aspirin alone with respect to death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, or major bleeding. Reference ESPRIT Study Group, Halkes PH, van Gijn J et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006 May 20;367(9523):1665-73. Open reference URL https://web.pathway.md/studies/recM11rZK4cqmMcZT 2/2

6/28/23, 10:01 PM ESSENCE Pathway Feedback Search Clinical Topics Home Studies ESSENCE ESSENCE Disease Non-ST-elevation myocardial inf Trial question Is enoxaparin superior to UFH in patients with angina at rest or non-Q-wave myocardial infarction receiving aspirin? Study design Multi-center Double blinded RCT Population Characteristics of study participants 33.0% female N = 3171 67.0% male 3171 patients (1059 female, 2112 male) Inclusion criteria: patients with angina at rest or non-Q-wave myocardial infarctio receiving aspirin Key exclusion criteria: left bundle-branch block or pacemaker, persistent ST-segment elevation, angina with HF or tachydysrhythmia, contraindications to anticoagulation, or a CrCl rate < 30 ml/min Interventions N=1607 enoxaparin (1 mg/kg of body weight SC BID for a minimum of 48 hours to maximum of 8 days) N=1564 UFH (continuous intravenous UFH for a minimum of 48 hours to maximum of 8 days) Primary outcome Death, myocardial infarction, or recurrent angina at 14 days https://web.pathway.md/studies/rec7UvmPii7texVYq 1/2 6/28/23, 10:01 PM ESSENCE Pathway 19.8 % 19.8 16.6 14.9 % 9.9 % Significant decrease 5.0 % NNT = 31 0.0 % Enoxaparin Unfractionated heparin Significant decrease in death, myocardial infarction, or recurrent angina at 14 days (16.6% vs. 19.8%; OR 0.8, 95% CI 0.67 to 0.96) Secondary outcomes Significant increase in need for revascularization at 30 days (27.1% vs. 32.2%; RR 16, 95% CI 6.51 to 25.49) Safety outcomes No significant difference in major bleeding at 30 days (6.5% vs. 7.0%). Significant differences in overall bleeding (18.4% vs. 14.2%, p = 0.001). Conclusion In patients with angina at rest or non-Q-wave myocardial infarctio receiving aspirin, enoxaparin was superior to UFH with respect to death, myocardial infarction, or recurrent angina at 14 days. Reference Cohen M, Demers C, Gurfinkel EP et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med. 1997 Aug 14;337(7):447-52. Open reference URL https://web.pathway.md/studies/rec7UvmPii7texVYq 2/2

6/28/23, 10:01 PM ETESRTA Pathway Feedback Search Clinical Topics Home Studies ETESRTA ETESRTA Disease Adenomyosis Trial question What is the effect of mifepristone in patients with adenomyosis with pain symptoms? Study design Multi-center Double blinded RCT Population 126 female patients Inclusion criteria: adult female patients with adenomyosis and dysmenorrhea Key exclusion criteria: history of undiagnosed vaginal bleeding outside reference ranges; endometrial malignant tumors; uterine fibroids or endometriosis Interventions N=61 mifepristone (at an oral dose of 10 mg/day for 12 weeks) N=65 placebo (matching placebo once daily for 12 weeks) Primary outcome Reduction in adenomyosis-associated dysmenorrhea intensity, evaluated by visual analog scale at 12 weeks 6.6 6.63 5.0 3.3 1.7 Significant increase 0.95 0.0 https://web.pathway.md/studies/recUb6iwbnm3HP58S 1/2 6/28/23, 10:01 PM ETESRTA Pathway 0.0 Mifepristone Placebo Significant increase in reduction in adenomyosis-associated dysmenorrhea intensity, evaluated by visual analog scale at 12 weeks (6.63 vs. 0.95; AD 5.68, 95% CI 4.99 to 6.37) Secondary outcomes Significant increase in complete remission rate for heavy menstrual bleeding (90% vs. 5.41%; AD 84.6%, 95% CI 72.8 to 96.4) Significant increase in total effective rate for heavy menstrual bleeding (95% vs. 37.84%; AD 57.2%, 95% CI 40.1 to 74.2) Significant increase in complete remission rate for anemia (77.78% vs. 22.85%; AD 53.5%, 95% CI 33.6 to 73.5) Safety outcomes No significant difference in adverse events. Conclusion In adult female patients with adenomyosis and dysmenorrhea, mifepristone was superior to placebo with respect to reduction in adenomyosis-associated dysmenorrhea intensity, evaluated by visual analog scale at 12 weeks. Reference Xuan Che, Jianzhang Wang, Wenting Sun et al. Effect of Mifepristone vs Placebo for Treatment of Adenomyosis With Pain Symptoms: A Randomized Clinical Trial. JAMA Netw Open. 2023 Jun 1;6(6):e2317860. Open reference URL https://web.pathway.md/studies/recUb6iwbnm3HP58S 2/2

6/28/23, 10:01 PM EUCLID Pathway Feedback Search Clinical Topics Home Studies EUCLID EUCLID Disease Peripheral artery disease of low Trial question What is the effect of ticagrelor in patients with symptomatic PAD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 28.0% female N = 13885 72.0% male 13885 patients (3888 female, 9997 male) Inclusion criteria: patients with symptomatic PAD who had an ABI of 0.80 or had undergone previous revascularization of the lower limbs Key exclusion criteria: current or planned use of dual antiplatelet therapy or aspirin, an increased risk of bleeding, treatment with long-term anticoagulation, or a poor clopidogrel metabolizer status for the cytochrome P-450 2C19 allele Interventions N=6930 ticagrelor (90 mg BID) N=6955 clopidogrel (75 mg once daily) Primary outcome Cardiovascular death, myocardial infarction, or ischemic stroke 10.8 % 10.8 10.6 8 1 % https://web.pathway.md/studies/recDEz1rgTJMlOk06 1/2 6/28/23, 10:01 PM EUCLID Pathway 8.1 % 5.4 % 2.7 % No significant difference 0.0 % Ticagrelor Clopidogrel No significant difference in cardiovascular death, myocardial infarction, or ischemic stroke (10.8% vs. 10.6%; HR 1.02, 95% CI 0.92 to 1.13) Secondary outcomes No significant difference in acute limb ischemia (1.7% vs. 1.7%; HR 1.03, 95% CI 0.79 to 1.33) Safety outcomes No significant differences in major bleeding (1.6% in each group, p=0.49; HR 1.10, 95% CI 0.84- 1.43). Conclusion In patients with symptomatic PAD who had an ABI of 0.80 or had undergone previous revascularization of the lower limbs, ticagrelor was not superior to clopidogrel with respect to cardiovascular death, myocardial infarction, or ischemic stroke. Reference Hiatt WR, Fowkes FG, Heizer G et al. Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease. N Engl J Med. 2017 Jan 5;376(1):32-40. Open reference URL https://web.pathway.md/studies/recDEz1rgTJMlOk06 2/2

6/28/23, 10:01 PM EUPHRATES Pathway Feedback Search Clinical Topics Home Studies EUPHRATES EUPHRATES Disease Sepsis and septic shock Trial question What is the effect of targeted polymyxin B hemoperfusion among patients with septic shock and high endotoxin activity? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.0% female N = 450 61.0% male 450 patients (177 female, 273 male) Inclusion criteria: adult critically ill patients with septic shock and an endotoxin activity assay level > 0.60 Key exclusion criteria: limits in treatment that prohibited further escalation in the intensity or scope of organ support or initiation of RRT or a terminal disease state precluding short-term survival Interventions N=224 polymyxin B hemoperfusion (2 hemoperfusion treatments within 24 hours with a target duration of 90-120 minutes plus standard therapy) N=226 sham hemoperfusion (recirculation of 0.9% saline for 2 hours to simulate hemoperfusion plus conventional medical therapy) Primary outcome https://web.pathway.md/studies/recbwB3DJbs1C3kHL 1/2 6/28/23, 10:02 PM EUPHRATES Pathway Death at day 28 among all participants and among participants with multiple organ dysfunction score > 9 37.7 % 37.7 34.5 28.3 % 18.9 % 9.4 % No significant difference 0.0 % Polymyxin B hemoperfusion Sham hemoperfusion No significant difference in death at day 28 among all participants and among participants with multiple organ dysfunction score > 9 (37.7% vs. 34.5%; RR 1.09, 95% CI 0.85 to 1.39) Secondary outcomes No significant difference in change in multiple organ dysfunction score for all participants (-2.2 vs. -1.6; AD -0.48, 95% CI -1.1 to 0.14) Significant increase in change in mean arterial pressure (9.4 mmHg vs. 4.1 mmHg; AD 5.5 mmHg, 95% CI 2.5 to 8.6) No significant difference in change in serum creatinine (AD 0.18 mg/dL, 95% CI -0.3 to 0.7) Safety outcomes No significant difference in serious adverse events including worsening of sepsis and septic shock. Significant difference in cardiac arrest/cardio-respiratory arrest (3.8% vs. 9.0%). Conclusion In adult critically ill patients with septic shock and an endotoxin activity assay level > 0.60, polymyxin B hemoperfusion was not superior to sham hemoperfusion with respect to death at day 28 among all participants and among participants with multiple organ dysfunction score > 9. Reference R Phillip Dellinger, Sean M Bagshaw, Massimo Antonelli et al. Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial. JAMA. 2018 Oct 9;320(14):1455-1463. Open reference URL https://web.pathway.md/studies/recbwB3DJbs1C3kHL 2/2

6/28/23, 10:07 PM EUROPA Pathway Feedback Search Clinical Topics Home Studies EUROPA EUROPA Disease Coronary artery disease Trial question What is the role of perindopril in patients with stable coronary heart disease without apparent HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 14.6% female N = 13655 85.4% male 13655 patients (1779 female, 10439 male) Inclusion criteria: patients with stable coronary heart disease without apparent HF Key exclusion criteria: clinical evidence of HF, planned revascularization, hypotension, uncontrolled hypertension, recent (< 1 month) use of ACE inhibitors or angiotensin-receptor blockers, renal insufficiency, and serum potassium > 5.5 mmol/L Interventions N=6110 perindopril (8 mg PO once daily) N=6108 placebo (matching placebo daily) Primary outcome Cardiovascular death, myocardial infarction, or cardiac arrest 10 10.0 % 8 https://web.pathway.md/studies/rec9sK4VzWVWNTgR0 1/2 6/28/23, 10:07 PM EUROPA Pathway 8 7.5 % 5.0 % Significant decrease 2.5 % NNT = 50 0.0 % Perindopril Placebo Significant decrease in cardiovascular death, myocardial infarction, or cardiac arrest (8% vs. 10%; HR 0.8, 95% CI 0.71 to 0.91) Secondary outcomes Significant decrease in total death, nonfatal MI, unstable angina, cardiac arrest (14.8% vs. 17.1%; RR 0.87, 95% CI 0.79 to 0.94) Safety outcomes No significant difference in withdrawal from treatment (22.8% vs. 20.7%). Significant difference in cough (2.7% vs. 0.5%) and hypotension (1.0% vs. 0.3%). Conclusion In patients with stable coronary heart disease without apparent HF, perindopril was superior to placebo with respect to cardiovascular death, myocardial infarction, or cardiac arrest. Reference Fox KM, EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003 Sep 6;362(9386):782-8. Open reference URL https://web.pathway.md/studies/rec9sK4VzWVWNTgR0 2/2