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6/29/23, 1:42 AM PREPIC Pathway Feedback Search Clinical Topics Home Studies PREPIC PREPIC Disease Disease Deep vein thrombosis Pulmonary embolism Trial question What is the effect of vena caval filter in patients with proximal deep vein thrombosis who were at risk for PE? Study design Multi-center Open label RCT Population Characteristics of study participants 52.5% female N = 400 47.5% male 400 patients (210 female, 190 male) Inclusion criteria: patients with proximal deep vein thrombosis who were at risk for PE Key exclusion criteria: placement of a previous filter, contraindication to or failure of anticoagulant therapy, curative anticoagulant therapy lasting > 48 hours, an indication for thrombolysis, short life expectancy, allergy to iodine, hereditary thrombophilia, severe renal or hepatic failure Interventions N=200 IVC filter implantation (insertion immediately after randomization and cavography performed, plus anticoagulation) N=200 no IVC filter implantation (anticoagulation alone with no filter implantation) https://web.pathway.md/studies/recykQg9jas5hkDOH 1/2 6/29/23, 1:42 AM PREPIC Pathway Primary outcome Symptomatic or asymptomatic pulmonary embolism at 12 days 4.8 % 4.8 3.6 % 2.4 % Significant decrease 1.2 % 1.1 NNT = 27 0.0 % Inferior vena cava filter implantation No inferior vena cava filter implantation Significant decrease in symptomatic or asymptomatic PE at 12 days (1.1% vs. 4.8%; OR 0.22, 95% CI 0.05 to 0.9) Secondary outcomes Significant increase in recurrent deep vein thrombosis at 2 years (20.8% vs. 11.6%; OR 1.87, 95% CI 1.1 to 3.2) No significant difference in symptomatic or asymptomatic PE at 12 days (1.6% vs. 4.2%; OR 0.38, 95% CI 0.1 to 1.38) Safety outcomes No significant difference in major bleeding at day 12 or long-term follow-up. Conclusion In patients with proximal deep vein thrombosis who were at risk for PE, IVC filter implantation was superior to no IVC filter implantation with respect to symptomatic or asymptomatic PE at 12 days. Reference Decousus H, Leizorovicz A, Parent F et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Pr vention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998 Feb 12;338(7):409- 15. Open reference URL https://web.pathway.md/studies/recykQg9jas5hkDOH 2/2

6/29/23, 1:41 AM PREV-HAP Pathway Feedback Search Clinical Topics Home Studies PREV HAP PREV HAP Trial question What is the role of interferon gamma-1b in critically ill patients? Study design Multi-center Double blinded RCT Population Characteristics of study participants 34.0% female N = 109 66.0% male 109 patients (37 female, 72 male) Inclusion criteria: critically ill adults, with 1 acute organ failure, under mechanical ventilation Key exclusion criteria: pregnancy; hypersensitivity to interferon gamma-1b; pre-existing immunosuppression; severe hepatic insufficiency; liver cytolysis; chronic renal failure; persisting coma after resuscitated cardiac arrest Interventions N=55 interferon gamma-1b (at a dose of 100 g every 48 hours from day 1-9) N=54 placebo (matching placebo every 48 hours from day 1-9) Primary outcome Hospital-acquired pneumonia or death at day 28 47.3 % 47.3 35.5 % 30.2 23.6 % 11.8 % https://web.pathway.md/studies/recG2oLFu02lTln0b 1/2 6/29/23, 1:41 AM PREV-HAP Pathway No significant difference 0.0 % Interferon gamma-1b Placebo No significant difference in hospital-acquired pneumonia or death at day 28 (47.3% vs. 30.2%; HR 1.76, 95% CI 0.94 to 3.29) Secondary outcomes No significant difference in death from all causes at day 28 (12.7% vs. 17%; HR 0.68, 95% CI 0.25 to 1.85) No significant difference in hospital-acquired pneumonia at day 28 (34.5% vs. 15.1%; HR 2.06, 95% CI 0.92 to 4.57) No significant difference in ARDS at day 28 (12.2% vs. 4.3%; OR 2.72, 95% CI 0.33 to 22.41) Safety outcomes No significant differences in serious adverse events, biological pancreatitis. Conclusion In critically ill adults, with 1 acute organ failure, under mechanical ventilation, interferon gamma-1b was not superior to placebo with respect to a hospital-acquired pneumonia or death at day 28. Reference Antoine Roquilly, Bruno Francois, Olivier Huet et al. Interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial. Intensive Care Med. 2023 Apr 18;1-15. Open reference URL https://web.pathway.md/studies/recG2oLFu02lTln0b 2/2

6/29/23, 1:44 AM PREVENT TB Pathway Feedback Search Clinical Topics Home Studies PREVENT TB PREVENT TB Disease Disease Extrapulmonary tuberculosis Pulmonary tuberculosis Reference Sterling TR, Villarino ME, Borisov AS et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011 Dec 8;365(23):2155-66. Open reference URL https://web.pathway.md/studies/recVVHu48FGaCU3Ad 1/1

6/29/23, 1:45 AM PReVENT Pathway Feedback Search Clinical Topics Home Studies PReVENT PReVENT Trial question What is the effect of low tidal volume strategy in ICU patients without ARDS? Study design Multi-center Open label RCT Population Characteristics of study participants 35.0% female N = 961 65.0% male 961 patients (340 female, 621 male) Inclusion criteria: ICU patients without ARDS expected to not be extubated within 24 hours after start of ventilation Key exclusion criteria: presence of ARDS; ventilation lasting > 12 hours before admission to the ICU; uncontrollable ICP; pulmonary disease and new pulmonary thromboembolism Interventions N=477 a low tidal volume ventilation strategy (at a tidal volume of 4-6 mL/kg predicted body weight) N=484 an intermediate tidal volume ventilation strategy (at a tidal volume of 8-10 mL/kg predicted body weight) Primary outcome Ventilator-free days 21.0 days 21 21 15.8 days 10.5 days https://web.pathway.md/studies/reclObYgO0Lk2bxOs 1/2 6/29/23, 1:45 AM PReVENT Pathway 5.3 days No significant difference 0.0 days A low tidal volume ventilation strategy An intermediate tidal volume ventilation strategy No significant difference in ventilator-free days (21 days vs. 21 days; AD -0.27 days, 95% CI -1.74 to 1.19) Secondary outcomes No significant difference in length of ICU stay (6 days vs. 6 days; AD 0.39 days, 95% CI -1.09 to 1.89) No significant difference in length of hospital stay (14 days vs. 15 days; AD -0.6 days, 95% CI -3.52 to 2.31) No significant difference in the rate of death by day 28 (34.9% vs. 32.1%; HR 1.12, 95% CI 0.9 to 1.4) Safety outcomes No significant differences in ARDS, pneumonia, severe atelectasis, pneumothorax, delirium, extrapulmonary infection and sepsis. Conclusion In ICU patients without ARDS expected to not be extubated within 24 hours after start of ventilation, a low tidal volume ventilation strategy was not superior to an intermediate tidal volume ventilation strategy with respect to a ventilator-free days. Reference Writing Group for the PReVENT Investigators, Fabienne D Simonis, Ary Serpa Neto et al. Effect of a Low vs Intermediate Tidal Volume Strategy on Ventilator-Free Days in Intensive Care Unit Patients Without ARDS: A Randomized Clinical Trial. JAMA. 2018 Nov 13;320(18):1872-1880. Open reference URL https://web.pathway.md/studies/reclObYgO0Lk2bxOs 2/2

6/29/23, 1:44 AM PreVent Pathway Feedback Search Clinical Topics Home Studies PreVent PreVent Trial question What is the role of bag-mask ventilation among critically ill adult patients undergoing tracheal intubation? Study design Multi-center Open label RCT Population Characteristics of study participants 44.0% female N = 401 56.0% male 401 patients (175 female, 226 male) Inclusion criteria: ICU adult patients undergoing tracheal intubation Key exclusion criteria: the urgency of intubation precludes randomization, the operator feels a specific approach to ventilation between induction and intubation is required or contraindicated, pregnancy, incarceration Interventions N=199 manual ventilation (bag-mask ventilation between induction and laryngoscopy) N=202 no manual ventilation (no bag-mask ventilation; except after a failed attempt at laryngoscopy, as a treatment for hypoxemia) Primary outcome Median lowest oxygen saturation 96.0 % 96 93 72.0 % 48.0 % Significant increase https://web.pathway.md/studies/recODhHKjHNPWXRlz 1/2 6/29/23, 1:45 AM PreVent Pathway 24.0 % NNH = 33 0.0 % Manual ventilation No manual ventilation Significant increase in median lowest oxygen saturation (96% vs. 93%; AD 3.9%, 95% CI 1.4 to 6.5) Secondary outcomes Borderline significant decrease in lowest oxygen saturation of < 80% (10.9% vs. 22.8%; RR 0.48, 95% CI 0.3 to 0.77) No significant difference in death before hospital discharge (35.7% vs. 35.6%; RR 1, 95% CI 0.77 to 1.3) Significant decrease in median oxygen saturation decline (1% vs. 5%; ARD -4.5, 95% CI -6.8 to -2.2) Safety outcomes No significant differences in operator-reported aspiration, new opacity on chest radiography in the 48 hours after tracheal intubation. Significant difference in oxygen saturation of < 90% (29.5% vs. 40.1%). Conclusion In ICU adult patients undergoing tracheal intubation, manual ventilation was superior to no manual ventilation with respect to median lowest oxygen saturation. Reference Jonathan D Casey, David R Janz, Derek W Russell et al. Bag-Mask Ventilation during Tracheal Intubation of Critically Ill Adults. N Engl J Med. 2019 Feb 28;380(9):811-821. Open reference URL https://web.pathway.md/studies/recODhHKjHNPWXRlz 2/2

6/29/23, 1:42 AM PREVENT Pathway Feedback Search Clinical Topics Home Studies PREVENT PREVENT Disease Deep vein thrombosis Trial question What is the role of adjunctive intermittent pneumatic compression in critically ill patients receiving pharmacologic thromboprophylaxis? Study design Multi-center Open label RCT Population Characteristics of study participants 43.0% female N = 2003 57.0% male 2003 patients (855 female, 1148 male) Inclusion criteria: adults patients within 48 hours after admission to an ICU Key exclusion criteria: ICU admittance > 48 hours, contraindications to pharmacologic thromboprophylaxis, inability or contraindication to applying intermittent pneumatic compression to both legs Interventions N=991 pneumatic compression (intermittent pneumatic compression for at least 18 hours each day plus pharmacologic thromboprophylaxis) N=1012 control (pharmacologic thromboprophylaxis with unfractionated or low-molecular-weight heparin alone) https://web.pathway.md/studies/rec0js2kV7GquyEQH 1/2 6/29/23, 1:42 AM PREVENT Pathway Primary outcome Incident proximal deep vein thrombosis 4.2 % 4.2 3.9 3.2 % 2.1 % 1.1 % No significant difference 0.0 % Pneumatic compression Control No significant difference in incident proximal deep vein thrombosis (3.9% vs. 4.2%; RR 0.93, 95% CI 0.6 to 1.44) Secondary outcomes No significant difference in VTE (10.4%% vs. 9.4%%; RR 1.11, 95% CI 0.85 to 1.44) No significant difference in lower-limb deep vein thrombosis, PE, or death from any cause at 28 days (23.3% vs. 24%; RR 0.97, 95% CI 0.83 to 1.14) No significant difference in death from any cause at 90 days (26.1% vs. 26.7%; RR 0.98, 95% CI 0.84 to 1.13) Safety outcomes No significant differences in lower limb skin injury, limb ischemia. Conclusion In adults patients within 48 hours after admission to an ICU, pneumatic compression was not superior to control with respect to incident proximal deep vein thrombosis. Reference Yaseen M Arabi, Fahad Al-Hameed, Karen E A Burns et al. Adjunctive Intermittent Pneumatic Compression for Venous Thromboprophylaxis. N Engl J Med. 2019 Apr 4;380(14):1305-1315. Open reference URL https://web.pathway.md/studies/rec0js2kV7GquyEQH 2/2

6/29/23, 1:44 AM PRIMA Pathway Feedback Search Clinical Topics Home Studies PRIMA PRIMA Trial question What's the effect of adding timing and coordination training to a standard strength and endurance training in community-dwelling older adults? Study design Multi-center Open label RCT Population Characteristics of study participants 65.0% female N = 249 35.0% male 249 patients (163 female, 86 male) Inclusion criteria: ambulatory adults 65 years of age with gait speed of 0.60-1.20 m/s and physical clearance to exercise Key exclusion criteria: dyspnea at rest or during activities; unstable medical condition; dementia or cognitive impairment; history of stroke; plans to leave the area during the study period Interventions N=124 standard-plus program (standard program plus task-specific timing and coordination training) N=125 standard program (physical therapist-supervised strength, endurance, and flexibility program for 50-60 min twice/week for 12 weeks) Primary outcome Mean improvement in gait speed at 12 weeks 0.1 m/s 0.081 0.079 0.1 m/s 0.0 m/s https://web.pathway.md/studies/recXmUurgAYuTj3mZ 1/2 6/29/23, 1:44 AM PRIMA Pathway 0 0 /s 0.0 m/s No significant difference 0.0 m/s Standard-plus program Standard program No significant difference in mean improvement in gait speed at 12 weeks (0.079 m/s vs. 0.081 m/s; MD 0.001, 95% CI -0.02 to 0.02) Secondary outcomes No significant difference in mean improvement in gait speed at 36 weeks (0.059 m/s vs. 0.065 m/s; MD -0.003, 95% CI -0.04 to 0.03) No significant difference in mean improvement in lower extremity strength at 24 weeks (-2.2 N vs. 2 N; MD -4.9, 95% CI -14.09 to 4.29) No significant difference in mean improvement in 6 minute walk distance at 24 weeks (31.8 m vs. 20.6 m; MD 7.3, 95% CI -12.1 to 26.7) Safety outcomes No significant difference in serious adverse events. Conclusion In ambulatory adults 65 years of age with gait speed of 0.60-1.20 m/s and physical clearance to exercise, standard-plus program was not superior to standard program with respect to mean improvement in gait speed at 12 weeks. Reference Jennifer S Brach, Subashan Perera, Valerie Shuman et al. Effect of Timing and Coordination Training on Mobility and Physical Activity Among Community-Dwelling Older Adults: A Randomized Clinical Trial. JAMA Netw Open. 2022 May 2;5(5):e2212921. Open reference URL https://web.pathway.md/studies/recXmUurgAYuTj3mZ 2/2

6/29/23, 1:44 AM Primary Spontaneous Pneumothorax Pathway Feedback Search Clinical Topics Home Studies Primary Spontaneous Pneumothorax Primary Spontaneous Pneumothorax Disease Pneumothorax Trial question Is conservative management of primary spontaneous pneumothorax noninferior to interventional management for uncomplicated, moderate-to-large primary spontaneous pneumothorax? Study design Multi-center Open label RCT Population Characteristics of study participants 14.0% female N = 316 86.0% male 316 patients (44 female, 272 male) Inclusion criteria: patients 14 to 50 years of age with a first-known, unilateral, moderate-to-large primary spontaneous pneumothorax Key exclusion criteria: secondary pneumothorax, previous spontaneous pneumothorax on the same side, coexistent hemothorax, bilateral pneumothorax, clinical instability suggesting tension pneumothorax, pregnancy, air travel within the next 12 weeks Interventions N=162 conservative management (a conservative observational approach with a minimum observation of 4 hours before repeat chest radiograph) https://web.pathway.md/studies/rec11fPh8vm82GumY 1/2 6/29/23, 1:44 AM Primary Spontaneous Pneumothorax Pathway N=154 interventional management (an immediate standard interventional treatment of the pneumothorax) Primary outcome Rate of lung reexpansion within 8 weeks 98.5 % 98.5 94.4 73.9 % 49.3 % Difference not exceeding nonferiority margin 24.6 % 0.0 % Conservative management Interventional management Difference not exceeding nonferiority margin in the rate of lung reexpansion within 8 weeks (94.4% vs. 98.5%; ARD -4.1, 95% CI -8.6 to 0.5) Secondary outcomes Borderline significant decrease in median time until radiographic resolution (30 days vs. 16 days; HR 0.49, 95% CI 0.39 to 0.63) No significant difference in the rate of pneumothorax recurrence within 12 months (8.8% vs. 16.8%; HR 0.59, 95% CI 0.34 to 1.02) No significant difference in median time until symptom resolution (14 days vs. 15.5 days; HR 1.11, 95% CI 0.88 to 1.4) Safety outcomes No significant differences in hemothorax, tension pneumothorax. Significant differences in adverse events (8.0% vs. 26.6%), serious adverse events (3.7% vs. 12.3%). Conclusion In patients 14 to 50 years of age with a first-known, unilateral, moderate-to-large primary spontaneous pneumothorax, conservative management was noninferior to interventional management with respect to the rate of lung reexpansion within 8 weeks. Reference Simon G A Brown, Emma L Ball, Kyle Perrin et al. Conservative versus Interventional Treatment for Spontaneous Pneumothorax. N Engl J Med. 2020 Jan 30;382(5):405-415. Open reference URL https://web.pathway.md/studies/rec11fPh8vm82GumY 2/2

6/29/23, 1:44 AM PRIME Care Pathway Feedback Search Clinical Topics Home Studies PRIME Care PRIME Care Disease Major depressive disorder Trial question What is the effect of pharmacogenomic testing for drug-gene interactions in patients with major depressive disorder? Study design Multi-center Open label RCT Population Characteristics of study participants 25.0% female N = 1944 75.0% male 1944 patients (491 female, 1453 male) Inclusion criteria: adults with major depressive disorder who were initiating or switching treatment with a single antidepressant Key exclusion criteria: active substance use disorder; mania; psychosis; concurrent treatment with a specified list of medications Interventions N=966 pharmacogenomic-guided testing (results from a commercial pharmacogenomic test were given to clinicians) N=978 usual care (usual care and access to pharmacogenomic results after 24 weeks) https://web.pathway.md/studies/recbmilW8Hfto6rHS 1/2 6/29/23, 1:44 AM PRIME Care Pathway Primary outcome Estimated chance of no drug-gene interaction 59.3 % 59.3 44.5 % 29.6 % 25.7 Significant increase 14.8 % NNH = 3 0.0 % Pharmacogenomic-guided testing Usual care Significant increase in estimated chance of no drug-gene interaction (59.3% vs. 25.7%; AD 33.6%, 95% CI 28.9 to 38.4) Secondary outcomes Significant increase in the rate of symptom remission over 24 weeks (17.2% vs. 16%; OR 1.28, 95% CI 1.05 to 1.57) Significant decrease in estimated risk of moderate drug-gene interaction (30% vs. 54.6%; ARD -24.6, 95% CI -29.5 to -19.7) Significant decrease in estimated risk of substantial drug-gene interaction (10.7% vs. 19.7%; ARD -9, 95% CI -12.7 to -5.3) Conclusion In adults with major depressive disorder who were initiating or switching treatment with a single antidepressant, pharmacogenomic-guided testing was superior to usual care with respect to estimated chance of no drug-gene interaction. Reference David W Oslin, Kevin G Lynch, Mei-Chiung Shih et al. Effect of Pharmacogenomic Testing for Drug- Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial. JAMA. 2022 Jul 12;328(2):151-161. Open reference URL https://web.pathway.md/studies/recbmilW8Hfto6rHS 2/2

6/29/23, 1:44 AM PROBESE Pathway Feedback Search Clinical Topics Home Studies PROBESE PROBESE Disease Obesity Trial question What is the effect of an intraoperative mechanical ventilation strategy with a higher level of PEEP and alveolar recruitment maneuvers in obese patients undergoing surgery under general anesthesia? Study design Multi-center Open label RCT Population Characteristics of study participants 70.0% female N = 1976 30.0% male 1976 patients (1381 female, 595 male) Inclusion criteria: adult patients with body mass indices 35 and substantial risk for postoperative pulmonary complications who were undergoing noncardiac, nonneurological surgery under general anesthesia Key exclusion criteria: previous lung surgery, receipt of invasive mechanical ventilation for > 30 minutes within the last 30 days, receipt of chemotherapy or radiotherapy within 2 months Interventions N=989 high level of PEEP (a PEEP level of 12 cmH O with alveolar recruitment maneuvers performed after endotracheal intubation) https://web.pathway.md/studies/recvh3VARokj9lQim 1/2 6/29/23, 1:44 AM PROBESE Pathway N=987 low level of PEEP (a PEEP level of 4 cmH O) Primary outcome Rate of postoperative pulmonary complications within the first 5 days 23.6 % 23.6 21.3 17.7 % 11.8 % 5.9 % No significant difference 0.0 % High level of PEEP Low level of PEEP No significant difference in the rate of postoperative pulmonary complications within the first 5 days (21.3% vs. 23.6%; RR 0.93, 95% CI 0.83 to 1.04) Secondary outcomes Significant decrease in hypoxemia (5% vs. 13.6%; RR 0.51, 95% CI 0.4 to 0.65) No significant difference in postoperative extrapulmonary complications (16.9% vs. 15.2%; RR 1.06, 95% CI 0.95 to 1.19) No significant difference in systemic inflammatory response syndrome (9.4% vs. 8.4%; RR 1.06, 95% CI 0.91 to 1.22) Safety outcomes No significant differences in death during the hospital stay, DIC, coma, hepatic failure, extrapulmonary infection, septic shock, severe sepsis. Significant differences in hypotension (31.6% vs. 17.2%), bradycardia (9.9% vs. 6.0%). Conclusion In adult patients with body mass indices 35 and substantial risk for postoperative pulmonary complications who were undergoing noncardiac, nonneurological surgery under general anesthesia, high level of PEEP was not superior to low level of PEEP with respect to the rate of postoperative pulmonary complications within the first 5 days. Reference Writing Committee for the PROBESE Collaborative Group of the PROtective VEntilation Network (PROVEnet) for the Clinical Trial Network of the European Society of Anaesthesiology, Thomas Bluth, Ary Serpa Neto et al. Effect of Intraoperative High Positive End-Expiratory Pressure (PEEP) With Recruitment Maneuvers vs Low PEEP on Postoperative Pulmonary Complications in Obese Patients: A Randomized Clinical Trial. JAMA. 2019 Jun 18;321(23):2292-2305. Open reference URL https://web.pathway.md/studies/recvh3VARokj9lQim 2/2

6/29/23, 1:45 AM ProCESS Pathway Feedback Search Clinical Topics Home Studies ProCESS ProCESS Disease Sepsis and septic shock Reference ProCESS Investigators, Yealy DM, Kellum JA et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. Open reference URL https://web.pathway.md/studies/recQtTJn5AKw6IdUi 1/1

6/29/23, 1:44 AM PROCOAG Pathway Feedback Search Clinical Topics Home Studies PROCOAG PROCOAG Disease Traumatic hemorrhage Trial question What is the role of four-factor PCC in patients with trauma at risk of massive transfusion? Study design Multi-center Double blinded RCT Population Characteristics of study participants 28.0% female N = 324 72.0% male 324 patients (91 female, 233 male) Inclusion criteria: adult patients with trauma at risk of massive transfusion Key exclusion criteria: traumatic cardiac arrest before randomization; devastating injuries expected to die within the first hour of admission; preinjury treatment with anticoagulants; preinjury terminal condition Interventions N=164 four-factor PCC (intravenous administration of 1 mL/kg; 25 IU of factor IX/kg) N=160 placebo (intravenous administration of 1 mL/kg of saline solution) Primary outcome Total blood product consumption at 24 hours https://web.pathway.md/studies/rec4G6hz3VLA5oSpb 1/2 6/29/23, 1:44 AM PROCOAG Pathway 12.0 IU 12 11 9.0 IU 6.0 IU 3.0 IU No significant difference 0.0 IU Four-factor prothrombin complex concentrate Placebo No significant difference in total blood product consumption at 24 hours (12 IU vs. 11 IU; AD 0.2 IU, 95% CI -2.99 to 3.33) Secondary outcomes No significant difference in RBC consumption (6 IU vs. 6 IU; AD -0.3 IU, 95% CI -1.8 to 1.3) No significant difference in death at day 28 (17% vs. 21%; ARD -3, 95% CI -12 to 5) No significant difference in hospital-free days through day 28 (6.5 days vs. 7 days; AD -0.15 days, 95% CI -1.65 to 1.35) Safety outcomes No significant differences in superficial venous thrombosis, deep vein thrombosis, PE, stroke. Significant difference in 1 thromboembolic event (35% vs. 24%). Conclusion In adult patients with trauma at risk of massive transfusion, four-factor PCC was not superior to placebo with respect to total blood product consumption at 24 hours. Reference Pierre Bouzat, Jonathan Charbit, Paer-Selim Abback et al. Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial. JAMA. 2023 Apr 25;329(16):1367- 1375. Open reference URL https://web.pathway.md/studies/rec4G6hz3VLA5oSpb 2/2

6/29/23, 1:45 AM PRODIGE 4 ACCORD 11 Pathway Feedback Search Clinical Topics Home Studies PRODIGE 4 ACCORD 11 PRODIGE 4 ACCORD 11 Disease Pancreatic cancer Trial question What is the effect of FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) combination regimen as first-line therapy in patients with metastatic pancreatic cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 38.0% female N = 342 62.0% male 342 patients (131 female, 211 male) Inclusion criteria: patients with metastatic pancreatic cancer and an ECOG performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) Key exclusion criteria: age 76 years, endocrine or acinar pancreatic carcinoma, previous radiotherapy for measurable lesions, cerebral metastases, history of another major cancer, active infection, chronic diarrhea, clinically significant history of cardiac disease, and pregnancy or breast-feeding Interventions N=171 FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square https://web.pathway.md/studies/recaSZ78Y0qAcklqP 1/2 6/29/23, 1:45 AM PRODIGE 4 ACCORD 11 Pathway meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) N=171 gemcitabine (at a dose of 1,000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks) Primary outcome Overall survival 11.1 months 11.1 8.3 months 6.8 5.5 months 2.8 months Significant increase 0.0 months FOLFIRINOX Gemcitabine Significant increase in overall survival (11.1 months vs. 6.8 months; HR 1.75, 95% CI 1.37 to 2.22) Secondary outcomes Significant increase in median progression-free survival (6.4 vs. 3.3; HR 2.13, 95% CI 1.69 to 2.7) Significant increase in objective response (31.6% vs. 9.4%; RR 3.36, 95% CI 1.37 to 5.35) Safety outcomes Significant differences in adverse events, including febrile neutropenia (5.4% vs. 1.2%, p = 0.03) and definitive degradation of quality of life (31% vs. 66%, p < 0.001; HR 0.47, 95% CI 0.30-0.70). Conclusion In patients with metastatic pancreatic cancer and an ECOG performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness), FOLFIRINOX was superior to gemcitabine with respect to overall survival. Reference Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. Open reference URL https://web.pathway.md/studies/recaSZ78Y0qAcklqP 2/2

6/29/23, 1:45 AM PRoFESS Pathway Feedback Search Clinical Topics Home Studies PRoFESS PRoFESS Disease Acute ischemic stroke Trial question What is the role of combination of aspirin and ER dipyridamole in patients with a recent stroke? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 20332 64.0% male 20332 patients (7310 female, 13022 male) Inclusion criteria: patients with a recent ischemic stroke Key exclusion criteria: contraindications to one of the antiplatelet agents, primary hemorrhagic stroke, brain tumor, dementia requiring institutional care, or a mRS score > 4 at baseline Interventions N=10181 ASA-ERDP (aspirin 25 mg plus 200 mg ER dipyridamole BID) N=10151 clopidogrel (75 mg daily) Primary outcome Recurrent stroke 9 9 0 % 8 8 https://web.pathway.md/studies/recEU8B5lCY04pQ98 1/2 6/29/23, 1:45 AM 9.0 % PRoFESS Pathway 9 8.8 6.8 % 4.5 % 2.3 % No significant difference 0.0 % ASA-ERDP Clopidogrel No significant difference in recurrent stroke (9% vs. 8.8%; HR 1.01, 95% CI 0.92 to 1.11) Secondary outcomes No significant difference in stroke, myocardial infarction, or death from vascular causes (13.1% vs. 13.1%; HR 0.99, 99% CI 0.92 to 1.07) No significant difference in recurrent stroke or major hemorrhagic event (11.7% vs. 11.4%; HR 1.03, 95% CI 0.95 to 1.11) No significant difference in myocardial infarction (1.7% vs. 1.9%; HR 0.9, 95% CI 0.73 to 1.1) Safety outcomes No significant differences in frequency of death, any hemorrhagic event, TTP or neutropenia. Significant differences in major hemorrhagic events (4.1% vs. 3.6%), intracranial hemorrhage (1.4% vs. 1.0%). Conclusion In patients with a recent ischemic stroke, ASA-ERDP was not superior to clopidogrel with respect to recurrent stroke. Reference Sacco RL, Diener HC, Yusuf S et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008 Sep 18;359(12):1238-51. Open reference URL https://web.pathway.md/studies/recEU8B5lCY04pQ98 2/2

6/29/23, 1:44 AM PROGRESS Pathway Feedback Search Clinical Topics Home Studies PROGRESS PROGRESS Disease Disease Acute ischemic stroke Transient ischemic attack Trial question What is the role of perindopril-based BP lowering regimen in patients with a history of stroke or TIA? Study design Multi-center Double blinded RCT Population Characteristics of study participants 30.0% female N = 6105 70.0% male 6105 patients (1852 female, 4253 male) Inclusion criteria: patients with a history of stroke or TIA Key exclusion criteria: definite indication or contraindication for treatment with ACEIs; < 2 weeks of clinical stability after the most recent vascular event Interventions N=3051 active treatment (a flexible regimen based on perindopril 4 mg daily, with the addition of indapamide at the discretion of treating physicians) N=3054 placebo (matching perindopril and indapamide placebo) Primary outcome Stroke https://web.pathway.md/studies/recg5cWTlX6NGcJ9f 1/2 6/29/23, 1:45 AM PROGRESS Pathway 14.0 % 14 10.5 % 10 7.0 % Significant decrease 3.5 % NNT = 25 0.0 % Active treatment Placebo Significant decrease in stroke (10% vs. 14%; RR 0.72, 95% CI 0.62 to 0.83) Secondary outcomes Borderline significant increase in composite outcome of nonfatal stroke, nonfatal myocardial infarction, or death from a vascular cause (15% vs. 20%; RR 26, 95% CI 16 to 34) No significant difference in death from all causes (10% vs. 10.4%; RR 0.96, 96% CI 0.82 to 1.12) Borderline significant decrease in hospital admissions (41% vs. 44%; RR 0.91, 95% CI 0.85 to 0.99) Conclusion In patients with a history of stroke or TIA, active treatment was superior to placebo with respect to stroke. Reference PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001 Sep 29;358(9287):1033-41. Open reference URL https://web.pathway.md/studies/recg5cWTlX6NGcJ9f 2/2

6/29/23, 1:44 AM PROLONG Pathway Feedback Search Clinical Topics Home Studies PROLONG PROLONG Disease Disease Deep vein thrombosis Pulmonary embolism Trial question What is the role of D-dimer testing in determining the duration of anticoagulation therapy in patients who had a first idiopathic episode of VTE? Study design Multi-center Open label RCT Population Characteristics of study participants 53.0% female N = 223 47.0% male 223 patients (118 female, 105 male) Inclusion criteria: patients with a first unprovoked proximal deep vein thrombosis or PE who had received a vitamin K antagonist for at least 3 months and underwent D-dimer testing Key exclusion criteria: serious liver disease, renal insufficiency, other indications or contraindications for anticoagulation, or a limited life expectancy Interventions N=120 abnormal D-dimer level with discontinuation of anticoagulation (discontinuation of vitamin K antagonist therapy) N=103 abnormal D-dimer level with resumption of anticoagulation (resumption of vitamin K antagonist therapy) https://web.pathway.md/studies/recLoeLMvlBocf071 1/2 6/29/23, 1:44 AM PROLONG Pathway Primary outcome Recurrence of thromboembolism 15.0 % 15 11.3 % 7.5 % Significant increase 3.8 % 2.9 NNH = 8 0.0 % Abnormal D-dimer level with discontinuation of anticoagulation Abnormal D-dimer level with resumption of anticoagulation Significant increase in recurrence of thromboembolism (15% vs. 2.9%; aHR 4.26, 95% CI 1.23 to 14.6) Safety outcomes No significant difference in deaths. Conclusion In patients with a first unprovoked proximal deep vein thrombosis or PE who had received a vitamin K antagonist for at least 3 months and underwent D-dimer testing, abnormal D-dimer level with discontinuation of anticoagulation was inferior to abnormal D-dimer level with resumption of anticoagulation with respect to recurrence of thromboembolism. Reference Palareti G, Cosmi B, Legnani C et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006 Oct 26;355(17):1780-9. Open reference URL https://web.pathway.md/studies/recLoeLMvlBocf071 2/2

6/29/23, 1:45 AM PROMINENT Pathway Feedback Search Clinical Topics Home Studies PROMINENT PROMINENT Disease Disease Disease Diabetes mellitus type 2 Dyslipidemia Hypertrig Trial question What is the role of pemafibrate in patients with T2DM and mild-to-moderate hypertriglyceridemia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 28.0% female N = 10497 72.0% male 10497 patients (2891 female, 7606 male) Inclusion criteria: patients with T2DM, mild-to-moderate hypertriglyceridemia, and high-density lipoprotein cholesterol levels 40 mg/dL Key exclusion criteria: T1DM; uncontrolled diabetes; untreated or inadequately treated hypothyroidism or hyperthyroidism; severe HF; severe kidney disease; clinically significant liver disease Interventions N=5240 pemafibrate (at a dose of 0.2 mg tablets BID) N=5257 placebo (matching placebo) Primary outcome https://web.pathway.md/studies/recOii51pFmFUuKwI 1/2 6/29/23, 1:45 AM PROMINENT Pathway Composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes 10.9 % 10.9 10.6 8.2 % 5.5 % 2.7 % No significant difference 0.0 % Pemafibrate Placebo No significant difference in composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes (10.9% vs. 10.6%; HR 1.03, 95% CI 0.91 to 1.15) Secondary outcomes No significant difference in composite of myocardial infarction, ischemic stroke, unstable angina warranting hospitalization for urgent coronary revascularization, or death from cardiovascular causes (8.2% vs. 7.9%; HR 1.04, 95% CI 0.91 to 1.19) No significant difference in composite of nonfatal myocardial infarction, nonfatal ischemic stroke, or death from cardiovascular causes (7.2% vs. 7.1%; HR 1.02, 95% CI 0.88 to 1.18) Significant increase in reduction in triglyceride levels at 4 months (31.1 vs. 6.9; AD 26.2, 95% CI 24.1 to 28.4) Safety outcomes No significant difference in serious adverse events. Significant differences in renal adverse event (27.9% vs. 25.6%), VTE (1.3% vs. 0.7%), nonalcoholic fatty liver disease (2.9% vs. 3.8%). Conclusion In patients with T2DM, mild-to-moderate hypertriglyceridemia, and high-density lipoprotein cholesterol levels 40 mg/dL, pemafibrate was not superior to placebo with respect to the composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. Reference Aruna Das Pradhan, Robert J Glynn, Jean-Charles Fruchart et al. Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk. N Engl J Med. 2022 Nov 24;387(21):1923-1934. Open reference URL https://web.pathway.md/studies/recOii51pFmFUuKwI 2/2

6/29/23, 1:45 AM ProMISe Pathway Feedback Search Clinical Topics Home Studies ProMISe ProMISe Disease Sepsis and septic shock Trial question What is the effect of early goal-directed therapy for the resuscitation of patients presenting with early septic shock? Study design Multi-center Open label RCT Population Characteristics of study participants 42.4% female N = 1260 57.6% male 1260 patients (528 female, 723 male) Inclusion criteria: patients presenting with early septic shock Key exclusion criteria: aged < 18 years, known pregnancy, drug overdose, injury from burns or trauma, acute coronary syndrome, requirement for immediate surgery, hemodynamic instability, known history of AIDS, or contraindication to central venous catheterization or blood transfusion Interventions N=630 early goal-directed therapy (target CVP > 8 mmHg, MAP > 65 mmHg, ScvO2 > 70%) N=630 usual care (decisions at discretion of treating clinician) Primary outcome https://web.pathway.md/studies/reciEVlP2zmmPNHJC 1/2 6/29/23, 1:45 AM ProMISe Pathway Death at 90 days 29.5 % 29.5 29.2 22.1 % 14.8 % 7.4 % No significant difference 0.0 % Early goal-directed therapy Usual care No significant difference in death at 90 days (29.5% vs. 29.2%; RR 1.01, 95% CI 0.85 to 1.2) Secondary outcomes Borderline significant decrease in quality-adjusted life years (4.584 vs. 4.582; ARR 0.002, 95% CI -0.41 to 0.41) No significant difference in lifetime cost per patient (33620 vs. 32142 ; AD 1478 , 95% CI -1434 to 4390) Safety outcomes No significant difference in adverse events. Conclusion In patients presenting with early septic shock, early goal-directed therapy was not superior to usual care with respect to death at 90 days. Reference Mouncey PR, Osborn TM, Power GS et al. Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock. Health Technol Assess. 2015 Nov;19(97):i-xxv, 1-150. Open reference URL https://web.pathway.md/studies/reciEVlP2zmmPNHJC 2/2

6/29/23, 1:45 AM Prone in hypoxemic ARF Pathway Feedback Search Clinical Topics Home Studies Prone in hypoxemic ARF Prone in hypoxemic ARF Trial question Is prone positioning superior to supine positioning in patients with hypoxemic acute respiratory failure? Study design Multi-center Open label RCT Population Characteristics of study participants 25.0% female N = 791 75.0% male 791 patients (198 female, 593 male) Inclusion criteria: hemodynamically stable, intubated patients with hypoxemic acute respiratory failure Key exclusion criteria: prone positioning for 6 hours/day in the preceding 4 days; contraindications to prone position; high risk of death in < 48 hours; chronic respiratory failure requiring mechanical ventilation Interventions N=413 prone position (face down position for 8 hours/day on standard beds) N=378 supine position (face up position) Primary outcome Death at day 28 32.4 % 32.4 31.5 24.3 % 16.2 % https://web.pathway.md/studies/rec2dTiOcnQqBJQkt 1/2 6/29/23, 1:45 AM Prone in hypoxemic ARF Pathway 8.1 % No significant difference 0.0 % Prone position Supine position No significant difference in death at day 28 (32.4% vs. 31.5%; RR 1.03, 95% CI 0.84 to 1.27) Secondary outcomes No significant difference in death at day 90 (43.3% vs. 42.2%; RR 1.02, 95% CI 0.88 to 1.19) No significant difference in mean duration of mechanical ventilation (13.7 days vs. 14.1 days; MD -0.4, 95% CI -8.58 to 7.78) Significant decrease in ventilator-associated pneumonia (1.66 episodes per 100-patients days vs. 2.14 episodes per 100-patients days; AD -0.48 episodes per 100-patients days, 95% CI -0.95 to -0.01) Safety outcomes No significant difference in adverse events. Significant differences in selective intubation (6 events vs. 0 events), endotracheal tube obstruction (34 events vs. 12 events), pressure sores (208 events vs. 157 events). Conclusion In hemodynamically stable, intubated patients with hypoxemic acute respiratory failure, prone position was not superior to supine position with respect to death at day 28. Reference Claude Guerin, Sandrine Gaillard, Stephane Lemasson et al. Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial. JAMA. 2004 Nov 17;292(19):2379-87. Open reference URL https://web.pathway.md/studies/rec2dTiOcnQqBJQkt 2/2

6/29/23, 1:45 AM Prone-Supine II Pathway Feedback Search Clinical Topics Home Studies Prone-Supine II Prone-Supine II Disease Acute respiratory distress syndr Trial question Is prone positioning superior to supine positioning in patients with moderate and severe ARDS? Study design Multi-center Open label RCT Population Characteristics of study participants 29.0% female N = 342 71.0% male 342 patients (98 female, 244 male) Inclusion criteria: adult patients with moderate and severe ARDS Key exclusion criteria: age < 16 years; > 72 hours since the diagnosis of ARDS; solid organ or BMT; contraindication to prone positioning including intracranial hypertension and spine or pelvic fractures Interventions N=168 prone positioning (face down position 20 hours/day) N=174 supine positioning (face up position) Primary outcome Death at day 28 https://web.pathway.md/studies/recyYYuzx6bUhMmkJ 1/2 6/29/23, 1:45 AM Prone-Supine II Pathway 32.8 % 32.8 31 24.6 % 16.4 % 8.2 % No significant difference 0.0 % Prone positioning Supine positioning No significant difference in death at day 28 (31% vs. 32.8%; RR 0.97, 95% CI 0.84 to 1.13) Secondary outcomes No significant difference in death in the ICU (38.1% vs. 42%; RR 0.94, 95% CI 0.79 to 1.12) No significant difference in death at 6 months (47% vs. 52.3%; RR 0.9, 95% CI 0.73 to 1.11) No significant difference in sequential organ failure assessment score (6.7 vs. 6.8; AD -0.1, 95% CI -1.21 to 1.01) Safety outcomes No significant difference in displacement of thoracotomy tube. Significant differences in need for increased sedation or muscle relaxants (80.4% vs. 56.3%), airway obstruction (50.6% vs. 33.9%), transient desaturation (63.7% vs. 50.6%). Conclusion In adult patients with moderate and severe ARDS, prone positioning was not superior to supine positioning with respect to death at day 28. Reference Paolo Taccone, Antonio Pesenti, Roberto Latini et al. Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2009 Nov 11;302(18):1977-84. Open reference URL https://web.pathway.md/studies/recyYYuzx6bUhMmkJ 2/2

6/29/23, 1:45 AM Prone-Supine Pathway Feedback Search Clinical Topics Home Studies Prone-Supine Prone-Supine Disease Acute respiratory distress syndr Trial question Is the prone position superior to the supine position in patients with acute respiratory failure? Study design Multi-center Open label RCT Population Characteristics of study participants 30.0% female N = 304 70.0% male 304 patients (90 female, 214 male) Inclusion criteria: patients with acute lung injury or the ARDS Key exclusion criteria: age < 16 years; contraindication to prone positioning; cardiogenic pulmonary edema; cerebral edema; intracranial hypertension; fractures of the spine; severe hemodynamic instability Interventions N=152 prone position (face down position for 6 hours/day for 10 days) N=152 supine position (face up position) Primary outcome Death at 10 days https://web.pathway.md/studies/recyaSFlXUnnfVin2 1/2 6/29/23, 1:45 AM Prone-Supine Pathway 25.0 % 25 21.1 18.8 % 12.5 % 6.3 % No significant difference 0.0 % Prone position Supine position No significant difference in death at 10 days (21.1% vs. 25%; RR 0.84, 95% CI 0.56 to 1.27) Secondary outcomes No significant difference in death at the time of discharge from the ICU (50.7% vs. 48%; RR 1.05, 95% CI 0.84 to 1.32) No significant difference in death at 6 months (62.5% vs. 58.6%; RR 1.06, 95% CI 0.88 to 1.28) Significant increase in improvement in the ratio of partial pressure of arterial oxygen to FiO2 (63 vs. 44.6; AD 18.4, 95% CI 2.88 to 33.92) Safety outcomes No significant difference in complications related to positioning. Conclusion In patients with acute lung injury or the ARDS, prone position was not superior to supine position with respect to death at 10 days. Reference L Gattinoni, G Tognoni, A Pesenti et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med. 2001 Aug 23;345(8):568-73. Open reference URL https://web.pathway.md/studies/recyaSFlXUnnfVin2 2/2

6/29/23, 1:44 AM PROPPR Pathway Feedback Search Clinical Topics Home Studies PROPPR PROPPR Disease Disease Platelet transfusion Traumatic hemorrhage Trial question What is the effect of early administration of plasma, platelets, and RBCs in a 1:1:1 ratio in patients with severe trauma and major bleeding? Study design Multi-center Open label RCT Population Characteristics of study participants 20.0% female N = 680 80.0% male 680 patients (134 female, 546 male) Inclusion criteria: patients with severe trauma and major bleeding who were predicted to receive a massive transfusion Key exclusion criteria: age < 15 years; weight < 50 kg; lethal TBI; receipt of lifesaving intervention from an outside hospital Interventions N=338 1:1:1 (receipt of blood transfusion of plasma, platelets, and RBCs in the ratio of 1:1:1) N=342 1:1:2 (receipt of blood transfusion of plasma, platelets, and RBCs in the ratio of 1:1:2) Primary outcome https://web.pathway.md/studies/recY9tNdHLej5wDKU 1/2 6/29/23, 1:44 AM PROPPR Pathway Death from all causes at 24 hours 17.0 % 17 12.8 % 12.7 8.5 % 4.3 % No significant difference 0.0 % 1:1:1 1:1:2 No significant difference in death from all causes at 24 hours (12.7% vs. 17%; ARD -4.2, 95% CI -9.6 to 1.1) Secondary outcomes No significant difference in death from all causes at 30 days (22.4% vs. 26.1%; ARD -3.7, 95% CI -10.2 to 2.7) Significant decrease in death due to exsanguination within 24 hours (9.2% vs. 14.6%; ARD -5.4, 95% CI -10.4 to -0.5) Significant increase in hemostasis (86.1% vs. 78.1%; AD 8%, 95% CI 2.3 to 13.7) Safety outcomes No significant differences in ARDS, multiple organ failure, VTE, sepsis and transfusion-related complications. Significant difference in receipt of plasma (7 U vs. 5 U) and platelets (12 U vs. 6 U). Conclusion In patients with severe trauma and major bleeding who were predicted to receive a massive transfusion, 1:1:1 was not superior to 1:1:2 with respect to death from all causes at 24 hours. Reference John B Holcomb, Barbara C Tilley, Sarah Baraniuk et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015 Feb 3;313(5):471-82. Open reference URL https://web.pathway.md/studies/recY9tNdHLej5wDKU 2/2

6/29/23, 1:45 AM PRORATA Pathway Feedback Search Clinical Topics Home Studies PRORATA PRORATA Trial question Is procalcitonin-guided strategy noninferior to standard guidelines of antibiotic treatment among patients ICU? Study design Multi-center Open label RCT Population Characteristics of study participants 33.7% female N = 630 66.3% male 630 patients (210 female, 411 male) Inclusion criteria: critically ill patients in ICU with suspected bacterial infections Key exclusion criteria: age < 18 years; known pregnancy; expected stay in the ICU < 3 days; bone-marrow transplant or chemotherapy induced neutropenia; infections for which long-term antibiotic treatment is strongly recommended poor chance of survival Interventions N=311 procalcitonin-guided antibiotic discontinuation (predefined algorithms to start or discontinue antibiotics according to serum procalcitonin concentrations) N=319 usual care (recommendations for duration of antimicrobial treatment derived from international and local guidelines) Primary outcome Death at days 28 21.2 % 21.2 20.4 15.9 % 10.6 % https://web.pathway.md/studies/recaqB7est4S6rEY3 1/2 6/29/23, 1:45 AM 10.6 % PRORATA Pathway Difference not exceeding nonferiority margin 5.3 % 0.0 % Procalcitonin-guided antibiotic discontinuation Usual care Difference not exceeding nonferiority margin in death at days 28 (21.2% vs. 20.4%; AD 0.8%, 90% CI -4.6 to 6.2) Secondary outcomes Significant increase in days without antibiotics by day 28 (14.3 vs. 11.6; AD 2.7, 95% CI 1.4 to 4.1) Conclusion In critically ill patients in ICU with suspected bacterial infections, procalcitonin-guided antibiotic discontinuation was noninferior to usual care with respect to death at days 28. Reference Bouadma L, Luyt CE, Tubach F et al. Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet. 2010 Feb 6;375(9713):463-74. Open reference URL https://web.pathway.md/studies/recaqB7est4S6rEY3 2/2

6/29/23, 1:45 AM PROSEVA Pathway Feedback Search Clinical Topics Home Studies PROSEVA PROSEVA Disease Acute respiratory distress syndr Trial question What is the role of prone positioning in patients with severe ARDS? Study design Multi-center Open label RCT Population Characteristics of study participants 32.0% female N = 466 68.0% male 466 patients (148 female, 318 male) Inclusion criteria: patients undergoing mechanical ventilation for severe ARDS Key exclusion criteria: contraindication for prone positioning, lung transplantation, underlying disease with a life expectancy of < 1 year, or end-of-life decision before inclusion Interventions N=237 performing prone-positioning sessions (within the first hour after randomization for at least 16 consecutive hours) N=229 standard supine positioning (remained in semirecumbent position) Primary outcome Death at 28 days https://web.pathway.md/studies/recqOLpJSjAuDgk7n 1/2 6/29/23, 1:45 AM PROSEVA Pathway 32.8 % 32.8 24.6 % 16.4 % 16 Significant decrease 8.2 % NNT = 6 0.0 % Performing prone-positioning sessions Standard supine positioning Significant decrease in death at 28 days (16% vs. 32.8%; HR 0.39, 95% CI 0.25 to 0.63) Secondary outcomes Significant decrease in death at 90 days (23.6% vs. 41%; HR 0.44, 95% CI 0.29 to 0.67) Significant decrease in successful extubation at 90 day (80.5% vs. 65%; HR 0.45, 95% CI 0.29 to 0.7) Safety outcomes No significant differences in overall incidence of complications, with the exception of cardiac arrest, which was more common in the supine group. Conclusion In patients undergoing mechanical ventilation for severe ARDS, performing prone-positioning sessions were superior to standard supine positioning with respect to death at 28 days. Reference Guerin C, Reignier J, Richard JC et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013 Jun 6;368(23):2159-68. Open reference URL https://web.pathway.md/studies/recqOLpJSjAuDgk7n 2/2

6/29/23, 1:44 AM PROSPECT Pathway Feedback Search Clinical Topics Home Studies PROSPECT PROSPECT Disease Rectal cancer Trial question Is preoperative neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin noninferior to chemoradiotherapy in patients with locally advanced rectal cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 34.0% female N = 1128 66.0% male 1128 patients (389 female, 739 male) Inclusion criteria: adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery Key exclusion criteria: T4 tumors; 4 pelvic lymph nodes with a short axis > 10 mm or tumor visible within 3 mm of the radial margin seen on baseline pelvic imaging; previous pelvic radiation therapy; chemotherapy within the previous 5 years; abnormal laboratory measures Interventions N=585 FOLFOX (neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin every 2 weeks for 6 cycles) https://web.pathway.md/studies/recMAVMwJT2DJsSRv 1/2 6/29/23, 1:45 AM PROSPECT Pathway N=543 chemoradiotherapy (pelvic radiotherapy with 50.4 Gy delivered in 28 fractions plus chemotherapy with 5-fluorouracil or capecitabine) Primary outcome Disease-free survival at 5 years 80.8 % 80.8 78.6 60.6 % 40.4 % Difference not exceeding nonferiority margin 20.2 % 0.0 % FOLFOX Chemoradiotherapy Difference not exceeding nonferiority margin in disease-free survival at 5 years (80.8% vs. 78.6%; AD 2.2%, 95% CI 0.67 to 3.73) Secondary outcomes No significant difference in overall survival at 5 years (89.5% vs. 90.2%; HR 0.96, 96% CI 0.69 to 1.35) No significant difference in local recurrence at 5 years (1.8% vs. 1.6%; HR 1.18, 95% CI 0.44 to 3.16) Safety outcomes No significant difference in hypertension. Significant difference in severe grade 3 adverse events (41.0% vs. 22.8%). Conclusion In adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery, FOLFOX was noninferior to chemoradiotherapy with respect to a disease-free survival at 5 years. Reference Deborah Schrag, Qian Shi, Martin R Weiser et al. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 2023 Jun 4. Online ahead of print. Open reference URL https://web.pathway.md/studies/recMAVMwJT2DJsSRv 2/2

6/29/23, 1:44 AM PROTECHT Pathway Feedback Search Clinical Topics Home Studies PROTECHT PROTECHT Disease Cancer-associated thrombosis Trial question What is the role of nadroparin in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 52.0% female N = 1150 48.0% male 1150 patients (595 female, 555 male) Inclusion criteria: ambulatory patients with lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer Key exclusion criteria: adjuvant or neoadjuvant chemotherapy; venous or arterial thromboembolism in < 3 months; ECOG score > 2; antithrombotic treatment for any indication; life expectancy < 3 months; active bleeding Interventions N=769 nadroparin (3800 IUs anti-Xa once daily) N=381 placebo (matching placebo once daily) https://web.pathway.md/studies/recFc7qawvkMpVWKE 1/2 6/29/23, 1:44 AM PROTECHT Pathway Primary outcome Symptomatic venous or arterial thromboembolic events 3.9 % 3.9 2.9 % 2 1.9 % Significant decrease 1.0 % NNT = 53 0.0 % Nadroparin Placebo Significant decrease in symptomatic venous or arterial thromboembolic events (2% vs. 3.9%; RR 0.51, 95% CI 0.08 to 0.94) Safety outcomes No significant difference in major bleeding and serious adverse events. Conclusion In ambulatory patients with lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer, nadroparin was superior to placebo with respect to symptomatic venous or arterial thromboembolic events. Reference Giancarlo Agnelli, Gualberto Gussoni, Carlo Bianchini et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol. 2009 Oct;10(10):943-9. Open reference URL https://web.pathway.md/studies/recFc7qawvkMpVWKE 2/2

6/29/23, 1:44 AM PROTECT AF Pathway Feedback Search Clinical Topics Home Studies PROTECT AF PROTECT AF Disease Disease Disease Acute ischemic stroke Atrial fibrillation Transient Reference Holmes DR, Reddy VY, Turi ZG et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non- inferiority trial. Lancet. 2009 Aug 15;374(9689):534-42. Open reference URL https://web.pathway.md/studies/recsgHzYh7zVjPdBq 1/1

6/29/23, 1:45 AM PROVE IT-TIMI 22 Pathway Feedback Search Clinical Topics Home Studies PROVE IT TIMI 22 PROVE IT TIMI 22 Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the role of intensive therapy in patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days? Study design Multi-center Double blinded RCT Population Characteristics of study participants 22.0% female N = 4162 78.0% male 4162 patients (911 female, 3251 male) Inclusion criteria: patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days Key exclusion criteria: current statin therapy at a dose of 80 mg/day, or current lipid lowering therapy with fibric acid derivatives or niacin, obstructive hepatobiliary disease or other serious hepatic disease Interventions N=2099 intensive statin therapy (80 mg of atorvastatin daily) N=2063 standard statin therapy (40 mg of pravastatin daily) https://web.pathway.md/studies/reccpjTP6VQ2ixy9K 1/2 6/29/23, 1:45 AM PROVE IT-TIMI 22 Pathway Primary outcome Death or major cardiovascular events at 2 years 26.3 % 26.3 22.4 19.7 % 13.2 % Significant increase 6.6 % NNH = 26 0.0 % Intensive statin therapy Standard statin therapy Significant increase in death or major cardiovascular events at 2 years (22.4% vs. 26.3%; RR 16, 95% CI 0.05 to 0.26) Secondary outcomes Significant increase in death due to coronary heart disease, myocardial infarction, or revascularization at 2 years (19.7% vs. 22.3%; RR 14, 95% CI 1.34 to 26.66) No significant difference in death from any cause (2.2% vs. 3.2%; RR 28, 95% CI -2.33 to 58.33) Safety outcomes No significant differences in discontinuation of treatment because of adverse events (22.8% vs. 21.4%, p=0.30). Significant differences in liver enzyme elevation (3.3% vs. 1.1%, p < 0.001). Conclusion In patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days, intensive statin therapy was superior to standard statin therapy with respect to death or major cardiovascular events at 2 years. Reference Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004 Apr 8;350(15):1495-504. Open reference URL https://web.pathway.md/studies/reccpjTP6VQ2ixy9K 2/2

6/29/23, 1:45 AM PROWESS Pathway Feedback Search Clinical Topics Home Studies PROWESS PROWESS Disease Sepsis and septic shock Trial question What is the role of drotrecogin alfa activated therapy in patients with systemic inflammation and organ failure due to acute infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 43.0% female N = 1690 57.0% male 1690 patients (726 female, 964 male) Inclusion criteria: patients with systemic inflammation and organ failure due to acute infection Key exclusion criteria: pregnancy or breast feeding, age < 18 years, weight > 135 kg, known hypercoagulable condition, moribund state, HIV infection, history of bone marrow, lung, liver, pancreas, or small-bowel transplantation Interventions N=850 drotrecogin alfa activated (24 g/kg of body weight per hour for a total duration of 96 hours) N=840 placebo (0.9% saline with or without 0.1% human serum albumin for a total of 96 hours) https://web.pathway.md/studies/recKGR8whmarlr4FD 1/2 6/29/23, 1:45 AM PROWESS Pathway Primary outcome Death 30.8 % 30.8 24.7 23.1 % 15.4 % Significant decrease 7.7 % NNT = 16 0.0 % Drotrecogin alfa activated Placebo Significant decrease in death (24.7% vs. 30.8%; RR 0.8, 95% CI 0.69 to 0.94) Secondary outcomes Significant decrease in risk of death, among patients with protein C deficiency (25.7% vs. 32.1%; RR 0.8, 95% CI 0.68 to 0.95) Safety outcomes No significant difference in at least one serious adverse event. Significant differences in serious bleeding (3.5% vs. 2.0%, p = 0.06). Conclusion In patients with systemic inflammation and organ failure due to acute infection, drotrecogin alfa activated was superior to placebo with respect to death. Reference Bernard GR, Vincent JL, Laterre PF et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699-709. Open reference URL https://web.pathway.md/studies/recKGR8whmarlr4FD 2/2

6/29/23, 1:45 AM PROWESS-SHOCK Pathway Feedback Search Clinical Topics Home Studies PROWESS SHOCK PROWESS SHOCK Disease Sepsis and septic shock Trial question What is the role of drotrecogin alfa (activated) in patients with septic shock? Study design Multi-center Double blinded RCT Population Characteristics of study participants 44.0% female N = 1697 56.0% male 1697 patients (739 female, 957 male) Inclusion criteria: patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours Key exclusion criteria: age < 18 years, no evidence of infection, coexisting illnesses with a high risk of death (e.g., metastatic cancer), major bleeding, pregnant or lactating, INR > 5.0, or sepsis induced organ dysfunction > 36 hours Interventions N=846 drotrecogin alfa activated (24 g/kg of body weight per hour for 96 hours) N=834 placebo (matching placebo for 96 hours) Primary outcome https://web.pathway.md/studies/recu2vSho1XZfsinm 1/2 6/29/23, 1:45 AM PROWESS-SHOCK Pathway Death at 28 days 26.4 % 26.4 24.2 19.8 % 13.2 % 6.6 % No significant difference 0.0 % Drotrecogin alfa activated Placebo No significant difference in death at 28 days (26.4% vs. 24.2%; RR 1.09, 95% CI 0.92 to 1.28) Secondary outcomes No significant difference in death at 90 days (34.1% vs. 32.7%; RR 1.04, 95% CI 0.9 to 1.19) No significant difference in death at 28 days, among patients with severe protein C deficiency (28.7% vs. 30.8%; RR 0.93, 95% CI 0.74 to 1.17) Safety outcomes No significant differences in serious bleeding (1.2% vs. 1.0%, p=0.81) and serious adverse events (14.3% vs. 11.5%, p=0.10). Conclusion In patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours, drotrecogin alfa activated was not superior to placebo with respect to death at 28 days. Reference Ranieri VM, Thompson BT, Barie PS et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med. 2012 May 31;366(22):2055-64. Open reference URL https://web.pathway.md/studies/recu2vSho1XZfsinm 2/2

6/29/23, 1:45 AM Psilocybin in AUD Pathway Feedback Search Clinical Topics Home Studies Psilocybin in AUD Psilocybin in AUD Disease Alcohol use disorder Trial question What is the role of psilocybin-assisted psychotherapy in patients with AUD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 44.0% female N = 95 56.0% male 95 patients (42 female, 53 male) Inclusion criteria: adults aged 25-65 years with a DSM-IV diagnosis of alcohol dependence and 4 heavy drinking days during the 30 days prior to screening Key exclusion criteria: major psychiatric and drug use disorders; hallucinogen use; medical conditions contraindicating the study medications; use of exclusionary medications; and current treatment for AUD Interventions N=49 psilocybin (administered at a dose of 25-40 mg/70 kg PO in 2 all-day sessions at week 4 and 8 plus psychotherapy) N=46 diphenhydramine (administered at a dose of 50-100 mg PO in 2 all-day sessions at week 4 and 8 plus psychotherapy) https://web.pathway.md/studies/recXPifTShXs8dsLX 1/2 6/29/23, 1:45 AM Psilocybin in AUD Pathway Primary outcome Percentage of heavy drinking days during 32-week period 23.6 % 23.6 17.7 % 11.8 % 9.7 Significant decrease 5.9 % NNT = 7 0.0 % Psilocybin Diphenhydramine Significant decrease in the percentage of heavy drinking days during 32-week period (9.7% vs. 23.6%; AD -13.9%, 95% CI -24.7 to -3) Secondary outcomes No significant difference in the percentage of drinking days during follow-up (29.4% vs. 42.8%; AD -13.44%, 95% CI -27.05 to 0.18) Significant decrease in drinks per day at follow-up (1.17 vs. 2.26; AD -1.09, 95% CI -1.92 to -0.27) Significant increase in abstinence at weeks 33-36 (47.9% vs. 24.4%; OR 2.84, 95% CI 1.17 to 6.89) Safety outcomes No significant difference in adverse events. Significant difference in headache (43.8% vs. 4.4%). Conclusion In adults aged 25-65 years with a DSM-IV diagnosis of alcohol dependence and 4 heavy drinking days during the 30 days prior to screening, psilocybin was superior to diphenhydramine with respect to the percentage of heavy drinking days during 32-week period. Reference Michael P Bogenschutz, Stephen Ross, Snehal Bhatt et al. Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2022 Oct 1;79(10):953-962. Open reference URL https://web.pathway.md/studies/recXPifTShXs8dsLX 2/2

6/29/23, 1:45 AM Pulmonary artery catheters for acute lung injury Pathway Feedback Search Clinical Topics Home Studies Pulmonary artery catheters for acute lung injury Pulmonary artery catheters for acute lung injury Disease Acute respiratory distress syndr Trial question What is the role of pulmonary artery catheter-guided treatment in patients with established acute lung injury? Study design Multi-center Single blinded RCT Population Characteristics of study participants 46.5% female N = 1000 53.5% male 1000 patients (465 female, 535 male) Inclusion criteria: patients with established acute lung injury Key exclusion criteria: acute lung injury > 48 hours, dependence on dialysis, severe lung or neuromuscular disease, advanced cancer Interventions N=513 pulmonary artery catheter-guided resuscitation N=487 central venous catheter-guided resuscitation Primary outcome Survival at 60 days https://web.pathway.md/studies/recFPXEojmv5YYcn8 1/2 6/29/23, 1:45 AM Pulmonary artery catheters for acute lung injury Pathway 27.4 % 27.4 26.3 20.5 % 13.7 % 6.8 % No significant difference 0.0 % Pulmonary artery catheter-guided resuscitation Central venous catheter-guided resuscitation No significant difference in survival at 60 days (27.4% vs. 26.3%; AD 1.1%, 95% CI -4.4 to 6.6) Secondary outcomes No significant difference in the number of ventilator free days (13.2 vs. 13.5; AD -0.3, 95% CI -1.33 to 0.73) Safety outcomes No significant differences in complications-related adverse events (0.08 vs. 0.06 per catheter inserted, p=0.35). Significant difference in arrhythmias (42 vs. 7). Conclusion In patients with established acute lung injury, pulmonary artery catheter-guided resuscitation was not superior to central venous catheter-guided resuscitation with respect to survival at 60 days. Reference National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med. 2006 May 25;354(21):2213-24. Open reference URL https://web.pathway.md/studies/recFPXEojmv5YYcn8 2/2

6/29/23, 1:45 AM PULSAR (high-dose sotatercept) Pathway Feedback Search Clinical Topics Home Studies PULSAR (high-dose sotatercept) PULSAR (high-dose sotatercept) Disease Pulmonary hypertension Trial question What is the role of high-dose sotatercept in patients with pulmonary arterial hypertension? Study design Multi-center Double blinded RCT Population Characteristics of study participants 89.0% female N = 74 11.0% male 74 patients (66 female, 8 male) Inclusion criteria: adults who were receiving background therapy for pulmonary arterial hypertension Key exclusion criteria: portopulmonary disease; schistosomiasis; and human immunodeficiency virus infection-associated pulmonary arterial hypertension; portal hypertension or chronic liver disease Interventions N=42 high-dose sotatercept (subcutaneous dose of 0.7 mg/kg every 3 weeks for 24 weeks) N=32 placebo (matching placebo every 3 weeks for 24 weeks) Primary outcome https://web.pathway.md/studies/recPqob7kKfaVUKk8 1/2 6/29/23, 1:45 AM PULSAR (high-dose sotatercept) Pathway Pulmonary vascular resistance reduction at week 24 255.9 dyn s/ 255.9 191.9 dyn s/ 128.0 dyn s/ 64.0 dyn s/ Significant increase 16.4 0.0 dyn s/ High-dose sotatercept Placebo Significant increase in pulmonary vascular resistance reduction at week 24 (255.9 dyn s/cm vs. 16.4 dyn s/cm ; AD 239.5 dyn s/cm , 95% CI 149.7 to 329.3) Secondary outcomes No significant difference in improvement in 6-minute walk distance at week 24 (50.1 m vs. 28.7 m; AD 21.4 m, 95% CI -2.8 to 45.7) Significant increase in N-terminal pro-BNP level reduction at week 24 (340.6 pg/mL vs. -310.4 pg/mL; AD 651 pg/mL, 95% CI 258.7 to 1043.3) Significant increase in reduction in systolic excursion from the tricuspid annular plane at week 24 (AD 0.1 cm, 95% CI 0.08 to 0.2) Safety outcomes No significant difference in any adverse event. Significant difference in thrombocytopenia (12% vs. 0%). Conclusion In adults who were receiving background therapy for pulmonary arterial hypertension, high-dose sotatercept was superior to placebo with respect to pulmonary vascular resistance reduction at week 24. Reference Marc Humbert, Vallerie McLaughlin, J Simon R Gibbs et al. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2021 Apr 1;384(13):1204-1215. Open reference URL https://web.pathway.md/studies/recPqob7kKfaVUKk8 2/2

6/29/23, 1:45 AM PULSAR (low-dose sotatercept) Pathway Feedback Search Clinical Topics Home Studies PULSAR (low-dose sotatercept) PULSAR (low-dose sotatercept) Disease Pulmonary hypertension Trial question What is the role of low-dose sotatercept in patients with pulmonary arterial hypertension? Study design Multi-center Double blinded RCT Population Characteristics of study participants 86.0% female N = 64 14.0% male 64 patients (55 female, 9 male) Inclusion criteria: adults who were receiving background therapy for pulmonary arterial hypertension Key exclusion criteria: portopulmonary disease; schistosomiasis; and human immunodeficiency virus infection-associated pulmonary arterial hypertension; portal hypertension or chronic liver disease Interventions N=32 low-dose sotatercept (subcutaneous dose of 0.3 mg/kg every 3 weeks for 24 weeks) N=32 placebo (matching placebo every 3 weeks for 24 weeks) Primary outcome https://web.pathway.md/studies/recEgbg5w6SnRUMwg 1/2 6/29/23, 1:45 AM PULSAR (low-dose sotatercept) Pathway Pulmonary vascular resistance reduction at week 24 162.2 dyn s/ 162.2 121.6 dyn s/ 81.1 dyn s/ 40.5 dyn s/ Significant increase 16.4 0.0 dyn s/ Low-dose sotatercept Placebo Significant increase in pulmonary vascular resistance reduction at week 24 (162.2 dyn s/cm vs. 16.4 dyn s/cm ; AD 145.8 dyn s/cm , 95% CI 50.6 to 241) Secondary outcomes Significant increase in improvement in 6-minute walk distance at week 24 (58.1 m vs. 28.7 m; AD 29.4 m, 95% CI 3.8 to 55) Significant increase in N-terminal pro-BNP level reduction at week 24 (621.1 pg/mL vs. -310.4 pg/mL; AD 931.5 pg/mL, 95% CI 509.7 to 1353.2) Safety outcomes No significant difference in any adverse event. Significant difference in thrombocytopenia (6% vs. 0%). Conclusion In adults who were receiving background therapy for pulmonary arterial hypertension, low-dose sotatercept was superior to placebo with respect to pulmonary vascular resistance reduction at week 24. Reference Marc Humbert, Vallerie McLaughlin, J Simon R Gibbs et al. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2021 Apr 1;384(13):1204-1215. Open reference URL https://web.pathway.md/studies/recEgbg5w6SnRUMwg 2/2

6/29/23, 12:42 AM RABBIT 2 Pathway Feedback Search Clinical Topics Home Studies RABBIT 2 RABBIT 2 Disease Disease Diabetes mellitus type 2 In-hospital hyperglycemia Trial question What is the effect of basal-bolus insulin therapy in the management of non-critically ill, hospitalized patients with T2DM? Study design Multi-center Open label RCT Population Characteristics of study participants 52.0% female N = 130 48.0% male 130 patients (67 female, 63 male) Inclusion criteria: non-critically ill, hospitalized patients with T2DM who are insulin-naive Key exclusion criteria: without a known history of diabetes, ICU patients, the use of corticosteroid therapy, expected to undergo surgery during the hospitalization course, clinically relevant hepatic disease, serum creatinine 3.0 mg/dl, or pregnancy Interventions N=65 use of a basal-bolus insulin regimen (glargine once daily and glulisine before meals at a starting dose of 0.4 units x kg(-1) x day(-1) for blood glucose 140-200 mg/dl or 0.5 units x kg(-1) x day(-1) for blood glucose 201-400 mg/dl) https://web.pathway.md/studies/recnUFXg8hIupargn 1/2 6/29/23, 12:42 AM RABBIT 2 Pathway N=65 use of a standard sliding-scale insulin protocol (sliding-scale regular insulin four times per day for blood glucose > 140 mg/dL) Primary outcome Percentage of patients achieving mean glucose target of < 140 mg/dL 66.0 % 66 49.5 % 38 33.0 % Significant increase 16.5 % NNT = 4 0.0 % Use of a basal-bolus insulin regimen Use of a standard sliding-scale insulin protocol Significant increase in the percentage of patients achieving mean glucose target of < 140 mg/dL (66% vs. 38%; RR 1.74, 95% CI 0.42 to 3.06) Conclusion In non-critically ill, hospitalized patients with T2DM who are insulin-naive, use of a basal-bolus insulin regimen was superior to use of a standard sliding-scale insulin protocol with respect to the percentage of patients achieving mean glucose target of < 140 mg/dL. Reference Umpierrez GE, Smiley D, Zisman A et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Diabetes Care. 2007 Sep;30(9):2181-6. Open reference URL https://web.pathway.md/studies/recnUFXg8hIupargn 2/2

6/29/23, 12:42 AM RACE II Pathway Feedback Search Clinical Topics Home Studies RACE II RACE II Disease Atrial fibrillation Trial question Is lenient rate control noninferior to strict rate control in patients with AF? Study design Multi-center Open label RCT Population Characteristics of study participants 34.0% female N = 614 66.0% male 614 patients (211 female, 403 male) Inclusion criteria: patients with permanent AF Key exclusion criteria: paroxysmal AF, previous adverse effects on negative chronotropic drugs, unstable HF defined as NYHA IV HF or HF necessitating hospital admission < 3 months before inclusion, cardiac surgery < 3 months, or any stroke Interventions N=311 lenient rate control (resting HR < 110 beats/min) N=303 strict rate control (resting HR < 80 beats/min and HR during exercise < 110 beats/min) Primary outcome https://web.pathway.md/studies/recvQSaRxtRS6PQg0 1/2 6/29/23, 12:42 AM RACE II Pathway Death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events at 3 years 14.9 % 14.9 12.9 11.2 % 7.5 % Difference not exceeding nonferiority margin 3.7 % 0.0 % Lenient rate control Strict rate control Difference not exceeding nonferiority margin in death from cardiovascular causes, hospitalization for HF, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events at 3 years (12.9% vs. 14.9%; HR 0.8, 90% CI 0.55 to 1.17) Secondary outcomes Significant decrease in stroke (1.6 vs. 3.9; HR 0.35, 90% CI 0.13 to 0.92) Significant decrease in death at 3 years (5.6% vs. 6.6%; HR 0.91, 90% CI 0.52 to 1.59) Safety outcomes No significant difference in frequencies of symptoms and adverse events. Conclusion In patients with permanent AF, lenient rate control was noninferior to strict rate control with respect to death from cardiovascular causes, hospitalization for HF, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events at 3 years. Reference Van Gelder IC, Groenveld HF, Crijns HJ et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010 Apr 15;362(15):1363-73. Open reference URL https://web.pathway.md/studies/recvQSaRxtRS6PQg0 2/2

6/29/23, 12:42 AM RACING Pathway Feedback Search Clinical Topics Home Studies RACING RACING Disease Disease Disease Coronary artery disease Diabetes mellitus type 2 Dyslipidem Trial question What is the role of ezetimibe combination therapy in patients with diabetes mellitus and ASCVD? Study design Multi-center Open label RCT Population 1398 patients Inclusion criteria: adult patients with diabetes mellitus and ASCVD Key exclusion criteria: active liver disease; solid organ transplantation recipient; allergy / hypersensitivity to any statin or ezetimibe; life expectancy < 3 years Interventions N=701 moderate-intensity statin plus ezetimibe combination therapy (rosuvastatin 10 mg plus ezetimibe 10 mg per day) N=697 high-intensity statin monotherapy (rosuvastatin 20 mg/day) Primary outcome Composite of cardiovascular death, major cardiovascular events, or nonfatal stroke at 3 years 11.3 % 11.3 10 8.5 % 5.7 % 2.8 % No significant difference 0.0 % https://web.pathway.md/studies/recAnspeFn8iknCC3 1/2 6/29/23, 12:42 AM RACING Pathway Moderate-intensity statin plus ezetimibe combination therapy High-intensity statin monotherapy No significant difference in composite of cardiovascular death, major cardiovascular events, or nonfatal stroke at 3 years (10% vs. 11.3%; HR 0.89, 95% CI -1.43 to 3.21) Secondary outcomes Significant decrease in intolerance-related discontinuation or dose reduction of the study drug (5.2% vs. 8.7%; ARD -3.5, 95% CI -6.29 to -0.71) Significant increase in low-density lipoprotein cholesterol levels < 70 mg/dL at 1 year (81% vs. 64.1%; AD 16.9%, 95% CI 6.87 to 26.93) Significant increase in low-density lipoprotein cholesterol levels < 70 mg/dL at 3 years (79.9% vs. 66.8%; AD 13.1%, 95% CI 5.33 to 20.87) Conclusion In adult patients with diabetes mellitus and ASCVD, moderate-intensity statin plus ezetimibe combination therapy was not superior to high-intensity statin monotherapy with respect to the composite of cardiovascular death, major cardiovascular events, or nonfatal stroke at 3 years. Reference Yong-Joon Lee, Jae Young Cho, Seng Chan You et al. Moderate-intensity statin with ezetimibe vs. high-intensity statin in patients with diabetes and atherosclerotic cardiovascular disease in the RACING trial. Eur Heart J. 2023 Mar 14;44(11):972-983. Open reference URL https://web.pathway.md/studies/recAnspeFn8iknCC3 2/2

6/29/23, 1:13 AM Radiograph vs. MRI for low back pain Pathway Feedback Search Clinical Topics Home Studies Radiograph vs. MRI for low back pain Radiograph vs. MRI for low back pain Disease Low back pain Trial question What is the role of rapid MRI for patients with low back pain? Study design Multi-center Open label RCT Population Characteristics of study participants 56.0% female N = 380 44.0% male 380 patients (211 female, 169 male) Inclusion criteria: patients age 18 years with low back pain Key exclusion criteria: lumbar surgery within 1 year prior to enrollment, history of acute external trauma, metallic implants in the lumbar spine, contraindications for MRI, age < 18 years, or pregnancy Interventions N=190 early MRI (pulse sequences of sagittal and axial T2-weighted fast spin echo images with total acquisition time of approximately 2 minutes on a 1.5-T scanner) N=190 initial imaging with spine radiograph (lumbar spine evaluation with anteroposterior, lateral, or oblique view) https://web.pathway.md/studies/rec17pNvrYSwgRj1V 1/2 6/29/23, 1:13 AM Radiograph vs. MRI for low back pain Pathway Primary outcome Back-related disability measured by 12-month Roland Scale score 9.3 9.34 8.75 7.0 4.7 2.3 No significant difference 0.0 Early magnetic resonance imaging Initial imaging with spine radiograph No significant difference in back-related disability measured by the 12-month Roland Scale score (9.34 vs. 8.75; MD -0.59, 95% CI -1.69 to 0.87) Secondary outcomes No significant difference in SF-36 subscales of bodily pain (51.34 vs. 52.59; MD 1.25, 95% CI -4.46 to 4.96) No significant difference in 12-month Roland Scale score (9.34 vs. 8.75; MD -0.59, 95% CI -1.69 to 0.87) Conclusion In patients age 18 years with low back pain, early MRI was not superior to initial imaging with spine radiograph with respect to a back-related disability measured by the 12-month Roland Scale score. Reference Jarvik JG, Hollingworth W, Martin B et al. Rapid magnetic resonance imaging vs radiographs for patients with low back pain: a randomized controlled trial. JAMA. 2003 Jun 4;289(21):2810-8. Open reference URL https://web.pathway.md/studies/rec17pNvrYSwgRj1V 2/2

6/29/23, 12:42 AM RAFT Pathway Feedback Search Clinical Topics Home Studies RAFT RAFT Disease Disease Heart failure Ventricular arrhythmias Trial question What is the role of addition of cardiac-resynchronization therapy to an ICD in patients with LV systolic dysfunction and a wide QRS complex? Study design Multi-center Double blinded RCT Population Characteristics of study participants 17.0% female N = 1798 83.0% male 1798 patients (308 female, 1490 male) Inclusion criteria: patients with NYHA (NYHA) class II or III HF, an LVEF 30%, and an intrinsic QRS duration 120 msec or a paced QRS duration 200 msec Key exclusion criteria: life expectancy of < 1 year from noncardiac causes, intravenous inotropic agent in the last 4 days, acute coronary syndrome, tricuspid prosthetic valve, severe primary pulmonary disease Interventions N=894 ICD-CRT implantation (ICD plus cardiac-resynchronization therapy and optimal medical therapy) N=904 ICD implantation alone (ICD and optimal medical therapy) https://web.pathway.md/studies/recgx6Oiz6JLaXNvl 1/2 6/29/23, 12:42 AM RAFT Pathway Primary outcome Death or hospitalization for heart failure 40.3 % 40.3 33.2 30.2 % 20.1 % Significant decrease 10.1 % NNT = 14 0.0 % ICD-CRT implantation ICD implantation alone Significant decrease in death or hospitalization for HF (33.2% vs. 40.3%; HR 0.75, 95% CI 0.64 to 0.87) Secondary outcomes Significant decrease in death from any cause (20.8% vs. 26.1%; HR 0.75, 95% CI 0.62 to 0.91) Significant decrease in hospitalization for HF (19.5% vs. 26.1%; HR 0.68, 95% CI 0.56 to 0.83) Significant decrease in death due to cardiovascular causes (14.5% vs. 17.9%; HR 0.76, 95% CI 0.6 to 0.96) Safety outcomes Significant differences in adverse events at 30 after device implantation (118 vs. 61 events, p < 0.001). Conclusion In patients with NYHA (NYHA) class II or III HF, an LVEF 30%, and an intrinsic QRS duration 120 msec or a paced QRS duration 200 msec, ICD-CRT implantation was superior to ICD implantation alone with respect to death or hospitalization for HF. Reference Tang AS, Wells GA, Talajic M et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. 2010 Dec 16;363(25):2385-95. Open reference URL https://web.pathway.md/studies/recgx6Oiz6JLaXNvl 2/2

6/29/23, 12:43 AM RAIHA Pathway Feedback Search Clinical Topics Home Studies RAIHA RAIHA Disease Autoimmune hemolytic anemia Trial question What is the role of rituximab in patients with warm autoimmune-hemolytic anemia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 53.0% female N = 32 47.0% male 32 patients (17 female, 15 male) Inclusion criteria: adult patients with warm autoimmune hemolytic anemia who received corticosteroids for < 6 weeks Key exclusion criteria: prior treatment with rituximab; warm autoimmune hemolytic anemia treated for > 6 weeks with corticosteroids; ongoing or recent treatment with immunosuppressants other than corticosteroids; any other associated cause of hereditary or acquired hemolytic anemia Interventions N=16 rituximab (1,000 mg at day 1 and day 15) N=16 placebo (1,000 mg of matching placebo at day 1 and day 15) Primary outcome https://web.pathway.md/studies/recYsRANNKDQLG1Kn 1/2 6/29/23, 12:43 AM RAIHA Pathway Complete or partial response at 1 year 75.0 % 75 56.3 % 37.5 % 31 Significant increase 18.8 % NNT = 2 0.0 % Rituximab Placebo Significant increase in complete or partial response at 1 year (75% vs. 31%; AD 44%, 95% CI 3.72 to 84.28) Secondary outcomes Significant increase in complete response at 2 years (63% vs. 19%; AD 44%, 95% CI 4.44 to 83.56) No significant difference in duration of hospital stay (13 days vs. 28 days; AD -15 days, 95% CI -31.59 to 1.59) Significant decrease in death at 2 years (ARD -38, 95% CI -69.24 to -6.76) Safety outcomes No significant difference in severe infections. Conclusion In adult patients with warm autoimmune hemolytic anemia who received corticosteroids for < 6 weeks, rituximab was superior to placebo with respect to complete or partial response at 1 year. Reference Marc Michel, Louis Terriou, Francoise Roudot-Thoraval et al. A randomized and double-blind controlled trial evaluating the safety and efficacy of rituximab for warm auto-immune hemolytic anemia in adults (the RAIHA study). Am J Hematol. 2017 Jan;92(1):23-27. Open reference URL https://web.pathway.md/studies/recYsRANNKDQLG1Kn 2/2

6/29/23, 12:43 AM RALES Pathway Feedback Search Clinical Topics Home Studies RALES RALES Disease Heart failure Trial question What is the role of spironolactone in patients with severe HF and a LVEF < 35% who were being treated with ACEi? Study design Multi-center Double blinded RCT Population Characteristics of study participants 27.0% female N = 1663 73.0% male 1663 patients (446 female, 1217 male) Inclusion criteria: patients with severe HF and an LVEF < 35% who were being treated with ACEi Key exclusion criteria: congenital heart disease, unstable angina, primary hepatic failure, active cancer, or any life-threatening disease (other than HF), or heart transplantation Interventions N=822 spironolactone (25 mg daily) N=841 placebo (matching placebo daily) Primary outcome Death at 24 months https://web.pathway.md/studies/rec1TTi3U6insNBVH 1/2 6/29/23, 12:43 AM RALES Pathway 46.0 % 46 35 34.5 % 23.0 % Significant decrease 11.5 % NNT = 9 0.0 % Spironolactone Placebo Significant decrease in death at 24 months (35% vs. 46%; RR 0.7, 95% CI 0.6 to 0.82) Secondary outcomes Significant decrease in frequency of hospitalization for worsening HF (26% vs. 35%; RR 0.65, 95% CI 0.54 to 0.77) Significant increase in gynecomastia or breast pain (10% vs. 1%; RR 10, 95% CI 4.07 to 15.93) Safety outcomes No significant difference in serious hyperkalemia. Significant differences in gynecomastia or breast pain (10% vs. 1%, p < 0.001). Conclusion In patients with severe HF and an LVEF < 35% who were being treated with ACEi, spironolactone was superior to placebo with respect to death at 24 months. Reference Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999 Sep 2;341(10):709-17. Open reference URL https://web.pathway.md/studies/rec1TTi3U6insNBVH 2/2

6/29/23, 12:43 AM RAPPORT Pathway Feedback Search Clinical Topics Home Studies RAPPORT RAPPORT Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the role of abciximab in patients with acute myocardial infarction of < 12 hours duration undergoing PCI in the pre-drug eluting stent era? Study design Multi-center Double blinded RCT Population Characteristics of study participants 28.0% female N = 483 72.0% male 483 patients (133 female, 350 male) Inclusion criteria: patients with acute myocardial infarction of < 12 hours duration undergoing PCI in the pre-drug eluting stent era Key exclusion criteria: severe thrombocytopenia, baseline PT > 1.2 times control, ongoing internal bleeding or recent major surgery, previous stroke, or severe uncontrolled hypertension Interventions N=241 abciximab (as a 0.25 mg/kg bolus followed by a 12-hour infusion of 0.125 g/kg/min, maximum, 10 g/min) N=242 placebo (matching placebo) https://web.pathway.md/studies/recz07io1cZZmVcaP 1/2 6/29/23, 12:43 AM RAPPORT Pathway Primary outcome Death, reinfarction, or urgent target vessel revascularization at 6 months 17.8 % 17.8 13.4 % 11.6 8.9 % Significant decrease 4.5 % NNT = 16 0.0 % Abciximab Placebo Significant decrease in death, reinfarction, or urgent target vessel revascularization at 6 months (11.6% vs. 17.8%; OR 0.61, 95% CI 0.36 to 1.02) Secondary outcomes No significant difference in death, reinfarction, or any target vessel revascularization at 6 months, by intention-to-treat analysis (28.2% vs. 28.1%; OR 1.01, 95% CI 0.68 to 1.5) Safety outcomes Significant differences in bleeding (16.6% vs. 9.5%, p = 0.02). Conclusion In patients with acute myocardial infarction of < 12 hours duration undergoing PCI in the pre-drug eluting stent era, abciximab was superior to placebo with respect to death, reinfarction, or urgent target vessel revascularization at 6 months. Reference Brener SJ, Barr LA, Burchenal JE et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators. Circulation. 1998 Aug 25;98(8):734- 41. Open reference URL https://web.pathway.md/studies/recz07io1cZZmVcaP 2/2

6/29/23, 12:43 AM RAVE Pathway Feedback Search Clinical Topics Home Studies RAVE RAVE Disease Disease Granulomatosis with polyangiitis Microscopic polyangiitis Trial question Is rituximab noninferior to cyclophosphamide in patients with severe ANCA-associated vasculitis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 50.0% female N = 197 50.0% male 197 patients (100 female, 100 male) Inclusion criteria: ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis Key exclusion criteria: Churg-Strauss syndrome or anti-GBM disease, alveolar hemorrhage severe enough to require mechanical ventilation, renal failure, active systemic infection, osteomyelitis, septic arthritis, or pneumonia complicated by empyema, or severe liver disease Interventions N=99 rituximab (intravenous 375 mg per square meter of body-surface area per week for 4 weeks plus corticosteroid regimen) N=98 cyclophosphamide (2 mg/kg of body weight per day, adjusted for renal insufficiency plus corticosteroid regimen) https://web.pathway.md/studies/recFNQpCVDftG6N4F 1/2 6/29/23, 12:43 AM RAVE Pathway Primary outcome Remission of disease without use of prednisone at 6 months 64.0 % 64 53 48.0 % 32.0 % Difference not exceeding nonferiority margin 16.0 % 0.0 % Rituximab Cyclophosphamide Difference not exceeding nonferiority margin in remission of disease without the use of prednisone at 6 months (64% vs. 53%; ARD 11, 95% CI 4.47 to 17.53) Secondary outcomes Significant increase in remission induction of relapsing disease (67% vs. 42%; RR 1.6, 95% CI 0.38 to 2.82) Significant increase in the rate of ANCA response, by 6 months (47% vs. 24%; RR 1.96, 95% CI 0.63 to 3.29) Safety outcomes No significant difference in rates of total or serious adverse events. Conclusion In ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis, rituximab was noninferior to cyclophosphamide with respect to remission of disease without the use of prednisone at 6 months. Reference Stone JH, Merkel PA, Spiera R et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. Open reference URL https://web.pathway.md/studies/recFNQpCVDftG6N4F 2/2

6/29/23, 12:43 AM RE-ALIGN Pathway Feedback Search Clinical Topics Home Studies RE ALIGN RE ALIGN Disease Disease Disease Aortic regurgitation Aortic stenosis Mitral regu Trial question What is the effect of dabigatran in patients with mechanical heart valves? Study design Multi-center Open label RCT Population Characteristics of study participants 35.0% female N = 252 65.0% male 252 patients (89 female, 163 male) Inclusion criteria: patients who had undergone aortic or mitral valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier Key exclusion criteria: previous prosthetic heart valve replacement, aortic root replacement, replacement of ascending aorta, concomitant bioprosthetic valve replacement, complex congenital heart abnormality, acute coronary syndrome within one month, uncontrolled hypertension, or recent emergency surgery Interventions N=168 dabigatran (150, 220, or 300 mg BID, adjusted to obtain a trough plasma level of at least 50 ng/mL) https://web.pathway.md/studies/reclzVrykLDLeUr98 1/2 6/29/23, 12:43 AM RE-ALIGN Pathway N=84 warfarin (adjusted to obtain an INR of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk) Primary outcome Death, stroke, systemic embolism, or myocardial infarction 8.0 % 8 6.0 % 4.0 % 2.0 % 2 No significant difference 0.0 % Dabigatran Warfarin No significant difference in death, stroke, systemic embolism, or myocardial infarction (8% vs. 2%; HR 3.37, 95% CI 0.76 to 14.95) Secondary outcomes No significant difference in death, stroke, TIA, systemic embolism, or myocardial infarction (9% vs. 5%; HR 1.94, 95% CI 0.64 to 5.86) Safety outcomes No significant differences in major bleeding (4% vs. 2%, p=0.48) and major bleeding with pericardial location (4% vs. 2%, p=0.48). Significant differences in any bleeding (27% vs. 12%, p = 0.01). Conclusion In patients who had undergone aortic or mitral valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier, dabigatran was inferior to warfarin with respect to death, stroke, systemic embolism, or myocardial infarction. Reference Eikelboom JW, Connolly SJ, Brueckmann M et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013 Sep 26;369(13):1206-14. Open reference URL https://web.pathway.md/studies/reclzVrykLDLeUr98 2/2

6/29/23, 12:43 AM RE-COVER Pathway Feedback Search Clinical Topics Home Studies RE COVER RE COVER Disease Disease Deep vein thrombosis Pulmonary embolism Trial question Is dabigatran noninferior to warfarin for patients who have acute VTE? Study design Multi-center Double blinded RCT Population Characteristics of study participants 41.4% female N = 2564 58.6% male 2564 patients (1055 female, 1484 male) Inclusion criteria: patients who have acute VTE Key exclusion criteria: duration of symptoms > 14 days, PE with hemodynamic instability or requiring thrombolytic therapy, another indication for warfarin therapy, recent unstable CVD, a high risk of bleeding, liver disease, or a life expectancy < 6 months Interventions N=1274 dabigatran (150 mg BID) N=1265 warfarin (dose-adjusted, to achieve INR 2.0 to 3.0) Primary outcome Recurrent venous thromboembolism https://web.pathway.md/studies/reclyCcgaB7ao3PZI 1/2 6/29/23, 12:43 AM RE-COVER Pathway 2.4 % 2.4 2.1 1.8 % 1.2 % Difference not exceeding nonferiority margin 0.6 % 0.0 % Dabigatran Warfarin Difference not exceeding nonferiority margin in recurrent VTE (2.4% vs. 2.1%; HR 1.1, 95% CI 0.65 to 1.84) Secondary outcomes Significant decrease in symptomatic DVT (1.3% vs. 1.4%; HR 0.87, 95% CI 0.44 to 1.71) Significant increase in symptomatic nonfatal PE (1% vs. 0.6%; HR 1.85, 95% CI 0.74 to 4.64) Significant decrease in death related to VTE (0.1% vs. 0.2%; HR 0.33, 95% CI 0.03 to 3.15) Safety outcomes No significant differences in major bleeding (1.6% vs. 1.9%; HR 0.82, 95% CI 0.45-1.48) and any bleeding episodes (16.1% vs. 21.9%; HR 0.71, 95% CI 0.59-0.85). Significant differences in adverse events leading to drug discontinuation (9.0% vs. 6.8%, p = 0.05). Conclusion In patients who have acute VTE, dabigatran was noninferior to warfarin with respect to recurrent VTE. Reference Schulman S, Kearon C, Kakkar AK et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. Open reference URL https://web.pathway.md/studies/reclyCcgaB7ao3PZI 2/2

6/29/23, 12:43 AM RE-DUAL PCI (dabigatran 110 mg BID) Pathway Feedback Search Clinical Topics Home Studies RE DUAL PCI (dabigatran 110 mg BID RE DUAL PCI (dabigatran 110 mg BID Disease Atrial fibrillation Trial question Is dual antithrombotic therapy with dabigatran superior to triple antithrombotic therapy with warfarin in AF? Study design Multi-center Open label RCT Population Characteristics of study participants 25.0% female N = 1962 75.0% male 1962 patients (484 female, 1478 male) Inclusion criteria: patients with AF who had undergone PCI Key exclusion criteria: bioprosthetic or mechanical heart valves; severe renal insufficiency or other major coexisting conditions Interventions N=981 dual therapy with dabigatran (dabigatran at a dose of 110 mg BID plus a P2Y12 inhibitor and no aspirin) N=981 triple therapy with warfarin (warfarin plus a P2Y12 inhibitor and aspirin for 1 to 3 months) Primary outcome https://web.pathway.md/studies/recuLNmhvkx7nUeF8 1/2 6/29/23, 12:43 AM RE-DUAL PCI (dabigatran 110 mg BID) Pathway Major or clinically relevant nonmajor bleeding event during follow-up 26.9 % 26.9 20.2 % 15.4 13.4 % Significant decrease 6.7 % NNT = 9 0.0 % Dual therapy with dabigatran Triple therapy with warfarin Significant decrease in major or clinically relevant nonmajor bleeding event during follow-up (15.4% vs. 26.9%; HR 0.52, 95% CI 0.42 to 0.63) Secondary outcomes No significant difference in composite of thromboembolic events, death, or unplanned revascularization (15.2% vs. 13.4%; HR 1.13, 95% CI 0.9 to 1.43) No significant difference in thromboembolic events or death (11% vs. 8.5%; HR 1.3, 95% CI 0.98 to 1.73) No significant difference in death from any cause (5.6% vs. 4.9%; HR 1.12, 95% CI 0.76 to 1.65) Safety outcomes No significant difference in intracranial hemorrhage. Significant differences in major bleeding (5.0% vs. 9.2%), total bleeding (27.1% vs. 42.9%). Conclusion In patients with AF who had undergone PCI, dual therapy with dabigatran was superior to triple therapy with warfarin with respect to major or clinically relevant nonmajor bleeding event during follow-up. Reference Christopher P Cannon, Deepak L Bhatt, Jonas Oldgren et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017 Oct 19;377(16):1513-1524. Open reference URL https://web.pathway.md/studies/recuLNmhvkx7nUeF8 2/2

6/29/23, 12:43 AM RE-DUAL PCI (dabigatran 150 mg BID) Pathway Feedback Search Clinical Topics Home Studies RE DUAL PCI (dabigatran 150 mg BID RE DUAL PCI (dabigatran 150 mg BID Disease Atrial fibrillation Trial question Is dual antithrombotic therapy with dabigatran superior to triple antithrombotic therapy with warfarin in AF? Study design Multi-center Open label RCT Population Characteristics of study participants 23.0% female N = 1744 77.0% male 1744 patients (402 female, 1342 male) Inclusion criteria: patients with AF who had undergone PCI to triple therapy Key exclusion criteria: bioprosthetic or mechanical heart valves; severe renal insufficiency or other major coexisting conditions Interventions N=763 dual therapy with dabigatran (dabigatran at a dose of 150 mg BID plus a P2Y12 inhibitor and no aspirin) N=981 triple therapy with warfarin (warfarin plus a P2Y12 inhibitor and aspirin for 1 to 3 months) Primary outcome https://web.pathway.md/studies/recxH79mcaj9dGSux 1/2 6/29/23, 12:43 AM RE-DUAL PCI (dabigatran 150 mg BID) Pathway Major or clinically relevant nonmajor bleeding event during follow-up 25.7 % 25.7 20.2 19.3 % 12.8 % Significant decrease 6.4 % NNT = 18 0.0 % Dual therapy with dabigatran Triple therapy with warfarin Significant decrease in major or clinically relevant nonmajor bleeding event during follow-up (20.2% vs. 25.7%; HR 0.72, 95% CI 0.58 to 0.88) Secondary outcomes No significant difference in composite of thromboembolic events, death, or unplanned revascularization (11.8% vs. 12.8%; HR 0.89, 95% CI 0.67 to 1.19) No significant difference in thromboembolic events or death (7.9% vs. 7.9%; HR 0.97, 95% CI 0.68 to 1.39) No significant difference in death (3.9% vs. 4.6%; HR 0.83, 95% CI 0.51 to 1.34) Safety outcomes Significant differences in major bleeding (5.6% vs. 8.4%), total bleeding (33.3% vs. 41.4%). Conclusion In patients with AF who had undergone PCI to triple therapy, dual therapy with dabigatran was superior to triple therapy with warfarin with respect to major or clinically relevant nonmajor bleeding event during follow-up. Reference Christopher P Cannon, Deepak L Bhatt, Jonas Oldgren et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017 Oct 19;377(16):1513-1524. Open reference URL https://web.pathway.md/studies/recxH79mcaj9dGSux 2/2

6/29/23, 12:44 AM RE-ENERGIZE Pathway Feedback Search Clinical Topics Home Studies RE ENERGIZE RE ENERGIZE Disease Burn injury Trial question What is the role of supplemental glutamine in patients with severe burns? Study design Multi-center Double blinded RCT Population Characteristics of study participants 26.0% female N = 1200 74.0% male 1200 patients (312 female, 888 male) Inclusion criteria: patients with deep second or third degree burns within 72 hours after hospital admission Key exclusion criteria: lack of consent in < 72 hours; moribund state; contraindication to enteral nutrition Interventions N=596 glutamine (0.5 g/kg/day mixed with water given via nasogastric or feeding tube every 4 hours or 3 or 4 times a day by mouth) N=604 placebo (maltodextrin mixed with water given via nasogastric or feeding tube every 4 hours or 3 or 4 times a day by mouth) https://web.pathway.md/studies/recDJ5alYD2qS6uJu 1/2 6/29/23, 12:44 AM RE-ENERGIZE Pathway Primary outcome Time to discharge alive from hospital 40.0 days 40 38 30.0 days 20.0 days 10.0 days No significant difference 0.0 days Glutamine Placebo No significant difference in time to discharge alive from hospital (40 days vs. 38 days; HR 1.01, 95% CI 0.96 to 1.25) Secondary outcomes No significant difference in death at 6 months (17.2% vs. 16.2%; HR 1.06, 95% CI 0.8 to 1.41) No significant difference in death in the hospital (15.3% vs. 13.9%; RR 1.1, 95% CI 0.83 to 1.44) No significant difference in acquired bacteremia due to Gram-negative organisms (19% vs. 18%; RR 1.05, 95% CI 0.83 to 1.33) Safety outcomes No significant differences in serious adverse events, AKI or use of RRT. Conclusion In patients with deep second or third degree burns within 72 hours after hospital admission, glutamine was not superior to placebo with respect to time to discharge alive from hospital. Reference Daren K Heyland, Lucy Wibbenmeyer, Jonathan A Pollack et al. A Randomized Trial of Enteral Glutamine for Treatment of Burn Injuries. N Engl J Med. 2022 Sep 15;387(11):1001-1010. Open reference URL https://web.pathway.md/studies/recDJ5alYD2qS6uJu 2/2

6/29/23, 12:44 AM READS Pathway Feedback Search Clinical Topics Home Studies READS READS Disease Acute respiratory distress syndr Trial question What is the impact of an educational intervention designed to improve the accuracy of identification of radiographic criteria for ARDS? Study design Multi-center Open label RCT Population 463 patients Inclusion criteria: study coordinators in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure study Key exclusion criteria: no informed consent to participate Interventions N=212 intervention (an online training module followed by a test module) N=252 control (test module followed by training module) Primary outcome Number of correct answers on test module 58.0 % 58 56 43.5 % 29.0 % 14.5 % No significant difference 0.0 % https://web.pathway.md/studies/recHG4NflE3LLQ0IF 1/2 6/29/23, 12:44 AM READS Pathway Intervention Control No significant difference in the number of correct answers on the test module (58% vs. 56%; AD 2%, 95% CI -0.72 to 4.72) Secondary outcomes Significant increase in between-rater agreement for all radiographs in the test module (0.296 vs. 0.272; AD 0.024, 95% CI 0.01 to 0.04) No significant difference in analysis restricted to physicians (60% vs. 57%; AD 3%, 95% CI -0.47 to 6.47) No significant difference in the number of correct answers on the test module with equivocal radiographs considered together with consistent radiographs (70% vs. 69%; AD 1%, 95% CI -4.21 to 6.21) Conclusion In study coordinators in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure study, intervention was not superior to control with respect to number of correct answers on the test module. Reference Shannon L Goddard, Gordon D Rubenfeld, Venika Manoharan et al. The Randomized Educational Acute Respiratory Distress Syndrome Diagnosis Study: A Trial to Improve the Radiographic Diagnosis of Acute Respiratory Distress Syndrome. Crit Care Med. 2018 May;46(5):743-748. Open reference URL https://web.pathway.md/studies/recHG4NflE3LLQ0IF 2/2

6/29/23, 12:44 AM REAL Pathway Feedback Search Clinical Topics Home Studies REAL REAL Disease Rectal cancer Trial question Is robotic surgery superior to laparoscopic surgery in patients with middle and low rectal cancer? Study design Multi-center Open label RCT Population 1171 patients Inclusion criteria: patients with middle or low rectal adenocarcinoma with no evidence of distant metastasis Key exclusion criteria: tumor assessed as clinical complete response after preoperative radio- or chemoradiotherapy or suitable for local excision; signs of acute intestinal obstruction, bleeding or perforation needing emergency surgery Interventions N=586 robotic surgery (robot-assisted resection using da Vinci system) N=585 laparoscopic surgery (traditional laparoscopic resection) Primary outcome Circumferential resection margin positivity 7.2 % 7.2 5.4 % 4 3.6 % Significant decrease 1.8 % https://web.pathway.md/studies/recY9xlnFTw3X5xHK 1/2 6/29/23, 12:44 AM REAL Pathway NNT = 31 0.0 % Robotic surgery Laparoscopic surgery Significant decrease in circumferential resection margin positivity (4% vs. 7.2%; ARD -3.2, 95% CI -6 to -0.4) Secondary outcomes Significant decrease in postoperative complication grade II at day 30 (16.2% vs. 23.1%; ARD -6.9, 95% CI -11.4 to -2.3) Significant increase in macroscopic complete resection (95.4% vs. 91.8%; AD 3.6%, 95% CI 0.8 to 6.5) Significant decrease in postoperative hospital stay (7 days vs. 8 days; AD -1 days, 95% CI -1 to 0) Conclusion In patients with middle or low rectal adenocarcinoma with no evidence of distant metastasis, robotic surgery was superior to laparoscopic surgery with respect to circumferential resection margin positivity. Reference Qingyang Feng, Weitang Yuan, Taiyuan Li et al. Robotic versus laparoscopic surgery for middle and low rectal cancer (REAL): short-term outcomes of a multicentre randomised controlled trial. 2022 Sep 7;S2468-1253(22)00248-5. Open reference URL https://web.pathway.md/studies/recY9xlnFTw3X5xHK 2/2

6/29/23, 1:08 AM REALITY Pathway Feedback Search Clinical Topics Home Studies REALITY REALITY Disease Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Transfusio Trial question Is a restrictive blood transfusion strategy noninferior to a liberal blood transfusion strategy in patients with acute myocardial infarction and anemia? Study design Multi-center Open label RCT Population Characteristics of study participants 42.0% female N = 666 58.0% male 666 patients (281 female, 385 male) Inclusion criteria: adult patients with myocardial infarction and anemia Key exclusion criteria: shock; myocardial infarction occurring after PCI or CABG; life-threatening or massive ongoing bleeding; blood transfusion in the past 30 days; and malignant hematologic disease Interventions N=342 a restrictive strategy (transfusion triggered by Hgb 8 g/dL) N=324 a liberal strategy (transfusion triggered by Hgb 10 g/dL) Primary outcome https://web.pathway.md/studies/recr0FOQ9vEASH2Lk 1/2 6/29/23, 1:08 AM REALITY Pathway Composite outcome of death, stroke, recurrent myocardial infarction, or emergency revascularization prompted by ischemia at 30 days 14.0 % 14 11 10.5 % 7.0 % Difference not exceeding nonferiority margin 3.5 % 0.0 % A restrictive strategy A liberal strategy Difference not exceeding nonferiority margin in composite outcome of death, stroke, recurrent myocardial infarction, or emergency revascularization prompted by ischemia at 30 days (11% vs. 14%; ARD -3, 95% CI -8.4 to 2.4) Safety outcomes No significant difference in adverse events. Conclusion In adult patients with myocardial infarction and anemia, a restrictive strategy was noninferior to a liberal strategy with respect to the composite outcome of death, stroke, recurrent myocardial infarction, or emergency revascularization prompted by ischemia at 30 days. Reference Gregory Ducrocq, Jose R Gonzalez-Juanatey, Etienne Puymirat et al. Effect of a Restrictive vs Liberal Blood Transfusion Strategy on Major Cardiovascular Events Among Patients With Acute Myocardial Infarction and Anemia: The REALITY Randomized Clinical Trial. JAMA. 2021 Feb 9;325(6):552-560. Open reference URL https://web.pathway.md/studies/recr0FOQ9vEASH2Lk 2/2

6/29/23, 1:08 AM RECORD1 Pathway Feedback Search Clinical Topics Home Studies RECORD1 RECORD1 Disease Disease Hip fracture Hip osteoarthritis Trial question What is the effect of rivaroxaban for extended thromboprophylaxis in patients undergoing total hip arthroplasty? Study design Multi-center Double blinded RCT Population Characteristics of study participants 55.7% female N = 4541 44.3% male 4541 patients (2462 female, 1971 male) Inclusion criteria: patients undergoing total hip arthroplasty Key exclusion criteria: bilateral hip arthroplasty, pregnant or breast-feeding, active bleeding or a high risk of bleeding, or a contraindication for prophylaxis with enoxaparin or a condition that might require an adjusted dose of enoxaparin, substantial liver disease, or severe renal impairment Interventions N=2209 rivaroxaban (10 mg PO once daily) N=2224 enoxaparin (40 mg SC once daily) https://web.pathway.md/studies/reckGSL1azqrstvxv 1/2 6/29/23, 1:08 AM RECORD1 Pathway Primary outcome Deep vein thrombosis, nonfatal pulmonary embolism, or death from any cause at 36 days 3.7 % 3.7 2.8 % 1.9 % Significant increase 1.1 0.9 % NNH = 38 0.0 % Rivaroxaban Enoxaparin Significant increase in deep vein thrombosis, nonfatal PE, or death from any cause at 36 days (1.1% vs. 3.7%; ARR 2.6, 95% CI 1.5 to 3.7) Secondary outcomes Significant increase in major VTE (0.2% vs. 2%; ARR 1.7, 95% CI 1 to 2.5) Significant increase in DVT (0.8% vs. 3.4%; ARR 2.7, 95% CI 2.7 to 1.2) Safety outcomes No significant differences in major bleeding (0.3% vs. 0.1%, p=0.18). Conclusion In patients undergoing total hip arthroplasty, rivaroxaban was superior to enoxaparin with respect to deep vein thrombosis, nonfatal PE, or death from any cause at 36 days. Reference Eriksson BI, Borris LC, Friedman RJ et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2765-75. Open reference URL https://web.pathway.md/studies/reckGSL1azqrstvxv 2/2

6/29/23, 1:13 AM ReCOVer Pathway Feedback Search Clinical Topics Home Studies ReCOVer ReCOVer Disease Disease COVID 19 infection Long COVID Trial question What is the effect of CBT on severe fatigue following COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 73.0% female N = 114 27.0% male 114 patients (83 female, 31 male) Inclusion criteria: patients being severely fatigued 3-12 months following COVID-19 Key exclusion criteria: known psychiatric or somatic condition that can explain fatigue; current participation in a multi-disciplinary rehabilitation program aimed to ameliorate the consequences of COVID-19; objective hypoxemia at rest for which oxygen therapy at home is indicated Interventions N=57 CBT (targeting perpetuating factors of fatigue known as Fit after COVID, provided for 17 weeks) N=57 care as usual (no access to Fit after COVID, but not restricted in seeking care including psychological interventions for fatigue or other symptoms) https://web.pathway.md/studies/rechgo7mlSZoSlVKR 1/2 6/29/23, 1:13 AM ReCOVer Pathway Primary outcome Reduction in fatigue severity 39.9 39.9 31.1 29.9 19.9 10.0 Significant decrease 0.0 Cognitive behavioral therapy Care as usual Significant decrease in reduction in fatigue severity (31.1 vs. 39.9; AD -8.8, 95% CI -11.9 to -5.8) Secondary outcomes Significant increase in improvement in physical functioning (78.8 vs. 71.6; AD 7.1, 95% CI 2.9 to 11.3) Significant decrease in reduction in social impairment (11.8 vs. 18.4; AD -6.6, 95% CI -9.1 to -4.2) Significant decrease in reduction in somatic symptoms (8.2 vs. 10.1; AD -2, 95% CI -2.9 to -1) Conclusion In patients being severely fatigued 3-12 months following COVID-19, CBT was superior to care as usual with respect to reduction in fatigue severity. Reference Tanja A Kuut, Fabiola M ller, Irene Csorba et al. Efficacy of cognitive behavioral therapy targeting severe fatigue following COVID-19: results of a randomized controlled trial. Clin Infect Dis. 2023 May 8;ciad257. Open reference URL https://web.pathway.md/studies/rechgo7mlSZoSlVKR 2/2

6/29/23, 1:09 AM RECOVERY (aspirin) Pathway Feedback Search Clinical Topics Home Studies RECOVERY (aspirin) RECOVERY (aspirin) Disease COVID 19 infection Trial question What is the role of aspirin in hospitalized patients with COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 38.0% female N = 14892 62.0% male 14892 patients (5691 female, 9201 male) Inclusion criteria: adults hospitalized with COVID-19 Key exclusion criteria: age < 18 years; hypersensitivity to aspirin; a recent history of major bleeding; receipt of aspirin; antiplatelet treatment Interventions N=7351 aspirin (usual standard of care plus 150 mg aspirin daily until discharge) N=7541 usual care (usual standard of care alone) Primary outcome Death at day 28 17.0 % 17 17 https://web.pathway.md/studies/rect8fNWragMmTXoG 1/2 6/29/23, 1:09 AM RECOVERY (aspirin) Pathway 12.8 % 8.5 % 4.3 % No significant difference 0.0 % Aspirin Usual care No significant difference in death at day 28 (17% vs. 17%; RR 0.96, 96% CI 0.89 to 1.04) Secondary outcomes Significant increase in alive discharges from the hospital at day 28 (75% vs. 74%; RR 1.06, 95% CI 1.02 to 1.1) No significant difference in invasive mechanical ventilation or death (21% vs. 22%; RR 0.96, 96% CI 0.9 to 1.03) No significant difference in invasive mechanical ventilation (11% vs. 12%; RR 0.95, 95% CI 0.87 to 1.05) Safety outcomes No significant differences in thrombotic events, new cardiac arrhythmias. Significant difference in major bleeding (1.6% vs. 1.0%). Conclusion In adults hospitalized with COVID-19, aspirin was not superior to usual care with respect to death at day 28. Reference RECOVERY Collaborative Group. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2022 Jan 8;399(10320):143-151. Open reference URL https://web.pathway.md/studies/rect8fNWragMmTXoG 2/2

6/29/23, 1:09 AM RECOVERY (dexamethasone) Pathway Feedback Search Clinical Topics Home Studies RECOVERY (dexamethasone) RECOVERY (dexamethasone) Disease COVID 19 infection Trial question What is the effect of dexamethasone in patients hospitalized with severe COVID-19? Study design Single center Open label RCT Population Characteristics of study participants 36.0% female N = 6425 64.0% male 6425 patients (2338 female, 4087 male) Inclusion criteria: hospitalized patients with severe COVID-19 Key exclusion criteria: unavailability of dexamethasone, clinical judgement of patients' unsuitability for randomization Interventions N=2104 dexamethasone therapy (oral or IV dexamethasone for up to 10 days) N=4321 no dexamethasone (standard of care) Primary outcome Death at 28 days 25.7 25 7 % https://web.pathway.md/studies/recTe4qpX9Bzb2GZf 1/2 6/29/23, 1:09 AM 25.7 % RECOVERY (dexamethasone) Pathway 5 22.9 19.3 % 12.8 % Significant decrease 6.4 % NNT = 36 0.0 % Dexamethasone therapy No dexamethasone Significant decrease in death at 28 days (22.9% vs. 25.7%; RR 0.83, 95% CI 0.75 to 0.93) Secondary outcomes Borderline significant increase in discharge from hospital within 28 days (12 vs. 13; RR 1.1, 95% CI 1.03 to 1.17) Borderline significant decrease in invasive mechanical ventilation (5.7% vs. 7.8%; RR 0.77, 95% CI 0.62 to 0.95) Conclusion In hospitalized patients with severe COVID-19, dexamethasone therapy was superior to no dexamethasone with respect to death at 28 days. Reference RECOVERY Collaborative Group, Peter Horby, Wei Shen Lim et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. Open reference URL https://web.pathway.md/studies/recTe4qpX9Bzb2GZf 2/2

6/29/23, 1:09 AM RECOVERY (lopinavir-ritonavir) Pathway Feedback Search Clinical Topics Home Studies RECOVERY (lopinavir-ritonavir) RECOVERY (lopinavir-ritonavir) Disease COVID 19 infection Trial question What is the role of lopinavir-ritonavir in patients admitted to hospital with COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 5040 61.0% male 5040 patients (1963 female, 3077 male) Inclusion criteria: patients admitted to hospital with COVID-19 Key exclusion criteria: severe hepatic insufficiency, using medicinal products that are highly dependent on cytochrome P450 3A4 for clearance and for whom elevated plasma concentrations would be associated with serious or life-threatening events Interventions N=1616 lopinavir-ritonavir (400 mg and 100 mg by mouth every 12 h for 10 days or until discharge) N=3424 usual care (standard of care) Primary outcome https://web.pathway.md/studies/recNgo5eyBTbG2PgA 1/2 6/29/23, 1:09 AM RECOVERY (lopinavir-ritonavir) Pathway Death from all causes at 28 days 23.0 % 23 22 17.3 % 11.5 % 5.8 % No significant difference 0.0 % Lopinavir-ritonavir Usual care No significant difference in death from all causes at 28 days (23% vs. 22%; RR 1.03, 95% CI 0.91 to 1.17) Secondary outcomes No significant difference in the rate of discharge from hospital within 28 days (69% vs. 70%; RR 0.98, 95% CI 0.91 to 1.05) No significant difference in receipt of invasive mechanical ventilation or death (29% vs. 27%; RR 1.09, 95% CI 0.99 to 1.2) No significant difference in invasive mechanical ventilation (10% vs. 9%; RR 1.15, 95% CI 0.95 to 1.39) Safety outcomes No significant difference in cardiac arrhythmias and requirement of renal dialysis or hemofiltration. Conclusion In patients admitted to hospital with COVID-19, lopinavir-ritonavir was not superior to usual care with respect to death from all causes at 28 days. Reference Peter W Horby, Marion Mafham, Jennifer L Bell et al. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020 Oct 5;396(10259):1345-1352. Open reference URL https://web.pathway.md/studies/recNgo5eyBTbG2PgA 2/2

6/29/23, 1:09 AM RED-HF Pathway Feedback Search Clinical Topics Home Studies RED HF RED HF Disease Heart failure Trial question What is the role of darbepoetin alfa in patients with systolic HF and mild-to-moderate anemia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 41.0% female N = 2278 59.0% male 2278 patients (944 female, 1334 male) Inclusion criteria: patients with systolic HF and mild-to-moderate anemia Key exclusion criteria: transferrin saturation < 15%, bleeding or other correctable causes of anemia, serum creatinine level > 3 mg/dL, and a BP > 160/100 mmHg Interventions N=1136 darbepoetin alfa (subcutaneous starting dose of 0.75 g/kg of body weight once every 2 weeks once Hgb level of 13.0 g/dL achieved) N=1142 placebo (matching dose adjustments) Primary outcome Death from any cause or hospitalization for worsening heart failure https://web.pathway.md/studies/rechWH6MjiwTLqvuE 1/2 6/29/23, 1:09 AM RED-HF Pathway 50.7 % 50.7 49.5 38.0 % 25.4 % 12.7 % No significant difference 0.0 % Darbepoetin alfa Placebo No significant difference in death from any cause or hospitalization for worsening HF (50.7% vs. 49.5%; HR 1.01, 95% CI 0.9 to 1.13) Secondary outcomes No significant difference in fatal or nonfatal stroke (3.7% vs. 2.7%; HR 1.33, 95% CI 0.83 to 2.12) No significant difference in death (41.7% vs. 40.1%; HR 1.04, 95% CI 0.92 to 1.19) Safety outcomes No significant difference in cancer-related adverse events. Significant differences in thromboembolic adverse events (13.5% vs. 10.0%, p = 0.01). Conclusion In patients with systolic HF and mild-to-moderate anemia, darbepoetin alfa was not superior to placebo with respect to death from any cause or hospitalization for worsening HF. Reference Swedberg K, Young JB, Anand IS et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013 Mar 28;368(13):1210-9. Open reference URL https://web.pathway.md/studies/rechWH6MjiwTLqvuE 2/2

6/29/23, 1:09 AM REDECAP Pathway Feedback Search Clinical Topics Home Studies REDECAP REDECAP Disease Weaning from mechanical ventil Trial question What is the role of high-flow oxygen and suctioning for tracheostomy decannulation in critically ill adults? Study design Multi-center Open label RCT Population Characteristics of study participants 32.0% female N = 330 68.0% male 330 patients (105 female, 225 male) Inclusion criteria: critically ill adults in the ICU who had a tracheostomy tube after being weaned from mechanical ventilation Key exclusion criteria: contraindication for decannulation at randomization, an age < 18 years, expected death before hospital discharge Interventions N=169 intervention (assessment of suctioning frequency plus receipt of continuous high-flow oxygen therapy) N=161 control (24-hour capping trial plus receipt of intermittent high-flow oxygen therapy) https://web.pathway.md/studies/recin0I7waNC91Gde 1/2 6/29/23, 1:09 AM REDECAP Pathway Primary outcome Time to decannulation 13.0 days 13 9.8 days 6.5 days 6 3.3 days No significant difference 0.0 days Intervention Control No significant difference in time to decannulation (6 days vs. 13 days; AD -7 days, 95% CI -9 to 5) Secondary outcomes Significant decrease in decannulation failure (2.4% vs. 5.6%; ARD -3.2, 95% CI -8.1 to -1.2) No significant difference in weaning failure (6.5% vs. 16.8%; ARD -10.3, 95% CI -17.4 to 3.4) No significant difference in duration of hospital stay (48 days vs. 62 days; AD -14 days, 95% CI -33 to 9) Conclusion In critically ill adults in the ICU who had a tracheostomy tube after being weaned from mechanical ventilation, intervention was superior to control with respect to time to decannulation. Reference Gonzalo Hern ndez Mart nez, Maria-Luisa Rodriguez, Maria-Concepci n Vaquero et al. High-Flow Oxygen with Capping or Suctioning for Tracheostomy Decannulation. N Engl J Med. 2020 Sep 10;383(11):1009-1017. Open reference URL https://web.pathway.md/studies/recin0I7waNC91Gde 2/2

6/29/23, 1:09 AM REDUCE (COPD) Pathway Feedback Search Clinical Topics Home Studies REDUCE COPD REDUCE COPD Disease Chronic obstructive pulmonary Trial question Is short-term systemic corticosteroid therapy noninferior to conventional corticosteroid therapy in patients with acute exacerbation of COPD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.4% female N = 314 60.6% male 314 patients (123 female, 188 male) Inclusion criteria: patients presenting to the emergency department with acute COPD exacerbation Key exclusion criteria: history of asthma, ratio of FEV in 1 second to FVC > 70% as evaluated by bedside postbronchodilator spirometry, radiological diagnosis of pneumonia, estimated survival < 6 months due to severe comorbidity, pregnancy or lactation Interventions N=156 short-term treatment (40 mg of prednisone daily for 5 days) N=155 conventional treatment (40 mg of prednisone daily for 14 days) https://web.pathway.md/studies/recXMiVhWbfjPnUJn 1/2 6/29/23, 1:09 AM REDUCE (COPD) Pathway Primary outcome Recurrent chronic obstructive pulmonary disease exacerbation at 6 months 36.8 % 36.8 35.9 27.6 % 18.4 % Difference not exceeding nonferiority margin 9.2 % 0.0 % Short-term treatment Conventional treatment Difference not exceeding nonferiority margin in recurrent COPD exacerbation at 6 months (35.9% vs. 36.8%; HR 0.95, 95% CI 0.7 to 1.29) Secondary outcomes No significant difference in need for mechanical ventilation (11% vs. 13.6%; OR 0.78, 95% CI 0.37 to 1.63) Significant increase in hospital stay (8 vs. 9; HR 1.25, 95% CI 0.99 to 1.59) Safety outcomes No significant differences in treatment-associated adverse reactions, including hyperglycemia and hypertension. Significant differences in mean cumulative prednisone dose (379 vs. 793 mg, p < 0.001). Conclusion In patients presenting to the emergency department with acute COPD exacerbation, short-term treatment was noninferior to conventional treatment with respect to recurrent COPD exacerbation at 6 months. Reference Leuppi JD, Schuetz P, Bingisser R et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013 Jun 5;309(21):2223-31. Open reference URL https://web.pathway.md/studies/recXMiVhWbfjPnUJn 2/2

6/29/23, 1:09 AM REDUCE (delirium) Pathway Feedback Search Clinical Topics Home Studies REDUCE (delirium) REDUCE (delirium) Disease ICU delirium Trial question What is the effect of haloperidol among critically ill patients with a high risk of delirium? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.0% female N = 1439 62.0% male 1439 patients (546 female, 893 male) Inclusion criteria: critically ill adults at high risk of delirium whose ICU stay was at least a day Key exclusion criteria: delirium prior to inclusion; Parkinson's disease, history of acute neurological conditions; history of psychiatric disease and use of antipsychotic agents; known allergy or intolerance to haloperidol Interventions N=732 haloperidol (2 mg intravenous infusion TID) N=707 placebo (intravenous infusion of 0.9% sodium chloride TID) Primary outcome Incidence of delirium at 28 days https://web.pathway.md/studies/rec5mxH2RbaYZXaKU 1/2 6/29/23, 1:09 AM REDUCE (delirium) Pathway 33.3 % 33.3 33 25.0 % 16.6 % 8.3 % No significant difference 0.0 % Haloperidol Placebo No significant difference in incidence of delirium at 28 days (33.3% vs. 33%; AD 0.4%, 95% CI -4.6 to 5.4) Safety outcomes No significant difference in reported adverse events. Conclusion In critically ill adults at high risk of delirium whose ICU stay was at least a day, haloperidol was not superior to placebo with respect to incidence of delirium at 28 days. Reference Mark van den Boogaard, Arjen J C Slooter, Roger J M Br ggemann et al. Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium: The REDUCE Randomized Clinical Trial. JAMA. 2018 Feb 20;319(7):680-690. Open reference URL https://web.pathway.md/studies/rec5mxH2RbaYZXaKU 2/2

6/29/23, 1:09 AM REDUCE-IT Pathway Feedback Search Clinical Topics Home Studies REDUCE IT REDUCE IT Disease Disease Dyslipidemia Hypertriglyceridemia Trial question What is the role of icosapent ethyl in patients with elevated triglyceride levels despite statins? Study design Multi-center Double blinded RCT Population Characteristics of study participants 29.0% female N = 8179 71.0% male 8179 patients (2357 female, 5822 male) Inclusion criteria: patients with elevated triglyceride levels despite the use of statins Key exclusion criteria: severe HF, active severe liver disease, history of acute or chronic pancreatitis, a planned coronary intervention or surgery, a glycated Hgb level > 10.0% Interventions N=4089 icosapent ethyl (2 g BID with food) N=4090 placebo (mineral oil BID) Primary outcome Major adverse cardiovascular events 22.0 % 22 https://web.pathway.md/studies/rec3pKWLW7X9jdi1e 1/2 6/29/23, 1:09 AM REDUCE-IT Pathway 17.2 16.5 % 11.0 % Significant decrease 5.5 % NNT = 21 0.0 % Icosapent ethyl Placebo Significant decrease in major adverse cardiovascular events (17.2% vs. 22%; HR 0.75, 95% CI 0.68 to 0.83) Secondary outcomes Significant decrease in CV death, nonfatal MI or nonfatal CVA (11.2% vs. 14.8%; HR 0.74, 95% CI 0.65 to 0.83) Significant decrease in cardiovascular death (4.3% vs. 5.2%; HR 0.8, 95% CI 0.66 to 0.98) No significant difference in death from any cause (6.7% vs. 7.6%; HR 0.87, 95% CI 0.74 to 1.02) Safety outcomes No significant differences in serious adverse bleeding events (2.7% vs. 2.1%, p=0.06) and serious adverse event, pneumonia (2.6% vs. 2.9%, p=0.42). Significant differences in a larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for AF or flutter (3.1% vs. 2.1%, p = 0.004). Conclusion In patients with elevated triglyceride levels despite the use of statins, icosapent ethyl was superior to placebo with respect to major adverse cardiovascular events. Reference Bhatt DL, Steg PG, Miller M et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22. Open reference URL https://web.pathway.md/studies/rec3pKWLW7X9jdi1e 2/2

6/29/23, 1:09 AM RELATIVITY-047 Pathway Feedback Search Clinical Topics Home Studies RELATIVITY 047 RELATIVITY 047 Disease Cutaneous melanoma Trial question Is relatlimab-nivolumab combination therapy superior to nivolumab monotherapy in patients with untreated advanced melanoma? Study design Multi-center Double blinded RCT Population Characteristics of study participants 42.0% female N = 714 58.0% male 714 patients (298 female, 416 male) Inclusion criteria: patients with previously untreated metastatic or unresectable melanoma Key exclusion criteria: uveal melanoma and active, untreated brain or leptomeningeal metastases Interventions N=355 relatlimab-nivolumab (intravenous infusion of 160 mg relatlimab and 480 mg nivolumab in a fixed-dose combination every 4 weeks) N=359 nivolumab (intravenous infusion of 480 mg every 4 weeks) Primary outcome Median progression-free survival https://web.pathway.md/studies/rec1UylQmvwqScDQn 1/2 6/29/23, 1:09 AM RELATIVITY-047 Pathway 10.1 months 10.1 7.6 months 5.0 months 4.6 2.5 months Significant increase 0.0 months Relatlimab-nivolumab Nivolumab Significant increase in median progression-free survival (10.1 months vs. 4.6 months; HR 1.33, 95% CI 1.09 to 1.61) Secondary outcomes Borderline significant increase in progression-free survival for 1% lymphocyte-activation gene 3 expression (12.6 months vs. 4.8 months; HR 1.33, 95% CI 1.05 to 1.69) No significant difference in progression-free survival for 1% programmed death ligand 1 expression (15.7 months vs. 14.7 months; HR 1.05, 95% CI 0.75 to 1.47) No significant difference in progression-free survival with BRAF mutation (10.1 months vs. 4.6 months; HR 1.35, 95% CI 0.97 to 1.85) Safety outcomes No significant difference in health-related quality of life. Conclusion In patients with previously untreated metastatic or unresectable melanoma, relatlimab-nivolumab was superior to nivolumab with respect to median progression-free survival. Reference Hussein A Tawbi, Dirk Schadendorf, Evan J Lipson et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. Open reference URL https://web.pathway.md/studies/rec1UylQmvwqScDQn 2/2

6/29/23, 1:10 AM RELAX Pathway Feedback Search Clinical Topics Home Studies RELAX RELAX Disease Heart failure Trial question What is the effect of PDE5 inhibition on exercise capacity and clinical status in patients with HFpEF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 48.0% female N = 216 52.0% male 216 patients (104 female, 112 male) Inclusion criteria: stable outpatients with HF, ejection fraction 50%, elevated N-terminal brain- type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity Key exclusion criteria: pericardial disease, hypertrophic cardiomyopathy, primary pulmonary arteriopathy, anemia, severe liver disease, severe renal dysfunction, or listed for cardiac transplantation Interventions N=113 sildenafil (administered PO at 20 mg, TID for 12 weeks, followed by 60 mg, TID for 12 weeks) https://web.pathway.md/studies/reclymLtwkkpeEk33 1/2 6/29/23, 1:10 AM RELAX Pathway N=103 placebo (matching placebo for 24 weeks) Primary outcome Mean clinical status rank score at 24 weeks 95.8 95.8 94.2 71.8 47.9 23.9 No significant difference 0.0 Sildenafil Placebo No significant difference in mean clinical status rank score at 24 weeks (94.2 vs. 95.8; MD 1.6, 95% CI -13.87 to 17.07) Secondary outcomes No significant difference in change in 6-minute walk distance (5 m vs. 15 m; MD 10, 95% CI -169.3 to 189.3) Safety outcomes No significant differences in adverse events (80% vs. 76%, p=0.49) and serious adverse events (22% vs. 16%, p=0.22). Conclusion In stable outpatients with HF, ejection fraction 50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity, sildenafil was not superior to placebo with respect to mean clinical status rank score at 24 weeks. Reference Redfield MM, Chen HH, Borlaug BA et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA. 2013 Mar 27;309(12):1268-77. Open reference URL https://web.pathway.md/studies/reclymLtwkkpeEk33 2/2

6/29/23, 1:10 AM RELIEF Pathway Feedback Search Clinical Topics Home Studies RELIEF RELIEF Trial question What is the role of restrictive fluid regimen among patients at increased risk for complications during major abdominal surgery? Study design Multi-center Open label RCT Population Characteristics of study participants 48.0% female N = 3000 52.0% male 3000 patients (1429 female, 1554 male) Inclusion criteria: patients who had an increased risk of complications while undergoing major abdominal surgery Key exclusion criteria: undergoing urgent or time-critical surgery, liver resection, or less extensive surgery, or end-stage kidney failure requiring dialysis Interventions N=1490 a restrictive fluid regimen (a median intravenous-fluid intake of 3.7 L) N=1493 a liberal fluid regimen (a median intravenous-fluid intake of 6.1 L) Primary outcome Disability-free survival at 1 year 82.3 % 82.3 81.9 61.7 % 41.1 % 20.6 % https://web.pathway.md/studies/recqW2vE0J1HecZzC 1/2 6/29/23, 1:10 AM RELIEF Pathway No significant difference 0.0 % A restrictive fluid regimen A liberal fluid regimen No significant difference in disability-free survival at 1 year (81.9% vs. 82.3%; HR 1.05, 95% CI 0.88 to 1.24) Secondary outcomes No significant difference in septic outcome or death (21.8% vs. 19.8%; HR 1.1, 95% CI 0.96 to 1.27) Significant increase in surgical site infection (16.5% vs. 13.6%; HR 1.22, 95% CI 1.03 to 1.45) No significant difference in sepsis (10.6% vs. 8.7%; HR 1.22, 95% CI 0.98 to 1.52) Safety outcomes No significant differences in pneumonia, pulmonary edema, death. Significant differences in AKI (8.6% vs. 5.0%), RRT (0.9% vs. 0.3%). Conclusion In patients who had an increased risk of complications while undergoing major abdominal surgery, a restrictive fluid regimen was not superior to a liberal fluid regimen with respect to a disability-free survival at 1 year. Reference Paul S Myles, Rinaldo Bellomo, Tomas Corcoran et al. Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery. N Engl J Med. 2018 Jun 14;378(24):2263-2274. Open reference URL https://web.pathway.md/studies/recqW2vE0J1HecZzC 2/2

6/29/23, 1:10 AM REMAP-CAP IL-6 Pathway Feedback Search Clinical Topics Home Studies REMAP CAP IL 6 REMAP CAP IL 6 Disease COVID 19 infection Trial question What is the effect of IL-6 receptor antagonists, tocilizumab and sarilumab, in critically ill patients with COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 27.0% female N = 865 73.0% male 865 patients (236 female, 629 male) Inclusion criteria: adult patients with COVID-19, within 24 hours after starting organ support in the ICU Key exclusion criteria: imminent death, or previous participation in REMAP-CAP within 90 days Interventions N=353 + 48 IL-6 receptor antagonists (intravenous infusion of tocilizumab at a dose of 8 mg/kg of body weight or sarilumab 400 mg once only) N=402 control (standard care) Primary outcome https://web.pathway.md/studies/recq0l3XSW6W1RsYU 1/2 6/29/23, 1:10 AM REMAP-CAP IL-6 Pathway Borderline significant increase in median organ support-free days (OR 1.64, 95% CI 1.25 to 2.14) Secondary outcomes Borderline significant increase in death in the hospital at 90 days (28% vs. 36%; OR 1.64, 95% CI 1.14 to 2.35) Borderline significant increase in respiratory support-free days (OR 1.73, 95% CI 1.31 to 2.27) Borderline significant increase in cardiovascular support-free days (19 days vs. 15 days; OR 1.68, 95% CI 1.25 to 2.24) Safety outcomes No significant difference in serious adverse events with tocilizumab and control. Significant difference in serious adverse events with sarilumab and control (0% vs. 2.7%). Conclusion In adult patients with COVID-19, within 24 hours after starting organ support in the ICU, IL-6 receptor antagonists were superior to control with respect to median organ support-free days. Reference REMAP-CAP Investigators, Anthony C Gordon, Paul R Mouncey et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Apr 22;384(16):1491-1502. Open reference URL https://web.pathway.md/studies/recq0l3XSW6W1RsYU 2/2

6/29/23, 1:10 AM REMICRUSH Pathway Feedback Search Clinical Topics Home Studies REMICRUSH REMICRUSH Trial question Is remifentanil noninferior to a rapid-onset neuromuscular blocker in patients at risk of aspiration during rapid sequence intubation in the operating room? Study design Multi-center Open label RCT Population Characteristics of study participants 50.0% female N = 1150 50.0% male 1150 patients (573 female, 572 male) Inclusion criteria: adults at risk of aspiration who underwent tracheal intubation in the operating room Key exclusion criteria: planned impossible intubation; contraindication to use of succinylcholine and rocuronium; cardiac arrest; preoperative hypoxemia; hemodynamic shock Interventions N=575 remifentanil (an intravenous dose of 3-4 g/kg, immediately after injection of a hypnotic) N=575 neuromuscular blockers (intravenous succinylcholine or rocuronium 1 mg/kg, immediately after injection of a hypnotic) Primary outcome Successful tracheal intubation on first attempt without major complications 71.6 % 71.6 66.1 53.7 % 35.8 % https://web.pathway.md/studies/recl3zjpxLgA7GPGI 1/2 6/29/23, 1:10 AM REMICRUSH Pathway 17.9 % Difference exceeding nonferiority margin 0.0 % Remifentanil Neuromuscular blockers Difference exceeding nonferiority margin in successful tracheal intubation on first attempt without major complications (66.1% vs. 71.6%; AD -6.1%, 95% CI -11.6 to -0.5) Secondary outcomes Significant increase in intubation difficulty scale score (3 vs. 2.7; AD 0.4, 95% CI 0.2 to 0.6) No significant difference in postoperative desaturation 92% (10.3% vs. 9.9%; AD 0.6%, 95% CI -2.7 to 3.9) Safety outcomes No significant difference in severe adverse events and hemodynamic instability. Conclusion In adults at risk of aspiration who underwent tracheal intubation in the operating room, remifentanil was not noninferior to neuromuscular blockers with respect to successful tracheal intubation on first attempt without major complications. Reference Nicolas Grillot, Gilles Lebuffe, Olivier Huet et al. Effect of Remifentanil vs Neuromuscular Blockers During Rapid Sequence Intubation on Successful Intubation Without Major Complications Among Patients at Risk of Aspiration. JAMA. 2023 Jan 3;329(1):28-38. Open reference URL https://web.pathway.md/studies/recl3zjpxLgA7GPGI 2/2

6/29/23, 1:10 AM RENAAL Pathway Feedback Search Clinical Topics Home Studies RENAAL RENAAL Disease Disease Chronic kidney disease Diabetes mellitus type 2 Trial question What is the role of losartan in patients with T2DM and diabetic nephropathy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 1513 63.0% male 1513 patients (557 female, 956 male) Inclusion criteria: patients with T2DM and diabetic nephropathy Key exclusion criteria: diagnosis of T1DM or nondiabetic renal disease, including renal artery stenosis, myocardial infarction, CABG within the previous month, cerebrovascular accident or percutaneous transluminal coronary angioplasty within the previous six months Interventions N=751 losartan (50 to 100 mg once daily in addition to conventional antihypertensive treatment) N=762 placebo (matching placebo daily plus conventional antihypertensive treatment) Primary outcome Death, end-stage renal renal disease, or doubling of serum creatinine https://web.pathway.md/studies/recC7nfcGcEOvidjG 1/2 6/29/23, 1:10 AM RENAAL Pathway 47.1 % 47.1 43.5 35.3 % 23.6 % Significant increase 11.8 % NNH = 28 0.0 % Losartan Placebo Significant increase in death, end-stage renal renal disease, or doubling of the serum creatinine (43.5% vs. 47.1%; RR 16, 95% CI 2 to 28) Secondary outcomes Significant increase in first hospitalization from HF (11.9% vs. 16.7%; RR 32, 95% CI 9.68 to 54.32) Significant increase in end stage renal disease (19.6% vs. 25.5%; RR 28, 95% CI 11 to 42) Safety outcomes Significant differences in reduction in the level of proteinuria with losartan compared with placebo (RR 35%, p < 0.001). Conclusion In patients with T2DM and diabetic nephropathy, losartan was superior to placebo with respect to death, end-stage renal renal disease, or doubling of the serum creatinine. Reference Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001 Sep 20;345(12):861-9. Open reference URL https://web.pathway.md/studies/recC7nfcGcEOvidjG 2/2

6/29/23, 1:10 AM RENOVATE-COMPLEX-PCI Pathway Feedback Search Clinical Topics Home Studies RENOVATE COMPLEX PCI RENOVATE COMPLEX PCI Disease Disease Disease Coronary artery disease Non-ST-elevation myocardial inf ST-elevat Trial question What is the role of intravascular imaging-guided PCI in patients with complex coronary artery lesions? Study design Multi-center Open label RCT Population Characteristics of study participants 21.0% female N = 1639 79.0% male 1639 patients (339 female, 1300 male) Inclusion criteria: adult patients undergoing PCI for complex coronary artery lesions Key exclusion criteria: coronary lesions not appropriate for PCI; cardiogenic shock at presentation; pregnancy; known hypersensitivity or contraindication to aspirin, clopidogrel, prasugrel, ticagrelor Interventions N=1092 intravascular imaging (intravascular imaging-guided PCI with either intravascular ultrasonography or optical coherence tomography) N=547 angiography (angiography-guided PCI) Primary outcome https://web.pathway.md/studies/rect45iiZwDPB5P9y 1/2 6/29/23, 1:10 AM RENOVATE-COMPLEX-PCI Pathway Composite of death from cardiac causes, target-vessel-related myocardial infarction or revascularization 12.3 % 12.3 9.2 % 7.7 6.2 % Significant decrease 3.1 % NNT = 22 0.0 % Intravascular imaging Angiography Significant decrease in composite of death from cardiac causes, target-vessel-related myocardial infarction or revascularization (7.7% vs. 12.3%; HR 0.64, 95% CI 0.45 to 0.89) Secondary outcomes Borderline significant decrease in target-vessel failure without procedure-related myocardial infarction (5.1% vs. 8.7%; HR 0.59, 95% CI 0.39 to 0.9) Borderline significant decrease in composite of target-vessel-related myocardial infarction and death from cardiac causes (5.3% vs. 8.5%; HR 0.63, 95% CI 0.42 to 0.93) No significant difference in death from any cause (5.3% vs. 6.4%; HR 0.71, 95% CI 0.44 to 1.15) Safety outcomes No significant difference in procedure-related complications. Conclusion In adult patients undergoing PCI for complex coronary artery lesions, intravascular imaging was superior to angiography with respect to the composite of death from cardiac causes, target-vessel- related myocardial infarction or revascularization. Reference Joo Myung Lee, Ki Hong Choi, Young Bin Song et al. Intravascular Imaging-Guided or Angiography- Guided Complex PCI. N Engl J Med. 2023 May 4;388(18):1668-1679. Open reference URL https://web.pathway.md/studies/rect45iiZwDPB5P9y 2/2

6/29/23, 1:10 AM REPRISE Pathway Feedback Search Clinical Topics Home Studies REPRISE REPRISE Disease Autosomal dominant polycystic Trial question What is the effect of tolvaptan in patients with later-stage autosomal dominant polycystic kidney disease? Study design Multi-center Double blinded RCT Population Characteristics of study participants 50.0% female N = 1370 50.0% male 1370 patients (690 female, 680 male) Inclusion criteria: patients with later-stage autosomal dominant polycystic kidney disease Key exclusion criteria: pregnant or breastfeeding women, need for chronic diuretic use, hepatic impairment or liver function abnormalities other than that expected for ADPKD, advanced diabetes, or contraindications to required trial assessments Interventions N=683 tolvaptan (daily morning and after doses of 90 mg and 30 mg; 60 mg and 30 mg; or 45 mg and 15 mg, or less for 12 months) N=687 placebo (mock morning and afternoon doses of 90 mg and 30 mg; 60 mg and 30 mg; or 45 mg and 15 mg, or less for 12 months) https://web.pathway.md/studies/recJGuV16VwtxRLiD 1/2 6/29/23, 1:10 AM REPRISE Pathway Primary outcome Significant increase in decline in estimated GFR at 1 year (-2.34 vs. -3.61; difference 1.27, 95% CI 0.86 to 1.68) Secondary outcomes Significant increase in slopes of the change in the estimated GFR at 1 year (-3.16 vs. -4.17; difference 1.01, 95% CI 0.62 to 1.4) Safety outcomes No significant difference in the rates of new or worsening adverse events. Conclusion In patients with later-stage autosomal dominant polycystic kidney disease, tolvaptan was superior to placebo with respect to decline in estimated GFR at 1 year. Reference Torres VE, Chapman AB, Devuyst O et al. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2017 Nov 16;377(20):1930-1942. Open reference URL https://web.pathway.md/studies/recJGuV16VwtxRLiD 2/2

6/29/23, 1:10 AM RESCUE BT Pathway Feedback Search Clinical Topics Home Studies RESCUE BT RESCUE BT Disease Acute ischemic stroke Trial question What is the role of intravenous tirofiban in patients with large vessel occlusion acute ischemic stroke undergoing endovascular thrombectomy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 41.0% female N = 948 59.0% male 948 patients (391 female, 557 male) Inclusion criteria: patients with stroke and proximal intracranial large vessel occlusion presenting < 24 hours of time last known well Key exclusion criteria: intracranial hemorrhage; dual antiplatelet therapy < 1 week of the index stroke; receipt of intravenous thrombolysis after stroke onset; renal insufficiency Interventions N=463 tirofiban (bolus of 10 g/kg, followed by continuous infusion of 0.15 g/kg/min before endovascular thrombectomy) N=485 placebo (saline placebo before endovascular thrombectomy) https://web.pathway.md/studies/recs7Wc0idF2hf9yw 1/2 6/29/23, 1:10 AM RESCUE BT Pathway Primary outcome Disability level, modified rankin scale score, at day 90 3.0 3 3 2.3 1.5 0.8 No significant difference 0.0 Tirofiban Placebo No significant difference in disability level, mRS score, at day 90 (3 vs. 3; OR 1.11, 95% CI 0.86 to 1.36) Secondary outcomes No significant difference in mRS score of 0-2 at day 90 (49.2% vs. 45.2%; OR 1.18, 95% CI 0.92 to 1.59) No significant difference in European Quality 5-Dimension 5-Level self-report questionnaire score at day 90 (0.71 vs. 0.66; AD 0.05, 95% CI -0.04 to 0.14) Safety outcomes No significant differences in symptomatic intracranial hemorrhage < 48 hours, mortality at day 90. Significant difference in any radiologic intracranial hemorrhage (34.9% vs. 28.0%). Conclusion In patients with stroke and proximal intracranial large vessel occlusion presenting < 24 hours of time last known well, tirofiban was not superior to placebo with respect to disability level, mRS score, at day 90. Reference RESCUE BT Trial Investigators, Zhongming Qiu, Fengli Li et al. Effect of Intravenous Tirofiban vs Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke: The RESCUE BT Randomized Clinical Trial. JAMA. 2022 Aug 9;328(6):543-553. Open reference URL https://web.pathway.md/studies/recs7Wc0idF2hf9yw 2/2

6/29/23, 1:11 AM RESCUE-Japan LIMIT Pathway Feedback Search Clinical Topics Home Studies RESCUE Japan LIMIT RESCUE Japan LIMIT Disease Acute ischemic stroke Trial question What is the role of endovascular therapy in patients with acute stroke with a large ischemic region? Study design Multi-center Open label RCT Population Characteristics of study participants 44.0% female N = 203 56.0% male 203 patients (90 female, 113 male) Inclusion criteria: patients with occlusion of large cerebral vessels and sizable strokes on imaging Key exclusion criteria: significant cerebral mass effect with midline shift; acute intracranial hemorrhage on CT or MRI; high risk of hemorrhage; known allergy to contrast agents Interventions N=101 endovascular therapy (acute thrombectomy plus best medical treatment) N=102 medical care (best medical treatment alone) Primary outcome Percentage of patients with modified Rankin scale score of 0-3 at 90 days 31.0 % 31 https://web.pathway.md/studies/rec36CHQqt0997B3f 1/2 6/29/23, 1:11 AM RESCUE-Japan LIMIT Pathway 3 23.3 % 15.5 % 12.7 Significant increase 7.8 % NNH = 5 0.0 % Endovascular therapy Medical care Significant increase in the percentage of patients with mRS score of 0-3 at 90 days (31% vs. 12.7%; RR 2.43, 95% CI 1.35 to 4.37) Secondary outcomes Borderline significant increase in the percentage of patients with of 8 points on the NIHSS score at 48 hours (31% vs. 8.8%; RR 3.51, 95% CI 1.76 to 7) No significant difference in the percentage of patients mRS score of 0-2 at 90 days (14% vs. 7.8%; RR 1.79, 95% CI 0.78 to 4.07) Safety outcomes No significant differences in symptomatic intracranial hemorrhage at 48 hours, death at 90 days, recurrence of an ischemic stroke at 90 days. Significant difference in intracranial hemorrhage within 48 hours (58.0% vs. 31.4%). Conclusion In patients with occlusion of large cerebral vessels and sizable strokes on imaging, endovascular therapy was superior to medical care with respect to the percentage of patients with mRS score of 0-3 at 90 days. Reference Shinichi Yoshimura, Nobuyuki Sakai, Hiroshi Yamagami et al. Endovascular Therapy for Acute Stroke with a Large Ischemic Region. N Engl J Med. 2022 Apr 7;386(14):1303-1313. Open reference URL https://web.pathway.md/studies/rec36CHQqt0997B3f 2/2

6/29/23, 1:12 AM RESCUEicp Pathway Feedback Search Clinical Topics Home Studies RESCUEicp RESCUEicp Disease Disease Cerebral edema Traumatic brain injury Trial question What is the effect of decompressive craniectomy on clinical outcomes in patients with refractory traumatic intracranial hypertension? Study design Multi-center Open label RCT Population Characteristics of study participants 19.4% female N = 408 80.6% male 408 patients (76 female, 321 male) Inclusion criteria: patients with TBI and refractory elevated ICP (> 25 mmHg) Key exclusion criteria: bilateral fixed and dilated pupils, bleeding diathesis, or an injury that was deemed to be unsurvivable Interventions N=202 surgical (decompressive craniectomy with medical therapy) N=196 medical (continued medical therapy with the option of adding barbiturates to reduce ICP) Primary outcome Death at 6 months https://web.pathway.md/studies/reccZYePxtkCyfvUk 1/2 6/29/23, 1:12 AM RESCUEicp Pathway 48.9 % 48.9 36.7 % 26.9 24.4 % Significant decrease 12.2 % NNT = 5 0.0 % Surgical Medical Significant decrease in death at 6 months (26.9% vs. 48.9%; AD -22.1%, 95% CI -31.5 to -12.7) Safety outcomes Significant differences in adverse events (16.3% vs. 9.2%, p = 0.03) and hours with ICP > 25 mmHg (median, 5.0 vs. 17.0 hours, p < 0.001). Conclusion In patients with TBI and refractory elevated ICP (> 25 mmHg), surgical was superior to medical with respect to death at 6 months. Reference Hutchinson PJ, Kolias AG, Timofeev IS et al. Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension. N Engl J Med. 2016 Sep 22;375(12):1119-30. Open reference URL https://web.pathway.md/studies/reccZYePxtkCyfvUk 2/2

6/29/23, 1:12 AM RESPECT Pathway Feedback Search Clinical Topics Home Studies RESPECT RESPECT Disease Disease Disease Acute ischemic stroke Patent foramen ovale Transient Trial question What is the role of closure of patent foramen ovale in patients who had a cryptogenic stroke? Study design Multi-center Open label RCT Population Characteristics of study participants 45.0% female N = 980 55.0% male 980 patients (444 female, 536 male) Inclusion criteria: patients who have had a cryptogenic stroke, and a patent foramen ovale identified by means of transesophageal echocardiography Key exclusion criteria: large-vessel disease, any cardioembolic source, a lacunar infarct that was probably due to intrinsic small-vessel disease, or an arterial hypercoagulable state Interventions N=499 patent foramen ovale closure (insertion of Amplatzer PFO Occluder) N=481 medical therapy (receipt of 1 antiplatelet medications or warfarin) Primary outcome Recurrent stroke https://web.pathway.md/studies/rec0R5rmojEBhKWn4 1/2 6/29/23, 1:12 AM RESPECT Pathway 3.3 % 3.3 2.5 % 1.8 1.6 % 0.8 % No significant difference 0.0 % Patent foramen ovale closure Medical therapy No significant difference in recurrent stroke (1.8% vs. 3.3%; HR 0.49, 95% CI 0.22 to 1.11) Secondary outcomes Significant decrease in recurrence of stroke, as treated cohort (1.1% vs. 3.3%; HR 0.27, 95% CI 0.1 to 0.75) Safety outcomes No significant difference in serious adverse events and AF. Conclusion In patients who have had a cryptogenic stroke, and a patent foramen ovale identified by means of transesophageal echocardiography, patent foramen ovale closure was not superior to medical therapy with respect to recurrent stroke. Reference Carroll JD, Saver JL, Thaler DE et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013 Mar 21;368(12):1092-100. Open reference URL https://web.pathway.md/studies/rec0R5rmojEBhKWn4 2/2

6/29/23, 1:12 AM REST Pathway Feedback Search Clinical Topics Home Studies REST REST Trial question What is the effect of lower tidal volume ventilation facilitated by extracorporeal CO2 removal in patients with acute hypoxemic respiratory failure? Study design Multi-center Open label RCT Population Characteristics of study participants 35.0% female N = 412 65.0% male 412 patients (143 female, 269 male) Inclusion criteria: adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure Key exclusion criteria: receipt of invasive mechanical ventilation > 7 days, contraindication to limited systemic anticoagulation with heparin, untreated PE, pleural effusion, pneumothorax, or LV failure or fluid overload Interventions N=202 extracorporeal CO2 removal (lower tidal volume ventilation facilitated by extracorporeal CO2 removal for at least 48 hours) N=210 standard care (standard care with conventional low tidal volume ventilation) Primary outcome Death from all causes at 90 days 41.5 % 41.5 39.5 31.1 % 20.8 % https://web.pathway.md/studies/reciheXMQpjy8eKPB 1/2 6/29/23, 1:12 AM 20.8 % REST Pathway 10.4 % No significant difference 0.0 % Extracorporeal carbon dioxide removal Standard care No significant difference in death from all causes at 90 days (41.5% vs. 39.5%; RR 1.05, 95% CI 0.83 to 1.33) Secondary outcomes Significant decrease in ventilator-free days (7.1 days vs. 9.2 days; AD -2.1 days, 95% CI -3.8 to -0.3) No significant difference in the rate of need for ECMO to day 7 (6% vs. 3%; RR 2.08, 95% CI 0.8 to 5.43) No significant difference in death at day 28 (38% vs. 36%; RR 1.06, 95% CI 0.82 to 1.37) Safety outcomes No significant differences in duration of ventilation, adverse events. Conclusion In adult patients receiving mechanical ventilation for acute hypoxemic respiratory failure, extracorporeal CO2 removal was not superior to standard care with respect to death from all causes at 90 days. Reference James J McNamee, Michael A Gillies, Nicholas A Barrett et al. Effect of Lower Tidal Volume Ventilation Facilitated by Extracorporeal Carbon Dioxide Removal vs Standard Care Ventilation on 90-Day Mortality in Patients With Acute Hypoxemic Respiratory Failure: The REST Randomized Clinical Trial. JAMA. 2021 Sep 21;326(11):1013-1023. Open reference URL https://web.pathway.md/studies/reciheXMQpjy8eKPB 2/2

6/29/23, 1:12 AM RESTART Pathway Feedback Search Clinical Topics Home Studies RESTART RESTART Disease Intracerebral hemorrhage Trial question What is the effect of antiplatelet therapy on recurrent intracerebral hemorrhage? Study design Multi-center Single blinded RCT Population Characteristics of study participants 33.0% female N = 537 67.0% male 537 patients (177 female, 360 male) Inclusion criteria: patients on antithrombotic therapy who survived 24h post ICH after discontinuation of antithrombotic therapy Key exclusion criteria: pregnant/breastfeeding or of childbearing age and not taking contraception; traumatic ICH, hemorrhagic transformation of an ischemic CVA, or intracranial hemorrhage without intracerebral extension, taking antithrombotic therapy after ICH Interventions N=268 restarting antiplatelets (aspirin, dipyridamole, or clopidogrel) N=268 avoiding antiplatelets (no antiplatelet therapy) Primary outcome https://web.pathway.md/studies/recbyUNbuFBtYgCER 1/2 6/29/23, 1:12 AM RESTART Pathway Rate of recurrence of ICH at a median of 2 years 9.0 % 9 6.8 % 4.5 % 4 2.3 % No significant difference 0.0 % Restarting antiplatelets Avoiding antiplatelets No significant difference in the rate of recurrence of ICH at a median of 2 years (4% vs. 9%; HR 0.51, 95% CI 0.25 to 1.03) Secondary outcomes No significant difference in major hemorrhagic events (7% vs. 9%; HR 0.71, 95% CI 0.39 to 1.3) No significant difference in major occlusive vascular events (15% vs. 14%; HR 1.02, 95% CI 0.65 to 1.6) Safety outcomes No significant difference in few serious adverse events (n=11) unrelated to stroke. Conclusion In patients on antithrombotic therapy who survived 24h post ICH after discontinuation of antithrombotic therapy, restarting antiplatelets were not superior to avoiding antiplatelets with respect to the rate of recurrence of ICH at a median of 2 years. Reference RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet. 2019 Jun 29;393(10191):2613- 2623. Open reference URL https://web.pathway.md/studies/recbyUNbuFBtYgCER 2/2

6/29/23, 1:13 AM ReSTORE Pathway Feedback Search Clinical Topics Home Studies ReSTORE ReSTORE Disease Invasive candidiasis Trial question Is rezafungin noninferior to caspofungin in patients with candidemia and invasive candidiasis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 41.0% female N = 199 59.0% male 199 patients (81 female, 118 male) Inclusion criteria: adult patients with systemic signs and mycological confirmation of candidemia or invasive candidiasis Key exclusion criteria: septic arthritis in a prosthetic joint; osteomyelitis; chronic disseminated candidiasis; severe hepatic impairment; severe ataxia; tremor; or neuropathy Interventions N=100 rezafungin (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses for no more than 4 weeks) N=99 caspofungin (70 mg loading dose on day 1, followed by 50 mg daily for no more than 4 weeks) https://web.pathway.md/studies/rec9vPU4TpyYscblP 1/2 6/29/23, 1:13 AM ReSTORE Pathway Primary outcome Global cure at day 14 61.0 % 61 59 45.8 % 30.5 % Difference not exceeding nonferiority margin 15.3 % 0.0 % Rezafungin Caspofungin Difference not exceeding nonferiority margin in global cure at day 14 (59% vs. 61%; ARD -2, 95% CI -4 to 0) Secondary outcomes No significant difference in death or unknown survival status at day 30 (24% vs. 21%; AD 3%, 95% CI -0.01 to 6.01) Safety outcomes No significant differences in serious adverse events, 1 treatment-emergent adverse event. Conclusion In adult patients with systemic signs and mycological confirmation of candidemia or invasive candidiasis, rezafungin was noninferior to caspofungin with respect to global cure at day 14. Reference George R Thompson rd, Alex Soriano, Oliver A Cornely et al. Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double- dummy, randomised phase 3 trial. Lancet. 2023 Jan 7;401(10370):49-59. Open reference URL https://web.pathway.md/studies/rec9vPU4TpyYscblP 2/2

6/29/23, 1:12 AM RETAPP Pathway Feedback Search Clinical Topics Home Studies RETAPP RETAPP Disease Community-acquired pneumonia Trial question Is placebo noninferior to amoxicillin among children younger than 5 years of age with nonsevere pneumonia and tachypnea? Study design Multi-center Double blinded RCT Population Characteristics of study participants 47.0% female N = 4002 53.0% male 4002 patients (1899 female, 2103 male) Inclusion criteria: children aged 2 to 59 months in a resource-limited primary healthcare setting who met WHO criteria of nonsevere pneumonia with tachypnea Key exclusion criteria: pedal edema, history of hospitalization in last two weeks, severe lower chest wall in-drawing, asthma, tuberculosis or other severe illness, antibiotics use in last 48 hours Interventions N=1999 a test regimen (matched volume of placebo for 3 days) N=2003 an active control (50 mg/mL suspension of amoxicillin for 3 days) Primary outcome https://web.pathway.md/studies/rec2y5fJFDJqO7S9G 1/2 6/29/23, 1:12 AM RETAPP Pathway Rate of treatment failure by day 3 4.9 % 4.9 3.7 % 2.6 2.5 % Difference exceeding nonferiority margin 1.2 % 0.0 % A test regimen An active control Difference exceeding nonferiority margin in the rate of treatment failure by day 3 (4.9% vs. 2.6%; AD 2.3%, 95% CI 0.9 to 3.7) Secondary outcomes No significant difference in the rate of relapse between day 4-14 (2.2% vs. 3.1%; AD -0.91%, 95% CI -2.08 to 0.27) Significant increase in fever (8% vs. 3.9%; AD 4.08%, 95% CI 1.48 to 6.68) Significant increase in wheeze (10.1% vs. 3.1%; AD 7.01%, 95% CI 1.35 to 12.67) Safety outcomes No significant difference in adverse events. Conclusion In children aged 2 to 59 months in a resource-limited primary healthcare setting who met WHO criteria of nonsevere pneumonia with tachypnea, a test regimen was not noninferior to an active control with respect to the rate of treatment failure by day 3. Reference Fyezah Jehan, Imran Nisar, Salima Kerai et al. Randomized Trial of Amoxicillin for Pneumonia in Pakistan. N Engl J Med. 2020 Jul 2;383(1):24-34. Open reference URL https://web.pathway.md/studies/rec2y5fJFDJqO7S9G 2/2

6/29/23, 1:12 AM REVIVED-BCIS2 Pathway Feedback Search Clinical Topics Home Studies REVIVED BCIS2 REVIVED BCIS2 Disease Disease Coronary artery disease Heart failure Trial question What is the role of PCI in patients with severe ischemic LV systolic dysfunction? Study design Multi-center Open label RCT Population Characteristics of study participants 12.0% female N = 700 88.0% male 700 patients (86 female, 614 male) Inclusion criteria: patients with a LVEF 35%, extensive coronary artery disease amenable to PCI and demonstrable myocardial viability Key exclusion criteria: acute myocardial infarction in the 4 weeks before randomization; acute decompensated HF or sustained ventricular arrhythmias within 72 hours before randomization Interventions N=347 PCI (coronary angioplasty or stents plus optimal medical therapy) N=353 medical therapy alone (optimal medical therapy alone) Primary outcome Death from any cause or hospitalization for heart failure https://web.pathway.md/studies/rechxeS8GkVtapM9h 1/2 6/29/23, 1:12 AM REVIVED-BCIS2 Pathway 38.0 % 38 37.2 28.5 % 19.0 % 9.5 % No significant difference 0.0 % Percutaneous coronary intervention Medical therapy alone No significant difference in death from any cause or hospitalization for HF (37.2% vs. 38%; HR 0.99, 99% CI 0.78 to 1.27) Secondary outcomes No significant difference in improvement in LVEF at 6 months (1.8% vs. 3.4%; ARD -1.6, 95% CI -3.7 to 0.5) No significant difference in improvement in LVEF at 12 months (2% vs. 1.1%; AD 0.9%, 95% CI -1.7 to 3.4) No significant difference in death from cardiovascular causes (21.9% vs. 24.9%; HR 0.88, 95% CI 0.65 to 1.2) Safety outcomes No significant differences in serious adverse event, bleeding at 2 years. Significant difference in major bleeding at year 1 (3.1% vs. 0.6%). Conclusion In patients with a LVEF 35%, extensive coronary artery disease amenable to PCI and demonstrable myocardial viability, PCI was not superior to medical therapy alone with respect to death from any cause or hospitalization for HF. Reference Divaka Perera, Tim Clayton, Peter D O'Kane et al. Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction. N Engl J Med. 2022 Oct 13;387(15):1351-1360. Open reference URL https://web.pathway.md/studies/rechxeS8GkVtapM9h 2/2

6/29/23, 1:13 AM Rifampin in latent TB Pathway Feedback Search Clinical Topics Home Studies Rifampin in latent TB Rifampin in latent TB Disease Disease Extrapulmonary tuberculosis Pulmonary tuberculosis Reference Menzies D, Adjobimey M, Ruslami R et al. Four Months of Rifampin or Nine Months of Isoniazid for Latent Tuberculosis in Adults. N Engl J Med. 2018 Aug 2;379(5):440-453. Open reference URL https://web.pathway.md/studies/reczfCE6Buj3uMBV3 1/1

6/29/23, 1:13 AM Rifampin in staphylococcal PJIs Pathway Feedback Search Clinical Topics Home Studies Rifampin in staphylococcal PJIs Rifampin in staphylococcal PJIs Disease Disease Prosthetic joint infection Septic arthritis Trial question What is the role of rifampin combination therapy in acute staphylococcal prosthetic joint infection treated with debridement and retention of the implant? Study design Multi-center Open label RCT Population Characteristics of study participants 33.3% female N = 99 66.7% male 99 patients (16 female, 32 male) Inclusion criteria: patients with prosthetic joint infection after hip and knee arthroplasties Key exclusion criteria: prosthetic joint infection with other bacteria than staphylococci, expected survival < 2 years, inability to comply with treatment and/or follow-up visits, and contraindications to the use of rifampin, cloxacillin, or vancomycin Interventions N=23 rifampin combination therapy (rifampin plus cloxacillin in methicillin-susceptible S. aureus or rifampin plus vancomycin in methicillin-resistant S. epidermidis for 6 weeks) N=25 monotherapy (cloxacillin in methicillin-susceptible staphylococci and vancomycin in methicillin-resistant S. epidermidis for 6 weeks) https://web.pathway.md/studies/recycPIuSVVZawDb4 1/2 6/29/23, 1:13 AM Rifampin in staphylococcal PJIs Pathway Primary outcome Rate of no signs of infection after 2 years of follow-up 74.0 % 74 72 55.5 % 37.0 % 18.5 % No significant difference 0.0 % Rifampin combination therapy Monotherapy No significant difference in the rate of no signs of infection after 2 years of follow-up (74% vs. 72%; RR 1.03, 95% CI 0.73 to 1.45) Secondary outcomes No significant difference in cure rate for S. aureus infection (77.8% vs. 65%; RR 1.2, 95% CI 0.8 to 1.8) No significant difference in cure rate for coagulase-negative Staphylococci (60% vs. 100%; RR 0.6, 95% CI 0.29 to 1.22) Safety outcomes No significant difference in discontinuation of rifampin or vancomycin due to side-effects. Significant difference in increased serum-creatinine levels for rifampin and vancomycin (0% vs. 65%). Conclusion In patients with prosthetic joint infection after hip and knee arthroplasties, rifampin combination therapy was not superior to monotherapy with respect to the rate of no signs of infection after 2 years of follow-up. Reference ystein Espeland Karlsen, P l Borgen, Bj rn Bragnes et al. Rifampin combination therapy in staphylococcal prosthetic joint infections: a randomized controlled trial. J Orthop Surg Res. 2020 Aug 28;15(1):365. Open reference URL https://web.pathway.md/studies/recycPIuSVVZawDb4 2/2

6/29/23, 1:13 AM Rifaximin plus lactulose for hepatic encephalopathy Pathway Feedback Search Clinical Topics Home Studies Rifaximin plus lactulose for hepatic encephalopathy Rifaximin plus lactulose for hepatic encephalopathy Disease Hepatic encephalopathy Trial question What is the effect of rifaximin plus lactulose in patients with overt hepatic encephalopathy? Study design Single center Double blinded RCT Population Characteristics of study participants 26.0% female N = 120 74.0% male 120 patients (31 female, 89 male) Inclusion criteria: patients with overt hepatic encephalopathy Key exclusion criteria: serum creatinine > 1.5 mg/dl, active alcohol intake < 4 weeks before present episode, other metabolic encephalopathies, HCC, degenerative CNS disease or major psychiatric illness, and significant comorbidity Interventions N=63 lactulose and rifaximin (lactulose 30-60 mL TID plus rifaximin 1,200 mg/day) N=57 lactulose only (lactulose 30-60 mL TID plus placebo capsule) Primary outcome Complete reversal of hepatic encephalopathy https://web.pathway.md/studies/recldqmyg8lJLE6Yo 1/2 6/29/23, 1:13 AM Rifaximin plus lactulose for hepatic encephalopathy Pathway 76.0 % 76 57.0 % 50.8 38.0 % Significant increase 19.0 % NNT = 4 0.0 % Lactulose and rifaximin Lactulose only Significant increase in complete reversal of hepatic encephalopathy (76% vs. 50.8%; RR 1.5, 95% CI 0.48 to 2.52) Secondary outcomes Borderline significant decrease in death (23.8% vs. 49.1%; RR 0.48, 95% CI 0 to 0.96) Significant increase in hospital stay (5.8 vs. 8.2; AD 2.4, 95% CI 0.98 to 3.82) Safety outcomes No significant difference in gastrointestinal bleeding (4 vs. 4) and hepatorenal syndrome (4 vs. 7). Significant differences in sepsis (7 vs. 17, p = 0.01). Conclusion In patients with overt hepatic encephalopathy, lactulose and rifaximin were superior to lactulose only with respect to complete reversal of hepatic encephalopathy. Reference Sharma BC, Sharma P, Lunia MK et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013 Sep;108(9):1458-63. Open reference URL https://web.pathway.md/studies/recldqmyg8lJLE6Yo 2/2

6/29/23, 1:13 AM Riskin Pathway Feedback Search Clinical Topics Home Studies Riskin Riskin Trial question What is the impact of rudeness on performance among medical team members? Study design Multi-center Double blinded RCT Population 72 patients Inclusion criteria: neonatal ICU teams in a training simulation involving a preterm infant whose condition acutely deteriorated due to necrotizing enterocolitis Key exclusion criteria: no prior written consent Interventions N=39 rudeness exposure (expert's comments included mildly rude statements completely unrelated to the teams' performance) N=33 control (neutral comments) Primary outcome Diagnostic performance score 3.2 3.2 2.6 2.4 1.6 0.8 Significant decrease 0.0 Rudeness exposure Control Significant decrease in diagnostic performance score (2.6 vs. 3.2; estimate -0.17, 95% CI -0.46 to 0.1) Secondary outcomes https://web.pathway.md/studies/recNx4Oyjf8DKQES0 1/2 6/29/23, 1:13 AM Riskin Pathway Significant decrease in procedural performance score (2.8 vs. 3.3; estimate -0.22, 95% CI -0.5 to 0.23) Conclusion In neonatal ICU teams in a training simulation involving a preterm infant whose condition acutely deteriorated due to necrotizing enterocolitis, rudeness exposure was superior to control with respect to diagnostic performance score. Reference Arieh Riskin, Amir Erez, Trevor A Foulk et al. The Impact of Rudeness on Medical Team Performance: A Randomized Trial. Pediatrics. 2015 Sep;136(3):487-95. Open reference URL https://web.pathway.md/studies/recNx4Oyjf8DKQES0 2/2

6/29/23, 1:12 AM RIVER Pathway Feedback Search Clinical Topics Home Studies RIVER RIVER Disease Disease Atrial fibrillation Mitral regurgitation Trial question Is rivaroxaban noninferior to warfarin in patients with AF and a bioprosthetic mitral valve? Study design Multi-center Open label RCT Population Characteristics of study participants 60.0% female N = 1005 40.0% male 1005 patients (607 female, 398 male) Inclusion criteria: patients with AF and a bioprosthetic mitral valve Key exclusion criteria: contraindication to either rivaroxaban or warfarin; high bleeding risk; transient AF caused by surgery; placement of mechanical valves Interventions N=500 rivaroxaban (oral dose of 20 mg daily) N=505 warfarin (dose adjustment to maintain a target INR of 2.0 to 3.0) Primary outcome Time until death, major cardiovascular events, or major bleeding at 12 months 347.5 347 5 days 340 1 https://web.pathway.md/studies/rec6jah9EcIrGNRk9 1/2 6/29/23, 1:12 AM 347.5 days RIVER Pathway 3 5 340.1 260.6 days 173.8 days Difference not exceeding nonferiority margin 86.9 days 0.0 days Rivaroxaban Warfarin Difference not exceeding nonferiority margin in time until death, major cardiovascular events, or major bleeding at 12 months (347.5 days vs. 340.1 days; AD 7.4 days, 95% CI -1.4 to 16.3) Secondary outcomes No significant difference in death from cardiovascular causes or thromboembolic events (3.4% vs. 5.1%; HR 0.65, 95% CI 0.35 to 1.2) Borderline significant decrease in stroke (0.6% vs. 2.4%; HR 0.25, 95% CI 0.07 to 0.88) No significant difference in valve thrombosis (1% vs. 0.6%; HR 1.68, 95% CI 0.4 to 7.01) Safety outcomes No significant differences in major bleeding, nonmajor bleeding, other serious adverse events. Conclusion In patients with AF and a bioprosthetic mitral valve, rivaroxaban was noninferior to warfarin with respect to time until death, major cardiovascular events, or major bleeding at 12 months. Reference Helio P Guimar es, Renato D Lopes, Pedro G M de Barros E Silva et al. Rivaroxaban in Patients with Atrial Fibrillation and a Bioprosthetic Mitral Valve. N Engl J Med. 2020 Nov 26;383(22):2117- 2126. Open reference URL https://web.pathway.md/studies/rec6jah9EcIrGNRk9 2/2

6/29/23, 1:13 AM Rivers Trial Pathway Feedback Search Clinical Topics Home Studies Rivers Trial Rivers Trial Disease Sepsis and septic shock Trial question Is early goal-directed therapy superior to standard therapy in patients with severe sepsis and septic shock? Study design Single center Double blinded RCT Population Characteristics of study participants 49.0% female N = 263 51.0% male 263 patients (130 female, 133 male) Inclusion criteria: patients with severe sepsis and septic shock Key exclusion criteria: age < 18 years, pregnancy, or the presence of an acute cerebral vascular event, acute coronary syndrome, acute pulmonary edema, status asthmaticus, contraindication to central venous catheterization, active gastrointestinal hemorrhage, or seizure Interventions N=130 early goal-directed therapy (according to a protocol for early goal-directed therapy for at least six hours) N=133 standard therapy (as per the protocol for hemodynamic support for at least six hours) https://web.pathway.md/studies/recOwqRBPsGIJB3Ha 1/2 6/29/23, 1:13 AM Rivers Trial Pathway Primary outcome In-hospital death 46.5 % 46.5 34.9 % 30.5 23.3 % Significant decrease 11.6 % NNT = 6 0.0 % Early goal-directed therapy Standard therapy Significant decrease in in-hospital death (30.5% vs. 46.5%; RR 0.58, 95% CI 0.38 to 0.87) Secondary outcomes Significant decrease in mean APACHE II scores (13 vs. 15.9; MD -2.9, 95% CI -4.62 to -1.18) Significant decrease in lactate concentration (3 mmol/L vs. 3.9 mmol/L; MD -0.9, 95% CI -1.66 to -0.14) Significant decrease in base deficit (2 mmol/L vs. 5.1 mmol/L; MD -3.1, 95% CI -5.72 to -0.48) Conclusion In patients with severe sepsis and septic shock, early goal-directed therapy was superior to standard therapy with respect to a in-hospital death. Reference Rivers E, Nguyen B, Havstad S et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. Open reference URL https://web.pathway.md/studies/recOwqRBPsGIJB3Ha 2/2

6/29/23, 1:12 AM ROADMAP Pathway Feedback Search Clinical Topics Home Studies ROADMAP ROADMAP Disease Diabetes mellitus type 2 Trial question What is the role of olmesartan in preventing the occurrence of microalbuminuria in patients with T2DM? Study design Multi-center Double blinded RCT Population Characteristics of study participants 54.0% female N = 4447 46.0% male 4447 patients (2395 female, 2052 male) Inclusion criteria: adult patients with T2DM Key exclusion criteria: CrCl <30 mL/min; severe uncontrolled hypertension; renal or renal-vascular disease; treatment with ARB or ACE inhibitors within 6 month prior to screening Interventions N=2232 olmesartan (a dose of 40 mg once daily) N=2215 placebo (matching placebo tablets) Primary outcome Time to first onset of microalbuminuria https://web.pathway.md/studies/recC5DUKW56gjkHeT 1/2 6/29/23, 1:12 AM ROADMAP Pathway 722.0 days 722 576 541.5 days 361.0 days 180.5 days Significant increase 0.0 days Olmesartan Placebo Significant increase in time to the first onset of microalbuminuria (722 days vs. 576 days; HR 1.3, 95% CI 1.06 to 1.59) Secondary outcomes No significant difference in composite of cardiovascular complications or death from cardiovascular causes (4.3% vs. 4.2%; HR 1, 95% CI 0.75 to 1.33) Significant increase in decline in eGFR (4.9 vs. 1; MD 3.9, 95% CI 1.59 to 6.21) Significant increase in death from cardiovascular causes (0.7% vs. 0.1%; HR 4.94, 95% CI 1.43 to 17.06) Safety outcomes No significant differences in serious adverse events, renal events. Significant difference in drug-related adverse events (11.4% vs. 7.5%). Conclusion In adult patients with T2DM, olmesartan was superior to placebo with respect to time to the first onset of microalbuminuria. Reference Hermann Haller, Sadayoshi Ito, Joseph L Izzo Jr et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011 Mar 10;364(10):907-17. Open reference URL https://web.pathway.md/studies/recC5DUKW56gjkHeT 2/2

6/29/23, 1:12 AM ROCKET AF Pathway Feedback Search Clinical Topics Home Studies ROCKET AF ROCKET AF Disease Disease Disease Acute ischemic stroke Atrial fibrillation Transient Trial question Is rivaroxaban noninferior to warfarin in patients with nonvalvular AF who are at an increased risk for stroke? Study design Multi-center Double blinded RCT Population Characteristics of study participants 40.0% female N = 14264 60.0% male 14264 patients (5663 female, 8601 male) Inclusion criteria: patients with nonvalvular AF who are at increased risk for stroke Key exclusion criteria: prosthetic heart valve, planned cardioversion, active endocarditis, active internal bleeding or increased risk of bleeding, platelet count < 90,000/uL, or sustained uncontrolled hypertension Interventions N=7131 rivaroxaban (at a daily dose of 20 mg) N=7133 warfarin (adjusted-dose to target INR 2.0-3.0) Primary outcome https://web.pathway.md/studies/rec2HYnuL6iEOeNnv 1/2 6/29/23, 1:12 AM ROCKET AF Pathway Incidence of stroke or systemic embolism 2.2 % / y 2.2 1.7 1.7 % / y 1.1 % / y Difference not exceeding nonferiority margin 0.6 % / y 0.0 % / y Rivaroxaban Warfarin Difference not exceeding nonferiority margin in the incidence of stroke or systemic embolism (1.7% / y vs. 2.2% / y; HR 0.79, 95% CI 0.66 to 0.96) Secondary outcomes No significant difference in the incidence of myocardial infarction (0.9% / y vs. 1.1% / y; HR 0.81, 95% CI 0.63 to 1.06) No significant difference in the incidence of death (1.9% / y vs. 2.2% / y; HR 0.85, 95% CI 0.7 to 1.02) Safety outcomes No significant difference in major and clinically relevant nonmajor bleeding and major bleeding. Significant difference in intracranial hemorrhage (0.8% vs. 1.2%) and fatal bleeding (0.4% vs. 0.8%). Conclusion In patients with nonvalvular AF who are at increased risk for stroke, rivaroxaban was noninferior to warfarin with respect to the incidence of stroke or systemic embolism. Reference Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. Open reference URL https://web.pathway.md/studies/rec2HYnuL6iEOeNnv 2/2

6/29/23, 1:13 AM Roflumilast in SD Pathway Feedback Search Clinical Topics Home Studies Roflumilast in SD Roflumilast in SD Disease Seborrheic dermatitis Trial question What is the effect of roflumilast 0.3% foam in patients with seborrheic dermatitis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 49.0% female N = 226 51.0% male 226 patients (110 female, 116 male) Inclusion criteria: adult patients with a clinical diagnosis of seborrheic dermatitis for 3 months and Investigator Global Assessment score of 3, affecting < = 20% of body, including scalp, face, trunk, and/or intertriginous areas Key exclusion criteria: use of topical antifungals; corticosteroids; topical calcineurin inhibitors; sulfur-based treatments; medical devices; crisaborole; azelaic acid or metronidazole 2 weeks before randomization Interventions N=154 roflumilast foam (once-daily topical application of 0.3% roflumilast in emollient foam) N=72 vehicle foam (once-daily topical application of vehicle foam without active ingredient) https://web.pathway.md/studies/recvctf1uNTxjHdmG 1/2 6/29/23, 1:13 AM Roflumilast in SD Pathway Primary outcome Investigator Global Assessment success at week 8 73.8 % 73.8 55.3 % 40.9 36.9 % Significant increase 18.4 % NNT = 3 0.0 % Roflumilast foam Vehicle foam Significant increase in Investigator Global Assessment success at week 8 (73.8% vs. 40.9%; AD 32.8%, 95% CI 18.5 to 45.7) Secondary outcomes Significant increase in Investigator Global Assessment success at week 2 (33.8% vs. 14.7%; AD 19.1%, 95% CI 6.6 to 29.3) Significant increase in erythema success at week 8 (44.7% vs. 21.2%; AD 23.5%, 95% CI 9.6 to 35) Significant increase in Worst Itch NRS success (64.6% vs. 34%; AD 30.6%, 95% CI 14.4 to 44.6) Safety outcomes No significant difference in adverse events. Conclusion In adult patients with a clinical diagnosis of seborrheic dermatitis for 3 months and Investigator Global Assessment score of 3, affecting < = 20% of body, including scalp, face, trunk, and/or intertriginous areas, roflumilast foam was superior to vehicle foam with respect to Investigator Global Assessment success at week 8. Reference Matthew J Zirwas, Zoe D Draelos, Janet DuBois et al. Efficacy of Roflumilast Foam, 0.3%, in Patients With Seborrheic Dermatitis: A Double-blind, Vehicle-Controlled Phase 2a Randomized Clinical Trial. JAMA Dermatol. 2023 May 3;e230846. Open reference URL https://web.pathway.md/studies/recvctf1uNTxjHdmG 2/2

6/29/23, 1:13 AM ROSE Pathway Feedback Search Clinical Topics Home Studies ROSE ROSE Disease Acute respiratory distress syndr Trial question What is the role of early continuous neuromuscular blockade in patients with ARDS receiving mechanical ventilation? Study design Multi-center Open label RCT Population Characteristics of study participants 44.0% female N = 1006 56.0% male 1006 patients (446 female, 560 male) Inclusion criteria: patients with moderate-to-severe ARDS receiving high PEEP mechanical ventilation Key exclusion criteria: continuous neuromuscular blockade at enrollment; chronic respiratory failure; severe chronic liver disease; expected duration of mechanical ventilation < 48 hours Interventions N=501 intervention (48-hour continuous neuromuscular blockade with cisatracurium and concomitant deep sedation) N=505 control (usual care with lighter sedation targets) https://web.pathway.md/studies/reckxGj47qZC4n8jm 1/2 6/29/23, 1:13 AM ROSE Pathway Primary outcome In-hospital death from any cause at 90 days 42.8 % 42.8 42.5 32.1 % 21.4 % 10.7 % No significant difference 0.0 % Intervention Control No significant difference in in-hospital death from any cause at 90 days (42.5% vs. 42.8%; ARD -0.3, 95% CI -6.4 to 5.9) Secondary outcomes No significant difference in the rate of in-hospital death by 28 days (36.7% vs. 37%; ARD -0.3, 95% CI -6.3 to 5.7) No significant difference in days free of ventilation at day 28 (9.6 days vs. 9.9 days; AD -0.3 days, 95% CI -1.7 to 1) No significant difference in days not in hospital at day 28 (5.7 days vs. 5.9 days; AD -0.2 days, 95% CI -1.1 to 0.8) Safety outcomes No significant differences in in-hospital recall of paralysis, ICU acquired weakness, serious adverse events. Significant difference in serious cardiovascular events (2.8% vs. 0.8%). Conclusion In patients with moderate-to-severe ARDS receiving high PEEP mechanical ventilation, intervention was not superior to control with respect to a in-hospital death from any cause at 90 days. Reference National Heart, Lung, and Blood Institute PETAL Clinical Trials Network et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 23;380(21):1997- 2008. Open reference URL https://web.pathway.md/studies/reckxGj47qZC4n8jm 2/2

6/29/23, 11:41 PM SADHART Pathway Feedback Search Clinical Topics Home Studies SADHART SADHART Disease Disease Disease Major depressive disorder Non-ST-elevation myocardial inf ST-elevat Trial question What is the role of sertraline treatment in patients with acute myocardial infarction or unstable angina? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 369 64.0% male 369 patients (133 female, 236 male) Inclusion criteria: patients with acute myocardial infarction or unstable angina and free of other life-threatening medical conditions who have major depressive disorder Key exclusion criteria: uncontrolled hypertension, MI or unstable angina of nonatherosclerotic etiology, alcohol or substance abuse or dependence in past 6 months, history of psychosis, bipolar disorder, organic brain syndrome, or dementia Interventions N=186 sertraline (in flexible dosages of 50 to 200 mg/d for 24 weeks) N=183 placebo (matching placebo for 24 weeks) https://web.pathway.md/studies/rec5znFJkMGBI5yjm 1/2 6/29/23, 11:41 PM SADHART Pathway Primary outcome Left ventricular ejection fraction at week 16 13.0 % 13 11 9.8 % 6.5 % 3.3 % No significant difference 0.0 % Sertraline Placebo No significant difference in LVEF at week 16 (11% vs. 13%; RR 0.85, 95% CI 0 to 1.7) Secondary outcomes No significant difference in death and urgent cardiovascular rehospitalizations (17.2% vs. 22.4%; RR 0.77, 95% CI 0.51 to 1.16) No significant difference in the rate of death during the 24-week course (1.1% vs. 2.7%; RR 0.39, 95% CI 0.08 to 1.39) Safety outcomes No significant difference in treatment-emergent increase in ventricular premature complex runs or other cardiac measures. Significant differences in nausea (19.9% vs. 10.9%), diarrhea (18.8% vs. 7.7%). Conclusion In patients with acute myocardial infarction or unstable angina and free of other life-threatening medical conditions who have major depressive disorder, sertraline was not superior to placebo with respect to LVEF at week 16. Reference Glassman AH, O'Connor CM, Califf RM et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002 Aug 14;288(6):701-9. Open reference URL https://web.pathway.md/studies/rec5znFJkMGBI5yjm 2/2

6/29/23, 11:41 PM SAFA Pathway Feedback Search Clinical Topics Home Studies SAFA SAFA Disease Acne vulgaris Trial question What is the effect of spironolactone in women with acne vulgaris? Study design Multi-center Double blinded RCT Population 410 female patients Inclusion criteria: adult women with facial acne for at least 6 months, judged to warrant oral antibiotics Key exclusion criteria: Investigator's Global Assessment acne score of 0-1; previous use of spironolactone; use of oral isotretinoin in the past 6 months; use of oral antibiotics for > 1 week for acne within the previous month Interventions N=201 spironolactone (50 mg/day until week 6, increasing to 100 mg/day until week 24) N=209 placebo (matching placebo) Primary outcome Improvement in Acne-Specific Quality of Life symptom subscale score at week 12 19.2 19.2 17.8 14.4 9.6 4.8 Significant increase 0.0 https://web.pathway.md/studies/recfv7P1VjnyLyeac 1/2 6/29/23, 11:41 PM SAFA Pathway 0 0 Spironolactone Placebo Significant increase in improvement in Acne-Specific Quality of Life symptom subscale score at week 12 (19.2 vs. 17.8; AD 1.27, 95% CI 0.07 to 2.46) Secondary outcomes Significant increase in improvement in Acne-Specific Quality of Life symptom subscale score at week 24 (21.2 vs. 17.4; AD 3.45, 95% CI 2.16 to 4.75) Borderline significant increase in self-assessed overall improvement score of 3-6 at week 24 (82% vs. 63%; OR 2.72, 95% CI 1.5 to 4.93) Borderline significant increase in Investigator's Global Assessment for treatment success at week 12 (19% vs. 6%; OR 5.18, 95% CI 2.18 to 12.28) Safety outcomes No significant differences in dizziness, drowsiness, fatigue. Significant differences in at least one adverse reaction (64% vs. 51%), headache (20% vs. 12%). Conclusion In adult women with facial acne for at least 6 months, judged to warrant oral antibiotics, spironolactone was superior to placebo with respect to improvement in Acne-Specific Quality of Life symptom subscale score at week 12. Reference Miriam Santer, Megan Lawrence, Susanne Renz et al. Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial. BMJ. 2023 May 16;381:e074349. Open reference URL https://web.pathway.md/studies/recfv7P1VjnyLyeac 2/2

6/29/23, 11:41 PM SAFE Pathway Feedback Search Clinical Topics Home Studies SAFE SAFE Trial question What is the effect of fluid resuscitation with saline in a heterogeneous population of patients in the ICU? Study design Multi-center Double blinded RCT Population Characteristics of study participants 40.0% female N = 6997 60.0% male 6997 patients (2800 female, 4197 male) Inclusion criteria: patients who had been admitted to the ICU Key exclusion criteria: ICU admittance after cardiac surgery, after liver transplantation, or for the treatment of burns Interventions N=3497 albumin (4% for a period of 28 days) N=3500 saline (0.9% for a period of 28 days) Primary outcome Rate of death from any cause during the 28-day period 21.1 % 21.1 20.9 15.8 % 10.6 % 5.3 % No significant difference 0.0 % https://web.pathway.md/studies/recBUYi8MaqnpulAi 1/2 6/29/23, 11:41 PM SAFE Pathway Albumin Saline No significant difference in the rate of death from any cause during the 28-day period (20.9% vs. 21.1%; RR 0.99, 99% CI 0.91 to 1.09) Secondary outcomes No significant difference in length of stay in the ICU (6.5 days vs. 6.2 days; AD 0.24 days, 95% CI -0.06 to 0.54) No significant difference in duration of mechanical ventilation (4.5 days vs. 4.3 days; AD 0.19 days, 95% CI -0.08 to 0.47) Borderline significant increase in duration of RRT (0.48 days vs. 0.39 days; AD 0.09 days, 95% CI 0 to 0.19) Safety outcomes No significant difference in new single-organ or multiple-organ failure. Conclusion In patients who had been admitted to the ICU, albumin was not superior to saline with respect to the rate of death from any cause during the 28-day period. Reference Finfer S, Bellomo R, Boyce N et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004 May 27;350(22):2247-56. Open reference URL https://web.pathway.md/studies/recBUYi8MaqnpulAi 2/2

6/29/23, 11:41 PM SALT-ED Pathway Feedback Search Clinical Topics Home Studies SALT ED SALT ED Trial question What is the effect of balanced crystalloids in noncritically ill patients treated with intravenous fluids in the emergency department? Study design Single center Open label RCT Population Characteristics of study participants 52.0% female N = 13347 48.0% male 13347 patients (6886 female, 6461 male) Inclusion criteria: noncritically ill patients who were treated with intravenous crystalloids in the emergency department and were subsequently hospitalized outside an ICU Key exclusion criteria: receipt of < 500 ml of crystalloids in the emergency department, age < 18 years, discharge from emergency department Interventions N=6708 balanced crystalloids (infusion of lactated Ringer's solution or Plasma-Lyte A) N=6639 normal saline (infusion of 0.9% saline) Primary outcome Hospital-free days 25.0 days 25 25 18.8 days 12.5 days 6.3 days https://web.pathway.md/studies/reckVfswV33qSNQS6 1/2 6/29/23, 11:41 PM SALT-ED Pathway No significant difference 0.0 days Balanced crystalloids Normal saline No significant difference in hospital-free days (25 days vs. 25 days; OR 0.98, 95% CI 0.92 to 1.04) Secondary outcomes Significant decrease in the rate of major adverse kidney events within 30 days (4.7% vs. 5.6%; OR 0.82, 95% CI 0.7 to 0.95) No significant difference in stage 2 or higher AKI (8% vs. 8.6%; OR 0.91, 95% CI 0.8 to 1.03) No significant difference in death in the hospital (1.4% vs. 1.6%; OR 0.88, 95% CI 0.66 to 1.16) Safety outcomes No significant differences in death, new RRT, final serum creatinine 200% of baseline. Conclusion In noncritically ill patients who were treated with intravenous crystalloids in the emergency department and were subsequently hospitalized outside an ICU, balanced crystalloids were not superior to normal saline with respect to a hospital-free days. Reference Self WH, Semler MW, Wanderer JP et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):819-828. Open reference URL https://web.pathway.md/studies/reckVfswV33qSNQS6 2/2

6/29/23, 11:41 PM SALTIRE Pathway Feedback Search Clinical Topics Home Studies SALTIRE SALTIRE Disease Aortic stenosis Reference Cowell SJ, Newby DE, Prescott RJ et al. A randomized trial of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med. 2005 Jun 9;352(23):2389-97. Open reference URL https://web.pathway.md/studies/rechIsQnrcN2X7UXq 1/1

6/29/23, 11:41 PM SAMMPRIS Pathway Feedback Search Clinical Topics Home Studies SAMMPRIS SAMMPRIS Disease Disease Acute ischemic stroke Transient ischemic attack Trial question What is the role of aggressive medical treatment in high-risk patients with intracranial artery stenosis? Study design Multi-center Open label RCT Population Characteristics of study participants 40.0% female N = 451 60.0% male 451 patients (179 female, 272 male) Inclusion criteria: patients with recent TIA or stroke related to 70-99% stenosis of a major intracranial artery Key exclusion criteria: tandem extracranial or intracranial stenosis proximal or distal to the target intracranial stenosis, intraluminal thrombus proximal to or at the target lesion, progressive neurological signs within 24 h before enrolment, any hemorrhagic infarct within 14 days before enrolment, non-atherosclerotic causes of intracranial stenosis, and the presence of a cardiac source of embolus Interventions https://web.pathway.md/studies/recih0Oi2meGPX9cf 1/3 6/29/23, 11:41 PM SAMMPRIS Pathway N=227 aggressive medical management (antiplatelet therapy, intensive management of vascular risk factors, and a lifestyle modification program) N=224 percutaneous transluminal angioplasty and stenting (with Wingspan stent, plus aggressive medical management) Primary outcome Rate of stroke or death within 30 days after enrolment, ischemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or any stroke or death within 30 days after a revascularization procedure of the qualifying lesion during follow-up 14.7 % 14.7 11.0 % 7.3 % Significant decrease 5.8 3.7 % NNT = 11 0.0 % Aggressive medical management Percutaneous transluminal angioplasty and stenting Significant decrease in the rate of stroke or death within 30 days after enrolment, ischemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or any stroke or death within 30 days after a revascularization procedure of the qualifying lesion during follow-up (5.8% vs. 14.7%; ARD -8.9, 95% CI -14.41 to -3.39) Secondary outcomes No significant difference in stroke or death at 1 year (23% vs. 29%; ARD -6, 95% CI -13.77 to 1.77) Significant decrease in any stroke (19% vs. 26%; ARD -7, 95% CI -13.91 to -0.09) Safety outcomes No significant differences in disabling or fatal stroke, major non-stroke hemorrhage. Significant difference in any major hemorrhage (4% vs. 13%). Conclusion In patients with recent TIA or stroke related to 70-99% stenosis of a major intracranial artery, aggressive medical management was superior to percutaneous transluminal angioplasty and stenting with respect to the rate of stroke or death within 30 days after enrolment, ischemic stroke in the territory of the qualifying artery beyond 30 days of enrolment, or any stroke or death within 30 days after a revascularization procedure of the qualifying lesion during follow-up. Reference Derdeyn CP, Chimowitz MI, Lynn MJ et al. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet. 2014 Jan 25;383(9914):333-41. https://web.pathway.md/studies/recih0Oi2meGPX9cf 2/3 6/29/23, 11:41 PM SAMMPRIS Pathway Open reference URL https://web.pathway.md/studies/recih0Oi2meGPX9cf 3/3

6/29/23, 11:41 PM SAVE (captopril) Pathway Feedback Search Clinical Topics Home Studies SAVE (captopril) SAVE (captopril) Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the role of captopril in patients with asymptomatic LV dysfunction after myocardial infarction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 17.0% female N = 2231 83.0% male 2231 patients (390 female, 1841 male) Inclusion criteria: patients with asymptomatic LV dysfunction after myocardial infarction Key exclusion criteria: contraindications to an ACE inhibitor, serum creatinine > 2.5 mg/dL, or comorbidities believed to limit survival Interventions N=1115 captopril (target dose 25 mg PO TID) N=1116 placebo (matching capsules) Primary outcome All-cause death https://web.pathway.md/studies/rechTdDJ8AN3dN9iO 1/2 6/29/23, 11:42 PM SAVE (captopril) Pathway 25.0 % 25 20 18.8 % 12.5 % Significant increase 6.3 % NNH = 20 0.0 % Captopril Placebo Significant increase in all-cause death (20% vs. 25%; RR 19, 95% CI 3 to 32) Secondary outcomes Significant increase in cardiovascular death (44.5% vs. 55.4%; RR 21, 95% CI 5 to 35) Significant increase in new-onset severe HF (11% vs. 16%; RR 37, 95% CI 20 to 50) Conclusion In patients with asymptomatic LV dysfunction after myocardial infarction, captopril was superior to placebo with respect to a all-cause death. Reference Pfeffer MA, Braunwald E, Moye LA et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992 Sep 3;327(10):669-77. Open reference URL https://web.pathway.md/studies/rechTdDJ8AN3dN9iO 2/2

6/29/23, 11:41 PM SAVE-ONCO Pathway Feedback Search Clinical Topics Home Studies SAVE ONCO SAVE ONCO Disease Cancer-associated thrombosis Trial question What is the role of semuloparin in patients receiving chemotherapy for cancer? Study design Multi-center Double blinded RCT Population Characteristics of study participants 40.0% female N = 3212 60.0% male 3212 patients (1282 female, 1930 male) Inclusion criteria: patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy Key exclusion criteria: life expectancy < 3 months; ECOG performance status 3; calculated CrCl < 30 mL/min; major surgery in < 4 weeks; contraindication to anticoagulation; requirement to thromboprophylaxis Interventions N=1608 semuloparin (subcutaneous dose of 20 mg once daily) N=1604 placebo (matching placebo once daily) Primary outcome https://web.pathway.md/studies/recpZojIJk86xWPqF 1/2 6/29/23, 11:41 PM SAVE-ONCO Pathway Composite outcome of symptomatic deep vein thrombosis, nonfatal pulmonary embolism, and death related to venous thromboembolism 3.4 % 3.4 2.5 % 1.7 % Significant decrease 1.2 0.8 % NNT = 45 0.0 % Semuloparin Placebo Significant decrease in composite outcome of symptomatic deep vein thrombosis, nonfatal PE, and death related to VTE (1.2% vs. 3.4%; HR 0.36, 95% CI 0.21 to 0.6) Secondary outcomes No significant difference in death (43.4% vs. 44.5%; HR 0.96, 96% CI 0.86 to 1.06) Borderline significant decrease in symptomatic deep vein thrombosis (0.7% vs. 2.1%; HR 0.32, 95% CI 0.15 to 0.62) Borderline significant decrease in PE (0.6% vs. 1.5%; HR 0.41, 95% CI 0.19 to 0.85) Safety outcomes No significant differences in major bleeding, clinically relevant nonmajor bleeding and serious adverse events. Conclusion In patients with metastatic or locally advanced solid tumors who were beginning to receive a course of chemotherapy, semuloparin was superior to placebo with respect to the composite outcome of symptomatic deep vein thrombosis, nonfatal PE, and death related to VTE. Reference Giancarlo Agnelli, Daniel J George, Ajay K Kakkar et al. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med. 2012 Feb 16;366(7):601-9. Open reference URL https://web.pathway.md/studies/recpZojIJk86xWPqF 2/2

6/29/23, 11:42 PM SCARLET Pathway Feedback Search Clinical Topics Home Studies SCARLET SCARLET Disease Sepsis and septic shock Trial question What is the effect of recombinant human soluble thrombomodulin in patients with sepsis-associated coagulopathy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 44.9% female N = 816 55.1% male 816 patients (363 female, 437 male) Inclusion criteria: ICU adult patients with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure Key exclusion criteria: platelets < 30,000/ mm , known allergy to ART-123 or any components of the drug product, history of head trauma, or other acute trauma with an increased risk of bleeding within 3 months Interventions N=395 recombinant human soluble thrombomodulin (an intravenous bolus or a 15-minute infusion of 0.06 mg/kg with a maximum dose of 6 mg/day, once daily for 6 consecutive days) N=405 placebo (matching placebo once daily for 6 consecutive days) https://web.pathway.md/studies/rec4k6l7rs3qEE2kz 1/2 6/29/23, 11:42 PM SCARLET Pathway Primary outcome Death from all causes at day 28 29.4 % 29.4 26.8 22.0 % 14.7 % 7.3 % No significant difference 0.0 % Recombinant human soluble thrombomodulin Placebo No significant difference in death from all causes at day 28 (26.8% vs. 29.4%; ARD -2.55, 95% CI -3.68 to 8.77) Secondary outcomes No significant difference in median plasma concentration of D-dimer at day 6 (1129.5 ng/mL vs. 1649 ng/mL; AD -519.5 ng/mL, 95% CI -1039.89 to 0.89) No significant difference in median plasma concentration of prothrombin fragment F1.2 at day 6 (309.6 pmol/L vs. 393.2 pmol/L; AD -83.6 pmol/L, 95% CI -167.34 to 0.14) No significant difference in median plasma concentration of thrombin-antithrombin complex at day 6 (5.2 ng/mL vs. 7.8 ng/mL; AD -2.6 ng/mL, 95% CI -5.2 to 0) Safety outcomes No significant differences in adverse events, serious adverse events, serious major bleeding event. Conclusion In ICU adult patients with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, recombinant human soluble thrombomodulin was not superior to placebo with respect to death from all causes at day 28. Reference Jean-Louis Vincent, Bruno Francois, Igor Zabolotskikh et al. Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial. JAMA. 2019 May 28;321(20):1993-2002. Open reference URL https://web.pathway.md/studies/rec4k6l7rs3qEE2kz 2/2

6/29/23, 11:41 PM SCENT2 Pathway Feedback Search Clinical Topics Home Studies SCENT2 SCENT2 Disease Disease COVID 19 infection Long COVID Trial question What is the role of theophylline saline nasal irrigation in patients with COVID-19-related olfactory dysfunction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 71.0% female N = 51 29.0% male 51 patients (36 female, 15 male) Inclusion criteria: adult patients with chronic olfactory dysfunction following suspected COVID-19 infection Key exclusion criteria: history of olfactory dysfunction prior to COVID-19; nasal polyps; prior sinonasal or anterior skull base surgery; neurodegenerative disease; prior seizures or arrhythmia Interventions N=26 theophylline nasal irrigation (400 mg dissolved in 240 mL isotonic nasal saline lavage BID for 6 weeks) N=25 placebo nasal irrigation (500 mg lactose dissolved in 240 mL isotonic nasal saline lavage daily for 6 weeks) https://web.pathway.md/studies/rec2sPnzp48zGyVIF 1/2 6/29/23, 11:42 PM SCENT2 Pathway Primary outcome Percentage of patients who experienced slightly better improvement in the clinical global impression- improvement scale 59.0 % 59 44.3 % 43 29.5 % 14.8 % No significant difference 0.0 % Theophylline nasal irrigation Placebo nasal irrigation No significant difference in the percentage of patients who experienced slightly better improvement in the clinical global impression-improvement scale (59% vs. 43%; AD 15.6%, 95% CI -13.2 to 44.5) Secondary outcomes No significant difference in improvement in the University of Pennsylvania Smell Identification Test at 6 weeks (AD 3, 95% CI -0.01 to 6.01) No significant difference in quality of life-related to smell loss score reduction at week 6 (0.86 vs. 1.43; AD -0.57, 95% CI -1.14 to 0) No significant difference in parosmia reduction at week 6 (-0.06 vs. 0.06; AD -0.12, 95% CI -0.24 to 0) Safety outcomes No significant difference in adverse events. Conclusion In adult patients with chronic olfactory dysfunction following suspected COVID-19 infection, theophylline nasal irrigation was not superior to placebo nasal irrigation with respect to the percentage of patients who experienced slightly better improvement in the clinical global impression-improvement scale. Reference Shruti Gupta, Jake J Lee, Amber Perrin et al. Efficacy and Safety of Saline Nasal Irrigation Plus Theophylline for Treatment of COVID-19-Related Olfactory Dysfunction: The SCENT2 Phase 2 Randomized Clinical Trial. JAMA Otolaryngol Head Neck Surg. 2022 Sep 1;148(9):830-837. Open reference URL https://web.pathway.md/studies/rec2sPnzp48zGyVIF 2/2

6/29/23, 11:41 PM SECURE Pathway Feedback Search Clinical Topics Home Studies SECURE SECURE Disease Disease Disease Coronary artery disease Non-ST-elevation myocardial inf ST-elevat Trial question What is the role of cardiovascular polypill strategy in the secondary prevention of CVD? Study design Multi-center Open label RCT Population Characteristics of study participants 31.0% female N = 2466 69.0% male 2466 patients (765 female, 1701 male) Inclusion criteria: elderly patients with myocardial infarction within the previous 6 months Key exclusion criteria: receipt of oral anticoagulation; severe congestive HF; severe renal disease; severe liver impairment; significant arrhythmias Interventions N=1237 polypill strategy (a single pill containing aspirin 100 mg, ramipril 2.5, 5, or 10 mg, and atorvastatin 40 mg) N=1229 usual care (standard of care therapies according to the ESC) Primary outcome https://web.pathway.md/studies/recOyXHbShw5uMbPC 1/2 6/29/23, 11:41 PM SECURE Pathway Composite outcome of cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization 12.7 % 12.7 9.5 % 9.5 6.3 % Significant decrease 3.2 % NNT = 31 0.0 % Polypill strategy Usual care Significant decrease in composite outcome of cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization (9.5% vs. 12.7%; HR 0.76, 95% CI 0.6 to 0.96) Secondary outcomes Significant decrease in composite outcome of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke (8.2% vs. 11.7%; HR 0.7, 95% CI 0.54 to 0.9) Borderline significant decrease in cardiovascular death (3.9% vs. 5.8%; HR 0.67, 95% CI 0.47 to 0.97) Borderline significant increase in the percentage of patients with high adherence to medication at 2 years (74.1% vs. 63.2%; RR 1.17, 95% CI 1.1 to 1.25) Safety outcomes No significant differences in death from any cause, adverse events, and nonfatal serious adverse events. Conclusion In elderly patients with myocardial infarction within the previous 6 months, polypill strategy was superior to usual care with respect to the composite outcome of cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. Reference Jose M Castellano, Stuart J Pocock, Deepak L Bhatt et al. Polypill Strategy in Secondary Cardiovascular Prevention. N Engl J Med. 2022 Sep 15;387(11):967-977. Open reference URL https://web.pathway.md/studies/recOyXHbShw5uMbPC 2/2

6/29/23, 11:41 PM SEDCOM Pathway Feedback Search Clinical Topics Home Studies SEDCOM SEDCOM Trial question What is the effect of dexmedetomidine for sedation in mechanically ventilated ICU patients? Study design Multi-center Double blinded RCT Population Characteristics of study participants 50.0% female N = 375 50.0% male 375 patients (184 female, 182 male) Inclusion criteria: adult patients intubated and mechanically ventilated for < 96 hours with expected mechanical ventilation for > 24 hours Key exclusion criteria: trauma or burns as admitting diagnoses, dialysis, pregnancy or lactation, neuromuscular blockade other than for intubation, epidural or spinal analgesia, serious CNS pathology, acute hepatitis or severe liver disease, unstable angina or acute myocardial infarction Interventions N=244 dexmedetomidine (0.2-1.4 g/kg/hour titrated to achieve light sedation) N=122 midazolam (0.02-0.1 mg/kg/hour titrated to achieve light sedation) Primary outcome Time within target Richmond Agitation and Sedation Scale range 77.3 % 77.3 75.1 58.0 % 38.6 % 19.3 % https://web.pathway.md/studies/recaIeEuSIAgfqnu5 1/2 6/29/23, 11:42 PM SEDCOM Pathway No significant difference 0.0 % Dexmedetomidine Midazolam No significant difference in time within the target Richmond Agitation and Sedation Scale range (77.3% vs. 75.1%; AD 2.2%, 95% CI -3.2 to 7.5) Secondary outcomes Significant decrease in prevalence of delirium during treatment (54% vs. 76.6%; ARD -22.6, 95% CI -36.01 to -9.19) Significant decrease in time to extubation (3.7 days vs. 5.6 days; AD -1.9 days, 95% CI -3.35 to -0.45) No significant difference in length of ICU stay (5.9 days vs. 7.6 days; AD -1.7 days, 95% CI -4.52 to 1.12) Safety outcomes No significant differences in death from all causes at 30 days, drug discontinuation due to adverse events. Significant differences in bradycardia (42.2% vs. 18.9%), tachycardia (25.4% vs. 44.3%), and hypertension requiring treatment (18.9% vs. 29.5%). Conclusion In adult patients intubated and mechanically ventilated for < 96 hours with expected mechanical ventilation for > 24 hours, dexmedetomidine was not superior to midazolam with respect to time within the target Richmond Agitation and Sedation Scale range. Reference Riker RR, Shehabi Y, Bokesch PM et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009 Feb 4;301(5):489-99. Open reference URL https://web.pathway.md/studies/recaIeEuSIAgfqnu5 2/2