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6/28/23, 10:13 PM European Dexamethasone Study Pathway Feedback Search Clinical Topics Home Studies European Dexamethasone Study European Dexamethasone Study Disease Acute bacterial meningitis Trial question What is the role of dexamethasone in adults with bacterial meningitis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 44.0% female N = 301 56.0% male 301 patients (132 female, 169 male) Inclusion criteria: adults with bacterial meningitis Key exclusion criteria: history of hypersensitivity to -lactam antibiotics or corticosteroids; pregnancy; treatment with oral or parenteral antibiotics in the previous 48 hours, history of active tuberculosis or fungal infection, or a recent history of head trauma, neurosurgery, or peptic ulcer disease Interventions N=157 dexamethasone (10 mg administered 15 to 20 minutes before or with the first dose of antibiotic and was given every 6 hours for four days) N=144 placebo (matching placebo) Primary outcome Unfavorable outcome 25.0 % 25 https://web.pathway.md/studies/recQmBCmsHskx4Lld 1/2 6/28/23, 10:13 PM European Dexamethasone Study Pathway 18.8 % 15 12.5 % Significant decrease 6.3 % NNT = 10 0.0 % Dexamethasone Placebo Significant decrease in unfavorable outcome (15% vs. 25%; RR 0.59, 95% CI 0.37 to 0.94) Secondary outcomes Significant decrease in death (7% vs. 15%; RR 0.48, 95% CI 0.24 to 0.96) Significant decrease in unfavorable outcomes (26% vs. 52%; RR 0.5, 95% CI 0.3 to 0.83) Safety outcomes No significant differences in gastrointestinal bleeding (1% vs. 3%, p=0.27). Conclusion In adults with bacterial meningitis, dexamethasone was superior to placebo with respect to unfavorable outcome. Reference de Gans J, van de Beek D, European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med. 2002 Nov 14;347(20):1549-56. Open reference URL https://web.pathway.md/studies/recQmBCmsHskx4Lld 2/2

6/28/23, 10:07 PM EVEREST-Outcomes Pathway Feedback Search Clinical Topics Home Studies EVEREST Outcomes EVEREST Outcomes Disease Heart failure Trial question What is the effect of tolvaptan initiation in patients hospitalized for worsening HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 26.0% female N = 4133 74.0% male 4133 patients (1058 female, 3075 male) Inclusion criteria: patient hospitalized with HF Key exclusion criteria: cardiac surgery within 60 days of enrollment, cardiac mechanical support, biventricular pacemaker placement within the last 60 days, comorbid conditions with an expected survival < 6 months, acute myocardial infarction at the time of hospitalization, hemodynamically significant uncorrected primary cardiac valvular disease, refractory end- stage HF Interventions N=2072 tolvaptan (30 mg PO once daily for a minimum of 60 days plus standard therapy) N=2061 placebo (matching placebo daily plus standard therapy) Primary outcome All-cause death 26.3 26.3 % 25.9 https://web.pathway.md/studies/recxbJj38p6jG8Zg9 1/2 6/28/23, 10:07 PM EVEREST-Outcomes Pathway 19.7 % 13.2 % 6.6 % No significant difference 0.0 % Tolvaptan Placebo No significant difference in all-cause death (25.9% vs. 26.3%; HR 0.98, 95% CI 0.87 to 1.11) Secondary outcomes No significant difference in cardiovascular death or hospitalization for HF (42% vs. 40.2%; HR 1.04, 95% CI 0.95 to 1.14) No significant difference in cardiovascular death or cardiovascular hospitalization (48.5% vs. 46.4%; HR 1.04, 95% CI 0.95 to 1.14) Safety outcomes No significant difference in major adverse events. Significant differences in thirst (16.0% vs. 2.1%, p < 0.001) and dry mouth (8.4% vs. 2.1%, p < 0.001). Conclusion In patient hospitalized with HF, tolvaptan was not superior to placebo with respect to a all-cause death. Reference Konstam MA, Gheorghiade M, Burnett JC Jr et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007 Mar 28;297(12):1319-31. Open reference URL https://web.pathway.md/studies/recxbJj38p6jG8Zg9 2/2

6/28/23, 10:13 PM Evolut low risk Pathway Feedback Search Clinical Topics Home Studies Evolut low risk Evolut low risk Disease Aortic stenosis Trial question Is TAVR noninferior to surgical AVR in low surgical risk patients with severe aortic stenosis? Study design Multi-center Open label RCT Population Characteristics of study participants 35.0% female N = 1403 65.0% male 1403 patients (490 female, 913 male) Inclusion criteria: patients with severe aortic stenosis at low surgical risk Key exclusion criteria: complex coronary artery disease, leukopenia, ventricular dysfunction, hemodynamic or respiratory instability, renal insufficiency, severe lung disease, active liver disease, severe pulmonary hypertension Interventions N=725 TAVR (with a self-expanding supraannular bioprosthesis) N=678 SAVR (with a bioprosthetic valve) Primary outcome Death or disabling stroke at 24 months 6.7 % 6.7 5.3 5.0 % https://web.pathway.md/studies/recZPQQ48b7qoFXLf 1/2 6/28/23, 10:13 PM Evolut low risk Pathway 3.4 % Difference not exceeding nonferiority margin 1.7 % 0.0 % Transcatheter aortic valve replacement Surgical aortic valve replacement Difference not exceeding nonferiority margin in death or disabling stroke at 24 months (5.3% vs. 6.7%; ARD -1.4, 95% CI -4.9 to 2.1) Secondary outcomes No significant difference in aortic valve gradient at 12 months (8.6 mmHg vs. 11.2 mmHg; ARD -2.6, 95% CI -3726.33 to 3721.13) No significant difference in effective orifice areas at 12 months (2.3 cm vs. 2 cm ; ARD 0.3, 95% CI -429.36 to 429.96) Safety outcomes No significant difference in secondary composite safety end point at 30 days (5.3% vs. 10.7%). Conclusion In patients with severe aortic stenosis at low surgical risk, TAVR was noninferior to SAVR with respect to death or disabling stroke at 24 months. Reference Popma JJ, Deeb GM, Yakubov SJ et al. Transcatheter Aortic-Valve Replacement with a Self- Expanding Valve in Low-Risk Patients. N Engl J Med. 2019 May 2;380(18):1706-1715. Open reference URL https://web.pathway.md/studies/recZPQQ48b7qoFXLf 2/2

6/28/23, 10:07 PM EVOLVE Pathway Feedback Search Clinical Topics Home Studies EVOLVE EVOLVE Disease Disease Chronic kidney disease Chronic kidney disease-mineral Trial question What is the effect of cinacalcet on CVD in patients undergoing dialysis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 41.0% female N = 3883 59.0% male 3883 patients (1578 female, 2305 male) Inclusion criteria: patients with moderate-to-severe secondary hyperparathyroidism (median level of intact PTH, 693 pg/mL) who were undergoing hemodialysis Key exclusion criteria: unstable medical condition, parathyroidectomy in the 12 weeks before the date of informed consent, severe concomitant disease, history of seizure within 12 weeks prior to randomization, scheduled date for kidney transplant from a known living donor, anticipated parathyroidectomy within 6 months after randomization, or pregnancy or breast feeding Interventions N=1948 cinacalcet (at a starting dose of 30 mg daily with dose adjustment up to 180 mg daily) N=1935 placebo (matching placebo) Primary outcome https://web.pathway.md/studies/recpEcH7Na3OmzpKO 1/2 6/28/23, 10:07 PM EVOLVE Pathway Death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event 49.2 % 49.2 48.2 36.9 % 24.6 % 12.3 % No significant difference 0.0 % Cinacalcet Placebo No significant difference in death, myocardial infarction, hospitalization for unstable angina, HF, or a peripheral vascular event (48.2% vs. 49.2%; HR 0.93, 95% CI 0.85 to 1.02) Secondary outcomes No significant difference in cardiovascular death (377 vs. 391; HR 0.92, 95% CI 0.8 to 1.07) No significant difference in adjudicated stroke (115 vs. 102; HR 1.07, 95% CI 0.82 to 1.4) Safety outcomes Significant difference in hypocalcemia (12.4% vs. 1.7%) and gastrointestinal adverse events (75.2% vs. 47.9%). Conclusion In patients with moderate-to-severe secondary hyperparathyroidism (median level of intact PTH, 693 pg/mL) who were undergoing hemodialysis, cinacalcet was not superior to placebo with respect to death, myocardial infarction, hospitalization for unstable angina, HF, or a peripheral vascular event. Reference EVOLVE Trial Investigators, Chertow GM, Block GA et al. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012 Dec 27;367(26):2482-94. Open reference URL https://web.pathway.md/studies/recpEcH7Na3OmzpKO 2/2

6/28/23, 10:08 PM EXCEL Pathway Feedback Search Clinical Topics Home Studies EXCEL EXCEL Disease Coronary artery disease Trial question Is PCI with everolimus-eluting stents noninferior to bypass surgery in patients with left main coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 23.0% female N = 1905 77.0% male 1905 patients (441 female, 1464 male) Inclusion criteria: patients with left main coronary artery disease who have low or intermediate anatomical complexity Key exclusion criteria: pregnancy, PCI of the left main trunk at any time prior to randomization, CABG at any time prior to randomization, noncardiac comorbidities with left expectancy < 3 years, SYNTAX score 33, Interventions N=948 PCI (PCI with fluoropolymer-based cobalt-chromium everolimus-eluting stents) N=957 CABG (standard surgical procedure) Primary outcome Death, stroke, or myocardial infarction at 3 years 15.4 15 4 % 14 7 https://web.pathway.md/studies/recGRKSalJ2WmCojy 1/2 6/28/23, 10:08 PM 15.4 % EXCEL Pathway 14.7 11.6 % 7.7 % Difference not exceeding nonferiority margin 3.9 % 0.0 % Percutaneous coronary intervention Coronary artery bypass graft Difference not exceeding nonferiority margin in death, stroke, or myocardial infarction at 3 years (15.4% vs. 14.7%; HR 1, 95% CI 0.79 to 1.26) Secondary outcomes Significant decrease in death, stroke, or myocardial infarction at 30 days (4.9% vs. 7.9%; MD -3.1, 95% CI -4.94 to -1.26) Safety outcomes Significant differences in major periprocedural adverse events within 30 days (12.4% vs. 44.0%, p < 0.001). Conclusion In patients with left main coronary artery disease who have low or intermediate anatomical complexity, PCI was noninferior to CABG with respect to death, stroke, or myocardial infarction at 3 years. Reference Stone GW, Sabik JF, Serruys PW et al. Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease. N Engl J Med. 2016 Dec 8;375(23):2223-2235. Open reference URL https://web.pathway.md/studies/recGRKSalJ2WmCojy 2/2

6/28/23, 10:09 PM EXPEDITION3 Pathway Feedback Search Clinical Topics Home Studies EXPEDITION3 EXPEDITION3 Disease Dementia Trial question What is the effect of solanezumab in patients with mild dementia due to Alzheimer's disease and with amyloid deposition? Study design Multi-center Double blinded RCT Population Characteristics of study participants 58.0% female N = 2129 42.0% male 2129 patients (1231 female, 898 male) Inclusion criteria: patients with mild dementia due to Alzheimer's disease and with amyloid deposition shown by means of florbetapir positron-emission tomography or Abeta1-42 measurements in CSF Key exclusion criteria: depression, serious or unstable medical conditions, recent infections, malignancies or psychiatric illnesses within the past 5 years, compromised renal function, clinically significant ECG abnormalities Interventions N=1057 solanezumab (intravenous infusion at a dose of 400 mg every 4 weeks for 76 weeks) N=1072 placebo (intravenous infusion every 4 weeks for 76 weeks) Primary outcome ADAS-cog14 score at 80 weeks https://web.pathway.md/studies/recynbFMZMCV2gnjE 1/2 6/28/23, 10:09 PM EXPEDITION3 Pathway 7.4 7.44 6.65 5.6 3.7 1.9 No significant difference 0.0 Solanezumab Placebo No significant difference in ADAS-cog14 score at 80 weeks (6.65 vs. 7.44; AD -0.8, 95% CI -1.73 to 0.14) Safety outcomes No significant differences in adverse events (84.5% vs. 83.4%), adverse cerebral edema or effusion (1 vs. 2 patient), serious adverse events (16.6% vs. 18.9%), deaths (0.9% vs. 1.6%). Conclusion In patients with mild dementia due to Alzheimer's disease and with amyloid deposition shown by means of florbetapir positron-emission tomography or Abeta1-42 measurements in CSF, solanezumab was not superior to placebo with respect to a ADAS-cog14 score at 80 weeks. Reference Honig LS, Vellas B, Woodward M et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease. N Engl J Med. 2018 Jan 25;378(4):321-330. Open reference URL https://web.pathway.md/studies/recynbFMZMCV2gnjE 2/2

6/28/23, 10:09 PM EXPLORER-HCM Pathway Feedback Search Clinical Topics Home Studies EXPLORER HCM EXPLORER HCM Disease Hypertrophic cardiomyopathy Trial question What is the role of mavacamten in patients with symptomatic obstructive hypertrophic cardiomyopathy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 41.0% female N = 251 59.0% male 251 patients (102 female, 149 male) Inclusion criteria: patients with hypertrophic cardiomyopathy with LVOT gradient 50 mmHg and NYHA class II-III symptoms Key exclusion criteria: history of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months before screening; QT interval corrected using Fridericia's formula > 500 ms; paroxysmal or intermittent AF; and persistent or permanent AF not on anticoagulation for 4 weeks or not adequately rate-controlled within 6 months before screening Interventions N=123 mavacamten (a starting dose of 5 mg for 30 weeks) N=128 placebo (matching placebo for 30 weeks) Primary outcome Clinical response at week 30 https://web.pathway.md/studies/recmb5FEo6RVbjNnT 1/2 6/28/23, 10:09 PM EXPLORER-HCM Pathway 37.0 % 37 27.8 % 18.5 % 17 Significant increase 9.3 % NNT = 5 0.0 % Mavacamten Placebo Significant increase in clinical response at week 30 (37% vs. 17%; AD 19.4%, 95% CI 8.7 to 30.1) Secondary outcomes Significant increase in improvement in peak oxygen consumption at week 30 (1.4 mL/kg/min vs. -0.1 mL/kg/min; AD 1.4 mL/kg/min, 95% CI 0.6 to 2.1) Significant increase in 1 NYHA class improvement at week 30 (65% vs. 31%; AD 34%, 95% CI 22.2 to 45.4) Safety outcomes No significant difference in serious adverse events. Conclusion In patients with hypertrophic cardiomyopathy with LVOT gradient 50 mmHg and NYHA class II- III symptoms, mavacamten was superior to placebo with respect to clinical response at week 30. Reference Iacopo Olivotto, Artur Oreziak, Roberto Barriales-Villa et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2020 Sep 12;396(10253):759-769. Open reference URL https://web.pathway.md/studies/recmb5FEo6RVbjNnT 2/2

6/28/23, 10:09 PM EXSCEL Pathway Feedback Search Clinical Topics Home Studies EXSCEL EXSCEL Disease Diabetes mellitus type 2 Trial question What is the effect of once-weekly exenatide on cardiovascular outcome in patients with T2DM? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.0% female N = 14752 62.0% male 14752 patients (5603 female, 9109 male) Inclusion criteria: patients with T2DM, with or without previous CVD who are on medication Key exclusion criteria: history of 2 episodes of severe hypoglycemia during the preceding 12 months, end-stage kidney disease, personal or family history of medullary thyroid carcinoma or MEN2, or a previous treatment with a GLP-1 receptor agonist Interventions N=7356 exenatide (ER dose of 2 mg subcutaneous injection once weekly) N=7356 placebo (matching placebo once weekly) Primary outcome Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke 12.2 % 12.2 11.4 9.1 % https://web.pathway.md/studies/reckie5LPKHF9T1QR 1/2 6/28/23, 10:09 PM EXSCEL Pathway 6.1 % Difference not exceeding nonferiority margin 3.0 % 0.0 % Exenatide Placebo Difference not exceeding nonferiority margin in death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (11.4% vs. 12.2%; HR 0.91, 95% CI 0.83 to 1) Secondary outcomes Significant decrease in death from any cause (6.9% vs. 7.9%; HR 0.86, 95% CI 0.77 to 0.97) No significant difference in death from cardiovascular causes (4.6% vs. 5.2%; HR 0.88, 95% CI 0.76 to 1.02) No significant difference in hospitalization for HF (3% vs. 3.1%; HR 0.94, 95% CI 0.78 to 1.13) Safety outcomes No significant difference in serious adverse events. Conclusion In patients with T2DM, with or without previous CVD who are on medication, exenatide was noninferior to placebo with respect to death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Reference Holman RR, Bethel MA, Mentz RJ et al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2017 Sep 28;377(13):1228-1239. Open reference URL https://web.pathway.md/studies/reckie5LPKHF9T1QR 2/2

6/28/23, 10:10 PM EXTEND-IA TNK Pathway Feedback Search Clinical Topics Home Studies EXTEND IA TNK EXTEND IA TNK Disease Acute ischemic stroke Trial question What is the role of tenecteplase among patients with ischemic stroke who are eligible to undergo thrombectomy? Study design Multi-center Open label RCT Population Characteristics of study participants 46.0% female N = 202 54.0% male 202 patients (92 female, 110 male) Inclusion criteria: patients within 4.5 hours after onset of ischemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy Key exclusion criteria: severe preexisting disability with mRS score > 3, pregnancy, intracranial hemorrhage, rapidly improving symptoms at the discretion of the investigator Interventions N=101 tenecteplase (at a dose of 0.25 mg/kg of body weight with a maximum dose of 25 mg) N=101 alteplase (at a dose of 0.9 mg/kg with a maximum dose of 90 mg) Primary outcome Reperfusion of > 50% of involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment https://web.pathway.md/studies/recjFUc1dRlxkd4Bz 1/2 6/28/23, 10:10 PM EXTEND-IA TNK Pathway 22.0 % 22 16.5 % 11.0 % 10 Significant increase 5.5 % NNH = 8 0.0 % Tenecteplase Alteplase Significant increase in reperfusion of > 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment (22% vs. 10%; IR 2.2, 95% CI 1.1 to 4.4) Secondary outcomes Significant increase in median mRS score at 90 days (2 vs. 3; OR 1.7, 95% CI 1 to 2.8) Borderline significant increase in incidence of recovery to independent function; mRS score of 0-2 at 90 days (64% vs. 51%; IR 1.2, 95% CI 1 to 1.5) No significant difference in early neurologic improvement at 72 hours (71% vs. 68%; IR 1, 95% CI 0.9 to 1.2) Safety outcomes No significant differences in symptomatic intracerebral hemorrhage, parenchymal hematoma. Significant difference in death (10% vs. 18%). Conclusion In patients within 4.5 hours after onset of ischemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy, tenecteplase was superior to alteplase with respect to reperfusion of > 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Reference Bruce C V Campbell, Peter J Mitchell, Leonid Churilov et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018 Apr 26;378(17):1573-1582. Open reference URL https://web.pathway.md/studies/recjFUc1dRlxkd4Bz 2/2

6/28/23, 10:10 PM EXTEND-IA Pathway Feedback Search Clinical Topics Home Studies EXTEND IA EXTEND IA Disease Acute ischemic stroke Trial question Is endovascular therapy superior to alteplase in patients with ischemic stroke? Study design Multi-center Open label RCT Population Characteristics of study participants 51.0% female N = 70 49.0% male 70 patients (36 female, 34 male) Inclusion criteria: patients with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging who were receiving alteplase Key exclusion criteria: pregnancy; intracranial hemorrhage; mRS score 2; rapidly improving symptoms; previous stroke within last 3 months; life expectancy < 1 year; current use of OACs Interventions N=35 endovascular therapy (endovascular thrombectomy with solitaire flow restoration stent retriever) N=35 alteplase only (continuation of alteplase alone at a dose of 0.9 mg/kg) Primary outcome Reperfusion at 24 hours 100.0 % 100 https://web.pathway.md/studies/recbLMzUdO3evxazH 1/2 6/28/23, 10:10 PM EXTEND-IA Pathway 75.0 % 50.0 % 37 Significant increase 25.0 % NNH = 2 0.0 % Endovascular therapy Alteplase only Significant increase in reperfusion at 24 hours (100% vs. 37%; OR 4.7, 95% CI 2.5 to 9) Secondary outcomes Significant increase in early neurologic improvement at day 3 (80% vs. 37%; OR 6, 95% CI 2 to 18) Significant decrease in reduction in mRS score at day 90 (1 vs. 3; OR 0.48, 95% CI 0.26 to 0.83) Significant increase in the percentage of patients achieving a modified Randkin scale score of 0-2 at day 90 (71% vs. 40%; OR 4.2, 95% CI 1.4 to 12) Safety outcomes No significant differences in death, sympatomatic intracerebral hemorrhage, parenchymal hematoma. Conclusion In patients with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging who were receiving alteplase, endovascular therapy was superior to alteplase only with respect to reperfusion at 24 hours. Reference Bruce C V Campbell, Peter J Mitchell, Timothy J Kleinig et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015 Mar 12;372(11):1009-18. Open reference URL https://web.pathway.md/studies/recbLMzUdO3evxazH 2/2

6/28/23, 10:09 PM EXTEND Pathway Feedback Search Clinical Topics Home Studies EXTEND EXTEND Disease Acute ischemic stroke Trial question What is the effect of alteplase between 4.5 and 9.0 hours after the onset of ischemic stroke? Study design Multi-center Double blinded RCT Population Characteristics of study participants 44.0% female N = 225 56.0% male 225 patients (100 female, 125 male) Inclusion criteria: patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging Key exclusion criteria: investigator consideration of the use of endovascular thrombectomy at the time of enrollment, intracranial hemorrhage, rapidly improving symptoms, previous stroke within last three months Interventions N=113 alteplase (intravenous administration of 0.9 mg/kg of body weight, maximum 90 mg, between 4.5 and 9.0 hours of stroke onset or on awakening with stroke) N=112 placebo (matching placebo between 4.5 and 9.0 hours of stroke onset or on awakening with stroke) Primary outcome Modified Rankin Scale score of 0 or 1 at 90 days https://web.pathway.md/studies/recsEBzmZ4JFQ7h6N 1/2 6/28/23, 10:09 PM EXTEND Pathway 35.4 % 35.4 29.5 26.5 % 17.7 % Significant increase 8.8 % NNH = 17 0.0 % Alteplase Placebo Significant increase in mRS score of 0 or 1 at 90 days (35.4% vs. 29.5%; aRR 1.44, 95% CI 1.01 to 2.06) Secondary outcomes Borderline significant increase in functional independence, a mRS score of 0 to 2 (49.6% vs. 42.9%; aRR 1.36, 95% CI 1.06 to 1.76) Borderline significant increase in reperfusion of at least 50% at 24 hours (71.7% vs. 52.3%; aRR 1.35, 95% CI 1.09 to 1.67) Borderline significant increase in recanalization at 24 hours after stroke (67.3% vs. 39.4%; aRR 1.68, 95% CI 1.29 to 2.19) Safety outcomes No significant difference in death within 90 days. Significant difference in symptomatic intracranial hemorrhage within 36 hours (6.2% vs. 0.9%). Conclusion In patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging, alteplase was superior to placebo with respect to mRS score of 0 or 1 at 90 days. Reference Henry Ma, Bruce C V Campbell, Mark W Parsons et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019 May 9;380(19):1795-1803. Open reference URL https://web.pathway.md/studies/recsEBzmZ4JFQ7h6N 2/2

6/28/23, 10:10 PM EXTRA Pathway Feedback Search Clinical Topics Home Studies EXTRA EXTRA Disease Disease Asthma Severe asthma phenotypes Trial question What is the effect of omalizumab in patients with severe allergic asthma that is inadequately controlled with standard therapy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 66.0% female N = 850 34.0% male 850 patients (557 female, 291 male) Inclusion criteria: patients with inadequately controlled severe asthma who are receiving high- dose ICS and long-acting -agonists, with or without additional controller therapy Key exclusion criteria: asthma exacerbation requiring intubation in the 12 months before screening or an exacerbation requiring treatment with systemic corticosteroids in the 30 days before screening, active lung disease other than asthma, treatment with omalizumab in the 12 months before screening, elevated serum IgE levels for reasons other than allergy, or smoking history of 10 pack-years Interventions N=427 omalizumab (minimum dose of 0.008 mg/kg of body weight per IgE (IU/mL) every 2 weeks or 0.016 mg/kg per IgE (IU/mL) every 4 weeks for 48 weeks) N=423 placebo (matching placebo for 48 weeks) P i t https://web.pathway.md/studies/recve9CmhhRxapBwR 1/2 6/28/23, 10:10 PM EXTRA Pathway Primary outcome Asthma exacerbations at 48 weeks 0.9/pt 0.88 0.7/pt 0.66 0.4/pt 0.2/pt Significant decrease 0.0/pt Omalizumab Placebo Significant decrease in asthma exacerbations at 48 weeks (0.66 per patient vs. 0.88 per patient; IRR 0.75, 95% CI 0.61 to 0.92) Secondary outcomes Significant increase in AQLQ[S] scores (1.15 vs. 0.92; MD 0.23, 95% CI 0.07 to 0.39) Significant decrease in Asthma Symptom Score (-1.56 points vs. -1.3 points; MD -0.26, 95% CI -0.49 to -0.1) No significant difference in daily albuterol puffs (-1.58 puffs vs. -1.31 puffs; MD -0.28, 95% CI -0.6 to 0.04) Safety outcomes No significant difference in adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%). Conclusion In patients with inadequately controlled severe asthma who are receiving high-dose ICS and long-acting -agonists, with or without additional controller therapy, omalizumab was superior to placebo with respect to asthma exacerbations at 48 weeks. Reference Hanania NA, Alpan O, Hamilos DL et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011 May 3;154(9):573-82. Open reference URL https://web.pathway.md/studies/recve9CmhhRxapBwR 2/2

6/28/23, 10:10 PM EXTUB-OBESE Pathway Feedback Search Clinical Topics Home Studies EXTUB OBESE EXTUB OBESE Disease Obesity Trial question What is the effect of noninvasive ventilation following extubation of critically ill patients with obesity? Study design Multi-center Open label RCT Population 981 patients Inclusion criteria: critically ill patients with obesity undergoing extubation Key exclusion criteria: formal indication of noninvasive ventilation; pregnancy; tracheostomy; anatomical factors precluding the use of noninvasive ventilation Interventions N=490 noninvasive ventilation (receipt of noninvasive ventilation) N=491 oxygen therapy (receipt of standard oxygen therapy) Primary outcome Rate of treatment failure within 3 days 26.5 % 26.5 19.9 % 13.5 13.3 % Significant decrease 6.6 % NNT = 8 0.0 % Noninvasive ventilation Oxygen therapy https://web.pathway.md/studies/recD0jACVMntFJTiS 1/2 6/28/23, 10:10 PM EXTUB-OBESE Pathway Significant decrease in the rate of treatment failure within 3 days (13.5% vs. 26.5%; RR 0.43, 95% CI 0.31 to 0.6) Secondary outcomes No significant difference in the rate of acute respiratory failure within 7 days after extubation (11% vs. 14%; RR 0.75, 95% CI 0.51 to 1.09) No significant difference in the rate of reintubation within 3 days after extubation (10% vs. 12%; RR 0.8, 95% CI 0.53 to 1.19) No significant difference in death at day 28 (5% vs. 6%; RR 0.87, 95% CI 0.51 to 1.49) Conclusion In critically ill patients with obesity undergoing extubation, noninvasive ventilation was superior to oxygen therapy with respect to the rate of treatment failure within 3 days. Reference Audrey De Jong, Anne Bignon, Fran ois Stephan et al. Effect of non-invasive ventilation after extubation in critically ill patients with obesity in France: a multicentre, unblinded, pragmatic randomised clinical trial. Lancet Respir Med. 2023 Jun;11(6):530-539. Open reference URL https://web.pathway.md/studies/recD0jACVMntFJTiS 2/2

6/28/23, 10:33 PM FACTT Pathway Feedback Search Clinical Topics Home Studies FACTT FACTT Disease Acute respiratory distress syndr Trial question What is the effect of conservative fluid management strategy in patients with acute lung injury? Study design Multi-center Open label RCT Population Characteristics of study participants 53.5% female N = 1000 46.5% male 1000 patients (535 female, 465 male) Inclusion criteria: patients with acute lung injury Key exclusion criteria: acute lung injury > 48 hours; chronic conditions that could independently influence survival, severe lung or neuromuscular disease or dependence on dialysis; and advanced cancer Interventions N=503 conservative fluid use (conservative use of fluids) N=497 liberal fluid use (liberal use of fluids) Primary outcome Death at 60 days 28.4 % 28.4 25.5 21.3 % https://web.pathway.md/studies/recvgro7oCzzI73U9 1/2 6/28/23, 10:33 PM FACTT Pathway 14.2 % 7.1 % No significant difference 0.0 % Conservative fluid use Liberal fluid use No significant difference in death at 60 days (25.5% vs. 28.4%; RR 0.9, 95% CI -2.6 to 8.4) Secondary outcomes Significant increase in ventilator-free days (14.6 vs. 12.1; MD 2.5, 95% CI 1.02 to 3.98) Significant increase in ICU free days (13.4 vs. 11.2; ARD 2.2, 95% CI 0.89 to 3.51) Conclusion In patients with acute lung injury, conservative fluid use was superior to liberal fluid use with respect to death at 60 days. Reference National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564-75. Open reference URL https://web.pathway.md/studies/recvgro7oCzzI73U9 2/2

6/28/23, 10:33 PM FAIR-HF Pathway Feedback Search Clinical Topics Home Studies FAIR HF FAIR HF Disease Disease Heart failure Iron deficiency anemia Trial question What is the role of intravenous ferric carboxymaltose in patients with chronic HF and iron deficiency? Study design Multi-center Double blinded RCT Population Characteristics of study participants 53.0% female N = 459 47.0% male 459 patients (244 female, 215 male) Inclusion criteria: patients with chronic HF, reduced LVEF, and iron deficiency, with or without anemia Key exclusion criteria: uncontrolled hypertension, other clinically significant heart disease, inflammation, or clinically significantly impaired liver or renal function Interventions N=304 ferric carboxymaltose (200 mg of intravenous iron weekly) N=155 placebo (intravenous saline weekly) Primary outcome Percentage of patients achieving good or moderate improvement on self-reported Patient Global Assessment at 24 weeks 50.0 % 50 https://web.pathway.md/studies/rec1abS95oy1jDBiW 1/2 6/28/23, 10:33 PM FAIR-HF Pathway 37.5 % 28 25.0 % Significant increase 12.5 % NNT = 5 0.0 % Ferric carboxymaltose Placebo Significant increase in the percentage of patients achieving good or moderate improvement on the self-reported Patient Global Assessment at 24 weeks (50% vs. 28%; OR 2.51, 95% CI 1.75 to 3.61) Secondary outcomes Significant increase in NYHA functional class I or II at 24 weeks (47% vs. 30%; OR 2.4, 95% CI 1.55 to 3.71) Safety outcomes No significant differences in rates of death, adverse events, and serious adverse events. Conclusion In patients with chronic HF, reduced LVEF, and iron deficiency, with or without anemia, ferric carboxymaltose was superior to placebo with respect to the percentage of patients achieving good or moderate improvement on the self-reported Patient Global Assessment at 24 weeks. Reference Anker SD, Comin Colet J, Filippatos G et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009 Dec 17;361(25):2436-48. Open reference URL https://web.pathway.md/studies/rec1abS95oy1jDBiW 2/2

6/28/23, 10:33 PM FAME 2 Pathway Feedback Search Clinical Topics Home Studies FAME 2 FAME 2 Disease Coronary artery disease Trial question What is the role of fractional flow reserve-guided PCI in patients with stable coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 22.0% female N = 888 78.0% male 888 patients (194 female, 694 male) Inclusion criteria: patients with stable coronary artery disease for whom PCI was being considered and in whom at least one stenosis was functionally significant, FFR 0.80 Key exclusion criteria: left main coronary artery disease requiring revascularization, recent < 1 week STEMI or non-STEMI, prior CABG, contraindication to dual antiplatelet therapy, LVEF < 30%, severe LV hypertrophy, age < 21 years, or pregnancy Interventions N=447 PCI (FFR-guided PCR plus best available medical therapy) N=441 medical therapy (best available medical therapy alone) Primary outcome Death, myocardial infarction, or urgent revascularization 12.7 % 12.7 https://web.pathway.md/studies/rec7w0QcBtEbqprPp 1/2 6/28/23, 10:33 PM FAME 2 Pathway 9.5 % 6.3 % Significant decrease 4.3 3.2 % NNT = 12 0.0 % Percutaneous coronary intervention Medical therapy Significant decrease in death, myocardial infarction, or urgent revascularization (4.3% vs. 12.7%; HR 0.32, 95% CI 0.19 to 0.53) Secondary outcomes Significant decrease in urgent revascularization (1.6% vs. 11.1%; HR 0.13, 95% CI 0.06 to 0.3) Significant decrease in urgent revascularization triggered by myocardial infarction or evidence of ischemia on electrocardiography (0.9% vs. 5.2%; HR 0.13, 95% CI 0.04 to 0.43) Conclusion In patients with stable coronary artery disease for whom PCI was being considered and in whom at least one stenosis was functionally significant, FFR 0.80, PCI was superior to medical therapy with respect to death, myocardial infarction, or urgent revascularization. Reference De Bruyne B, Pijls NH, Kalesan B et al. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med. 2012 Sep 13;367(11):991-1001. Open reference URL https://web.pathway.md/studies/rec7w0QcBtEbqprPp 2/2

6/28/23, 10:34 PM FAME 3 Pathway Feedback Search Clinical Topics Home Studies FAME 3 FAME 3 Disease Coronary artery disease Trial question Is fractional flow reserve guided PCI noninferior to CABG in patients with three-vessel coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 18.0% female N = 1500 82.0% male 1500 patients (270 female, 1230 male) Inclusion criteria: patients with three-vessel coronary artery disease Key exclusion criteria: cardiogenic shock; STEMI within 5 days; LVEF < 30%; life expectancy < 2 years; previous CABG Interventions N=757 PCI (fractional flow reserve guided PCI with current-generation zotarolimus-eluting stents) N=743 CABG (surgery performed as per standard practice with complete arterial revascularization) Primary outcome Death from any cause, myocardial infarction, stroke, or repeat revascularization at 1 year 10.6 % 10.6 https://web.pathway.md/studies/recb7fyneTYGXI9sT 1/2 6/28/23, 10:34 PM FAME 3 Pathway 7.9 % 6.9 5.3 % Difference exceeding nonferiority margin 2.6 % 0.0 % Percutaneous coronary intervention Coronary artery bypass graft Difference exceeding nonferiority margin in death from any cause, myocardial infarction, stroke, or repeat revascularization at 1 year (10.6% vs. 6.9%; HR 1.5, 95% CI 1.1 to 2.2) Secondary outcomes No significant difference in death, myocardial infarction, or stroke (7.3% vs. 5.2%; HR 1.4, 95% CI 0.9 to 2.1) No significant difference in death (1.6% vs. 0.9%; HR 1.7, 95% CI 0.7 to 4.3) No significant difference in the percentage of patients with myocardial infarction (5.2% vs. 3.5%; HR 1.5, 95% CI 0.9 to 2.5) Safety outcomes No significant differences in definite stent thrombosis, symptomatic graft occlusion. Significant differences in severe bleeding (1.6% vs. 3.8%), AKI (0.1% vs. 0.9%), arrhythmia or AF (2.4% vs. 14.1%). Conclusion In patients with three-vessel coronary artery disease, PCI was not noninferior to CABG with respect to death from any cause, myocardial infarction, stroke, or repeat revascularization at 1 year. Reference William F Fearon, Frederik M Zimmermann, Bernard De Bruyne et al. Fractional Flow Reserve- Guided PCI as Compared with Coronary Bypass Surgery. N Engl J Med. 2022 Jan 13;386(2):128-137. Open reference URL https://web.pathway.md/studies/recb7fyneTYGXI9sT 2/2

6/28/23, 10:33 PM FAME Pathway Feedback Search Clinical Topics Home Studies FAME FAME Disease Coronary artery disease Trial question What is the role of fractional flow reserve for guiding PCI in patients with multivessel coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 26.0% female N = 1005 74.0% male 1005 patients (261 female, 744 male) Inclusion criteria: patients with multivessel coronary artery disease Key exclusion criteria: angiographically significant left main coronary artery disease, previous coronary artery bypass surgery, cardiogenic shock, extremely tortuous or calcified coronary arteries, a life expectancy < 2 years, or a contraindication to the placement of drug-eluting stents and pregnancy Interventions N=509 FFR-guided PCI (implantation of drug-eluting stents in indicated lesions if the FFR is 0.80 guided by FFR measurements in addition to angiography) N=496 angiography-guided PCI (implantation of drug-eluting stents in all indicated lesions guided by angiography alone) Primary outcome https://web.pathway.md/studies/recwyvir98yHqQszX 1/2 6/28/23, 10:33 PM FAME Pathway Death, nonfatal myocardial infarction, or repeat revascularization at 1 year 18.3 % 18.3 13.7 % 13.2 9.2 % Significant decrease 4.6 % NNT = 20 0.0 % FFR-guided percutaneous coronary intervention Angiography-guided percutaneous coronary intervention Significant decrease in death, nonfatal myocardial infarction, or repeat revascularization at 1 year (13.2% vs. 18.3%; RR 0.72, 95% CI 0.54 to 0.96) Secondary outcomes No significant difference in free from angina at 1 year (81.3% vs. 77.9%; RR 1.04, 95% CI -0.55 to 2.63) No significant difference in death from any cause (1.8% vs. 3%; RR 0.58, 95% CI 0.26 to 1.32) No significant difference in myocardial infarction (5.7% vs. 8.7%; RR 0.66, 95% CI 0.42 to 1.04) Conclusion In patients with multivessel coronary artery disease, FFR-guided PCI was superior to angiography-guided PCI with respect to death, nonfatal myocardial infarction, or repeat revascularization at 1 year. Reference Tonino PA, De Bruyne B, Pijls NH et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med. 2009 Jan 15;360(3):213-24. Open reference URL https://web.pathway.md/studies/recwyvir98yHqQszX 2/2

6/28/23, 10:34 PM FAST Pathway Feedback Search Clinical Topics Home Studies FAST FAST Disease Disease Asthma Severe asthma phenotypes Trial question What is the effect of temporary quadrupling of the dose of ICSs in patients who had a severe asthma exacerbation? Study design Multi-center Open label RCT Population Characteristics of study participants 68.0% female N = 1922 32.0% male 1922 patients (1305 female, 617 male) Inclusion criteria: adult and adolescent patients with asthma who were receiving ICSs, with or without add-on therapy, and who had at least one exacerbation in the previous 12 months Key exclusion criteria: history of smoking related to COPD, on maintenance oral corticosteroids, use of a corticosteroid/long-acting bronchodilator combination inhaler for both maintenance and relief treatment, an exacerbation within four weeks of randomization, pregnancy Interventions N=957 quadrupling (increased bronchodilator medication and an increase in the dose of ICSs by a factor of 4) N=965 non-quadrupling (increased bronchodilator medication alone) Primary outcome https://web.pathway.md/studies/recXmW9eKC1LTalZj 1/2 6/28/23, 10:34 PM FAST Pathway Use of systemic corticosteroids 40.0 % 40 33 30.0 % 20.0 % 10.0 % Borderline significant decrease 0.0 % Quadrupling Non-quadrupling Borderline significant decrease in use of systemic corticosteroids (33% vs. 40%; RR 0.82, 95% CI 0.7 to 0.96) Secondary outcomes Borderline significant decrease in unscheduled healthcare consultation (41% vs. 47%; RR 0.86, 95% CI 0.75 to 0.99) Significant increase in mean AUC of the peak flow (1166 L/min/day vs. 1130 L/min/day; AD 38 L/min/day, 95% CI 13 to 62) Safety outcomes No significant difference in pneumonia or lower respiratory tract infection. Significant difference in serious adverse events (2% vs. 4%) and nonserious adverse events (7% vs. 2%). Conclusion In adult and adolescent patients with asthma who were receiving ICSs, with or without add-on therapy, and who had at least one exacerbation in the previous 12 months, quadrupling was superior to non-quadrupling with respect to use of systemic corticosteroids. Reference McKeever T, Mortimer K, Wilson A et al. Quadrupling Inhaled Glucocorticoid Dose to Abort Asthma Exacerbations. N Engl J Med. 2018 Mar 8;378(10):902-910. Open reference URL https://web.pathway.md/studies/recXmW9eKC1LTalZj 2/2

6/28/23, 10:41 PM Fecal transplant for recurrent C. difficile colitis Pathway Feedback Search Clinical Topics Home Studies Fecal transplant for recurrent C. difficile colitis Fecal transplant for recurrent C. difficile colitis Disease Clostridioides difficile infection Reference van Nood E, Vrieze A, Nieuwdorp M et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013 Jan 31;368(5):407-15. Open reference URL https://web.pathway.md/studies/recumfCPCXpnIIjGv 1/1

6/28/23, 10:41 PM Fecal transplant for ulcerative colitis Pathway Feedback Search Clinical Topics Home Studies Fecal transplant for ulcerative colitis Fecal transplant for ulcerative colitis Disease Ulcerative colitis Trial question What is the effect of anaerobically prepared fecal microbiota in patients with mild to moderately active ulcerative colitis? Study design Multi-center Open label RCT Population Characteristics of study participants 45.0% female N = 73 55.0% male 73 patients (33 female, 40 male) Inclusion criteria: patients with mild to moderately active ulcerative colitis Key exclusion criteria: previous colonic surgery, gastrointestinal infection, pregnancy, stool infections, anticoagulant therapy, or current use of antibiotics or probiotics Interventions N=38 pooled donor fecal transplant (200 mL via colonoscopy, then 2 enemas over 7 days) N=35 autologous fecal transplant (200 mL via colonoscopy, then 2 enemas over 7 days) Primary outcome Steroid-free remission at 8 weeks 32.0 % 32 24 0 % https://web.pathway.md/studies/recDUZIwumy12rA1W 1/2 6/28/23, 10:41 PM 24.0 % Fecal transplant for ulcerative colitis Pathway 16.0 % Significant increase 9 8.0 % NNT = 4 0.0 % Pooled donor fecal transplant Autologous fecal transplant Significant increase in steroid-free remission at 8 weeks (32% vs. 9%; OR 5, 95% CI 1.2 to 20.1) Secondary outcomes Significant increase in clinical response at 8 weeks (55% vs. 23%; ARD 32, 95% CI 10 to 54) Significant increase in clinical remission at 8 weeks (47% vs. 17%; ARD 30, 95% CI 7 to 51) No significant difference in steroid-free endoscopic remission at 8 weeks (ARD 11, 95% CI -1 to 27) Safety outcomes No significant difference in serious adverse events (3 vs. 2). Conclusion In patients with mild to moderately active ulcerative colitis, pooled donor fecal transplant was superior to autologous fecal transplant with respect to a steroid-free remission at 8 weeks. Reference Costello SP, Hughes PA, Waters O et al. Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial. JAMA. 2019 Jan 15;321(2):156-164. Open reference URL https://web.pathway.md/studies/recDUZIwumy12rA1W 2/2

6/28/23, 10:34 PM FEDORA Pathway Feedback Search Clinical Topics Home Studies FEDORA FEDORA Trial question What is the effect of esophageal Doppler monitor-guided goal-directed hemodynamic therapy among low-moderate risk patients undergoing intermediate-risk surgery? Study design Multi-center Single blinded RCT Population Characteristics of study participants 38.3% female N = 450 61.7% male 450 patients (160 female, 260 male) Inclusion criteria: adult patients scheduled for major elective surgery Key exclusion criteria: emergency surgery, ASA physical status > 3, contraindications for esophageal Doppler monitor intervention, aortic pathology Interventions N=224 goal-directed hemodynamic therapy (the intraoperative goals to maintain a maximal stroke volume, with mean arterial pressure > 70 mmHg, and cardiac index 2.5 litres/min/m using esophageal Doppler monitor) N=226 control (continuous infusion of Ringer's lactate at 3-5 mL/kg/hour for laparoscopic surgery, or 5-7 mL/kg/hour for open surgery without cardiac output monitoring) Primary outcome Rate of moderate or severe postoperative complications during the first 180 days after surgery 16.6 % 16.6 12.5 % 8.6 8.3 % Significant decrease 4.2 % https://web.pathway.md/studies/recNUmCuHsa4X7ZNj 1/2 6/28/23, 10:34 PM FEDORA Pathway NNT = 12 0.0 % Goal-directed hemodynamic therapy Control Significant decrease in the rate of moderate or severe postoperative complications during the first 180 days after surgery (8.6% vs. 16.6%; OR 0.48, 95% CI 0.27 to 0.89) Secondary outcomes Significant decrease in time to oral tolerance (1 day vs. 2 day; AD -1 day, 95% CI -1.59 to -0.41) Significant decrease in time to ambulation (2 days vs. 3 days; AD -1 days, 95% CI -1.59 to -0.41) Significant decrease in length of hospital stay (5 days vs. 7 days; AD -2 days, 95% CI -3.19 to -0.81) Safety outcomes No significant difference in death at 180 days. Significant difference in ICU length of stay (16 hours vs. 24 hours). Conclusion In adult patients scheduled for major elective surgery, goal-directed hemodynamic therapy was superior to control with respect to the rate of moderate or severe postoperative complications during the first 180 days after surgery. Reference J M Calvo-Vecino, J Ripoll s-Melchor, M G Mythen et al. Effect of goal-directed haemodynamic therapy on postoperative complications in low-moderate risk surgical patients: a multicentre randomised controlled trial (FEDORA trial). Br J Anaesth. 2018 Apr;120(4):734-744. Open reference URL https://web.pathway.md/studies/recNUmCuHsa4X7ZNj 2/2

6/28/23, 10:41 PM Fidaxomicin for C. difficile colitis Pathway Feedback Search Clinical Topics Home Studies Fidaxomicin for C. difficile colitis Fidaxomicin for C. difficile colitis Disease Clostridioides difficile infection Trial question Is fidaxomicin noninferior to vancomycin in patients with acute C. difficile infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 55.8% female N = 629 44.2% male 629 patients (333 female, 263 male) Inclusion criteria: adults with acute symptoms of C. difficile infection and a positive result on a stool toxin test Key exclusion criteria: life-threatening or fulminant C. difficile infection, toxic megacolon, previous exposure to fidaxomicin, history of ulcerative colitis or Crohn's disease, or > 1 occurrence of C. difficile infection within 3 months before the start of the study Interventions N=302 fidaxomicin (200 mg BID PO for 10 days) N=327 vancomycin (125 mg QID PO for 10 days) Primary outcome Recurrence of infection 25.3 % 25.3 https://web.pathway.md/studies/recMkAXIOKqIliDcC 1/2 6/28/23, 10:41 PM Fidaxomicin for C. difficile colitis Pathway 19.0 % 15.4 12.7 % Significant increase 6.3 % NNH = 10 0.0 % Fidaxomicin Vancomycin Significant increase in recurrence of infection (15.4% vs. 25.3%; ARR 9.9, 95% CI -16.6 to -2.9) Secondary outcomes Significant increase in resolution of diarrhea without recurrence (74.6% vs. 64.1%; ARD 10.5, 95% CI 3.1 to 17.7) Safety outcomes No significant difference in adverse events. Conclusion In adults with acute symptoms of C. difficile infection and a positive result on a stool toxin test, fidaxomicin was noninferior to vancomycin with respect to recurrence of infection. Reference Louie TJ, Miller MA, Mullane KM et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011 Feb 3;364(5):422-31. Open reference URL https://web.pathway.md/studies/recMkAXIOKqIliDcC 2/2

6/28/23, 10:35 PM FIDELIO DKD Pathway Feedback Search Clinical Topics Home Studies FIDELIO DKD FIDELIO DKD Disease Disease Chronic kidney disease Diabetes mellitus type 2 Trial question What is the long-term effect of finerenone on CKD outcomes in T2DM patients? Study design Multi-center Double blinded RCT Population Characteristics of study participants 29.6% female N = 5734 70.4% male 5734 patients (1691 female, 3983 male) Inclusion criteria: patients with CKD and T2DM Key exclusion criteria: confirmed significant non-diabetic renal disease, uncontrolled arterial hypertension, chronic HFrEF, dialysis for acute renal failure within 12 weeks of run-in visit, renal allograft in place, scheduled kidney transplant within next 12 months, or glycated Hgb HbA1c > 12% Interventions N=2833 finerenone (10 mg or 20 mg PO once daily) N=2841 placebo (matching placebo tablet PO once daily) Primary outcome Kidney failure, sustained decline of at least 40% in eGFR from baseline, or death from renal causes 21.1 21.1 % 17.8 https://web.pathway.md/studies/recjZZkd3LcsVzSze 1/2 6/28/23, 10:35 PM FIDELIO DKD Pathway 15.8 % 10.6 % Significant decrease 5.3 % NNT = 30 0.0 % Finerenone Placebo Significant decrease in kidney failure, sustained decline of at least 40% in the eGFR from baseline, or death from renal causes (17.8% vs. 21.1%; HR 0.82, 95% CI 0.73 to 0.93) Secondary outcomes Significant decrease in death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for HF (13% vs. 14.8%; HR 0.86, 95% CI 0.75 to 0.99) No significant difference in death from any cause (7.7% vs. 8.6%; HR 0.9, 95% CI 0.75 to 1.07) No significant difference in hospitalization for any cause (44.6% vs. 46.5%; HR 0.95, 95% CI 0.88 to 1.02) Safety outcomes No significant difference in adverse events or AKI. Significant differences in serious adverse events (31.9% vs. 34.3%), hyperkalemia-related adverse events (18.3% vs. 9.0%), incidence of hyperkalemia-related discontinuation (2.3% vs. 0.9%). Conclusion In patients with CKD and T2DM, finerenone was superior to placebo with respect to kidney failure, sustained decline of at least 40% in the eGFR from baseline, or death from renal causes. Reference George L Bakris, Rajiv Agarwal, Stefan D Anker et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020 Dec 3;383(23):2219-2229. Open reference URL https://web.pathway.md/studies/recjZZkd3LcsVzSze 2/2

6/28/23, 10:35 PM FIGARO-DKD Pathway Feedback Search Clinical Topics Home Studies FIGARO DKD FIGARO DKD Disease Disease Diabetes mellitus type 2 Diabetic nephropathy Trial question What is the role of finerenone in patients with CKD and T2DM? Study design Multi-center Double blinded RCT Population Characteristics of study participants 31.0% female N = 7352 69.0% male 7352 patients (2247 female, 5105 male) Inclusion criteria: patients with T2DM and CKD treated with a renin-angiotensin system inhibitor at the maximum dose Key exclusion criteria: urinary albumin-to-creatinine ratio of 300-5,000 and an eGFR of 25 to < 60 mL/min/1.73 m , symptomatic chronic HFrEF Interventions N=3686 finerenone (oral dose of 10 or 20 mg tablet once daily) N=3666 placebo (oral dose of matching placebo once daily) Primary outcome Death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure 14.2 % 14.2 12.4 10 6 % https://web.pathway.md/studies/reciik5jup6NrERRS 1/2 6/28/23, 10:35 PM 10.6 % FIGARO-DKD Pathway 7.1 % Significant decrease 3.5 % NNT = 56 0.0 % Finerenone Placebo Significant decrease in death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for HF (12.4% vs. 14.2%; HR 0.87, 95% CI 0.76 to 0.98) Secondary outcomes No significant difference in kidney failure, 40% sustained decline in the eGFR, or death from renal causes (9.5% vs. 10.8%; HR 0.87, 95% CI 0.76 to 1.01) No significant difference in hospitalization for any cause (42.7% vs. 43.8%; HR 0.97, 95% CI 0.9 to 1.04) No significant difference in death from any cause (9% vs. 10.1%; HR 0.89, 95% CI 0.77 to 1.04) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In patients with T2DM and CKD treated with a renin-angiotensin system inhibitor at the maximum dose, finerenone was superior to placebo with respect to death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for HF. Reference Bertram Pitt, Gerasimos Filippatos, Rajiv Agarwal et al. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med. 2021 Dec 9;385(24):2252-2263. Open reference URL https://web.pathway.md/studies/reciik5jup6NrERRS 2/2

6/28/23, 10:37 PM FIRE AND ICE Pathway Feedback Search Clinical Topics Home Studies FIRE AND ICE FIRE AND ICE Disease Atrial fibrillation Trial question Is cryoballoon ablation noninferior to radiofrequency ablation in patients with drug-refractory paroxysmal AF? Study design Multi-center Open label RCT Population Characteristics of study participants 38.8% female N = 762 61.2% male 762 patients (293 female, 457 male) Inclusion criteria: symptomatic patients with drug-refractory paroxysmal AF Key exclusion criteria: pregnancy or breastfeeding, any disease limiting life expectancy to < 1 year, substance misuse, active systemic infection, cryoglobulinemia, unstable angina pectoris, symptomatic carotid stenosis, or COPD with detected pulmonary hypertension Interventions N=378 cryoballoon (pulmonary vein isolation with cryoballoon ablation with fluoroscopic guidance) N=384 radiofrequency (radiofrequency ablation using electroanatomical navigation) Primary outcome Documented clinical failure (recurrence of atrial fibrillation, occurrence of atrial flutter or atrial tachycardia, use of antiarrhythmic drugs, or repeat ablation) https://web.pathway.md/studies/recF1ItGSpSqSvnlY 1/2 6/28/23, 10:37 PM FIRE AND ICE Pathway 35.9 % 35.9 34.6 26.9 % 17.9 % Difference not exceeding nonferiority margin 9.0 % 0.0 % Cryoballoon Radiofrequency Difference not exceeding nonferiority margin in documented clinical failure (recurrence of AF, occurrence of atrial flutter or AT, use of antiarrhythmic drugs, or repeat ablation) (34.6% vs. 35.9%; HR 0.96, 96% CI 0.76 to 1.22) Secondary outcomes No significant difference in death, cerebrovascular events, or serious treatment-related adverse events at 1 year (10.2% vs. 12.8%; HR 0.78, 95% CI 0.52 to 1.18) Safety outcomes No significant difference in overall safety events. Conclusion In symptomatic patients with drug-refractory paroxysmal AF, cryoballoon was noninferior to radiofrequency with respect to documented clinical failure (recurrence of AF, occurrence of atrial flutter or AT, use of antiarrhythmic drugs, or repeat ablation). Reference Kuck KH, Brugada J, Furnkranz A et al. Cryoballoon or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation. N Engl J Med. 2016 Jun 9;374(23):2235-45. Open reference URL https://web.pathway.md/studies/recF1ItGSpSqSvnlY 2/2

6/28/23, 10:37 PM FLAME (fluoxetine) Pathway Feedback Search Clinical Topics Home Studies FLAME (fluoxetine) FLAME (fluoxetine) Disease Acute ischemic stroke Trial question What is the effect of fluoxetine in patients who have motor deficits secondary to ischemic stroke? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.0% female N = 118 61.0% male 118 patients (46 female, 72 male) Inclusion criteria: patients aged between 18-85 years with ischemic stroke and hemiplegia or hemiparesis, who had Fugl-Meyer Motor Scale scores < 55 Key exclusion criteria: severe post-stroke disability, substantial premorbid disability, clinically diagnosed with depression, receipt of antidepressants, residual motor deficit from a previous stroke, severe aphasia Interventions N=59 fluoxetine (20 mg once per day PO for 3 months starting 5-10 days after the onset of stroke) N=59 placebo (matching placebo for 3 months starting 5-10 days after the onset of stroke) Primary outcome Change in Fugl-Meyer Motor Scale scores at day 90 34.0 points 34 https://web.pathway.md/studies/recaADdxEUULKch93 1/2 6/28/23, 10:37 PM FLAME (fluoxetine) Pathway 25.5 points 24.3 17.0 points 8.5 points Significant increase 0.0 points Fluoxetine Placebo Significant increase in change in Fugl-Meyer Motor Scale scores at day 90 (34 points vs. 24.3 points; AD 9.8 points, 95% CI 3.4 to 16.1) Secondary outcomes Significant increase in mRS score of 0-2 at day 90 (26% vs. 9%; AD 17%, 95% CI 3.29 to 30.71) Significant increase in change in Montgomery Asberg Depression Rating Scale score at day 90 (-0.1 vs. 3.2; AD 3.3, 95% CI 0.28 to 6.32) Safety outcomes No significant differences in adverse events, including hyponatremia, insomnia, psychiatric disorders, and partial seizure. Significant difference in transient digestive disorders (25% vs. 11%) and hepatic enzyme disorders (9% vs. 18%). Conclusion In patients aged between 18-85 years with ischemic stroke and hemiplegia or hemiparesis, who had Fugl-Meyer Motor Scale scores < 55, fluoxetine was superior to placebo with respect to change in Fugl-Meyer Motor Scale scores at day 90. Reference Chollet F, Tardy J, Albucher JF et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 2011 Feb;10(2):123-30. Open reference URL https://web.pathway.md/studies/recaADdxEUULKch93 2/2

6/28/23, 10:37 PM FLAME (indacaterol-glycopyrronium) Pathway Feedback Search Clinical Topics Home Studies FLAME (indacaterol-glycopyrronium) FLAME (indacaterol-glycopyrronium) Disease Chronic obstructive pulmonary Trial question What is the role of indacaterol-glycopyrronium in patients with COPD who have high risk of exacerbations? Study design Multi-center Double blinded RCT Population Characteristics of study participants 24.0% female N = 3362 76.0% male 3362 patients (805 female, 2557 male) Inclusion criteria: patients who had COPD with a history of at least one exacerbation during the previous year Key exclusion criteria: type 1 or uncontrolled T2DM, history of long QT syndrome, clinically significant ECG abnormality, clinically significant renal, cardiovascular, neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, or hematological abnormalities Interventions N=1680 indacaterol and glycopyrronium (indacaterol at a dose of 110 g plus glycopyrronium at a dose of 50 g once daily by inhalation for 52 weeks) N=1682 salmeterol and fluticasone (salmeterol at a dose of 50 g plus fluticasone at a dose of 500 g BID by inhalation for 52 weeks) Primary outcome https://web.pathway.md/studies/recK7rf9aCyD4yXEi 1/2 6/28/23, 10:37 PM FLAME (indacaterol-glycopyrronium) Pathway Chronic obstructive pulmonary disease exacerbation 4.0/ p-y 4.03 3.59 3.0/ p-y 2.0/ p-y 1.0/ p-y Significant decrease 0.0/ p-y Indacaterol and glycopyrronium Salmeterol and fluticasone Significant decrease in COPD exacerbation (3.59 / p-y vs. 4.03 / p-y; RR 0.89, 95% CI 0.83 to 0.96) Secondary outcomes Significant decrease in time to first exacerbation (71 days vs. 51 days; HR 0.84, 95% CI 0.78 to 0.91) Significant decrease in moderate or severe exacerbations (0.98 vs. 1.19; RR 0.83, 95% CI 0.75 to 0.91) Significant decrease in time to first moderate or severe exacerbation (127 days vs. 87 days; HR 0.78, 95% CI 0.7 to 0.86) Safety outcomes No significant difference in incidence of adverse events and deaths. Significant difference in pneumonia (3.2% vs. 4.8%). Conclusion In patients who had COPD with a history of at least one exacerbation during the previous year, indacaterol and glycopyrronium were superior to salmeterol and fluticasone with respect to COPD exacerbation. Reference Wedzicha JA, Banerji D, Chapman KR et al. Indacaterol-Glycopyrronium versus Salmeterol- Fluticasone for COPD. N Engl J Med. 2016 Jun 9;374(23):2222-34. Open reference URL https://web.pathway.md/studies/recK7rf9aCyD4yXEi 2/2

6/28/23, 10:39 PM FLASH-UK Pathway Feedback Search Clinical Topics Home Studies FLASH UK FLASH UK Disease Diabetes mellitus type 1 Trial question What is the role of intermittently scanned continuous glucose monitoring in patients with T1DM? Study design Multi-center Open label RCT Population Characteristics of study participants 44.0% female N = 156 56.0% male 156 patients (69 female, 87 male) Inclusion criteria: adult participants with T1DM and glycated Hgb levels between 7.5-11.0% Key exclusion criteria: current use of real-time continuous glucose monitors or intermittently scanned continuous glucose monitoring for > 4 weeks within the previous 12 weeks; pregnancy or planned pregnancy; and complete loss of awareness of hypoglycemia Interventions N=78 flash glucose monitoring (intermittently scanned continuous glucose monitoring with free style libre 2 device) N=78 self-monitoring of blood glucose (monitoring own blood glucose levels with fingerstick testing) Primary outcome Glycated hemoglobin level at 24 weeks 8.3 8 3 % 7 9 https://web.pathway.md/studies/recdV4yxtXoOocrMX 1/2 6/28/23, 10:39 PM FLASH-UK Pathway 8.3 % 7.9 6.2 % 4.2 % Significant decrease 2.1 % NNT = 250 0.0 % Flash glucose monitoring Self-monitoring of blood glucose Significant decrease in glycated Hgb level at 24 weeks (7.9% vs. 8.3%; ARD -0.5, 95% CI -0.7 to -0.3) Secondary outcomes Significant increase in the percentage of time spent in target glucose range of 70-180 mg/dL at week 24 (52.1% vs. 45.2%; AD 9%, 95% CI 4.7 to 13.3) Significant decrease in time spent in hypoglycemia at week 24 (3.5% vs. 6.5%; ARD -3, 95% CI -4.5 to -1.4) Significant decrease in time spent in hyperglycemia at week 24 (44.5% vs. 48.3%; ARD -6, 95% CI -11 to -0.9) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In adult participants with T1DM and glycated Hgb levels between 7.5-11.0%, flash glucose monitoring was superior to self-monitoring of blood glucose with respect to glycated Hgb level at 24 weeks. Reference Lalantha Leelarathna, Mark L Evans, Sankalpa Neupane et al. Intermittently Scanned Continuous Glucose Monitoring for Type 1 Diabetes. N Engl J Med. 2022 Oct 20;387(16):1477- 1487. Open reference URL https://web.pathway.md/studies/recdV4yxtXoOocrMX 2/2

6/28/23, 10:39 PM FLAURA Pathway Feedback Search Clinical Topics Home Studies FLAURA FLAURA Disease Non-small cell lung cancer Trial question What is the role of osimertinib in untreated epidermal growth factor receptor-mutation-positive advanced non-small cell lung cancer? Study design Multi-center Double blinded RCT Population Characteristics of study participants 63.0% female N = 556 37.0% male 556 patients (350 female, 206 male) Inclusion criteria: patients with untreated epidermal growth factor receptor-mutation-positive advanced non-small cell lung cancer Key exclusion criteria: prior treatment with any systemic anti-cancer therapy for locally advanced/metastatic non-small cell lung cancer; alternative anti-cancer treatment; major surgery within 4 weeks of the first dose of study drug Interventions N=279 osimertinib (at a dose of 80 mg once daily) N=277 standard EGFR-TKI (gefitinib 250 mg once daily or erlotinib 150 mg once daily) Primary outcome Progression-free survival 18.9 months 18.9 https://web.pathway.md/studies/recwxfSaPLYpC8zm0 1/2 6/28/23, 10:39 PM FLAURA Pathway 14.2 months 10.2 9.4 months 4.7 months Significant increase 0.0 months Osimertinib Standard EGFR-TKI Significant increase in progression-free survival (18.9 months vs. 10.2 months; AD 8.7 months, 95% CI 3.54 to 13.86) Secondary outcomes No significant difference in objective response rate (80% vs. 76%; OR 1.27, 95% CI 0.85 to 1.9) Significant increase in survival rate at 18 months (83% vs. 71%; AD 12%, 95% CI 3.28 to 20.72) Safety outcomes No significant difference in adverse events and serious adverse events. Conclusion In patients with untreated epidermal growth factor receptor-mutation-positive advanced non- small cell lung cancer, osimertinib was superior to standard EGFR-TKI with respect to a progression-free survival. Reference Jean-Charles Soria, Yuichiro Ohe, Johan Vansteenkiste et al. Osimertinib in Untreated EGFR- Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Open reference URL https://web.pathway.md/studies/recwxfSaPLYpC8zm0 2/2

6/28/23, 10:39 PM FLAVOUR Pathway Feedback Search Clinical Topics Home Studies FLAVOUR FLAVOUR Disease Coronary artery disease Trial question Is fractional flow reserve guidance noninferior to intravascular ultrasound guidance in patients with intermediate stenosis being evaluated for PCI? Study design Multi-center Open label RCT Population Characteristics of study participants 29.0% female N = 1682 71.0% male 1682 patients (495 female, 1187 male) Inclusion criteria: adult patients being evaluated for PCI for the treatment of intermediate stenosis Key exclusion criteria: noncardiac coexisting illness; life expectancy < 2 years; target lesion in the left main coronary artery or in a CABG; increased bleeding risk Interventions N=838 fractional flow reserve guidance (criterion for revascularization, fractional flow reserve 0.80) N=844 intravascular ultrasound guidance (criterion for revascularization, minimum lumen area 3 mm or minimum lumen area 4 mm and plaque burden > 70%) Primary outcome Composite outcome of death, myocardial infarction, or revascularization at 24 months https://web.pathway.md/studies/recg0XhuHwuREAQtQ 1/2 6/28/23, 10:39 PM FLAVOUR Pathway 8.5 % 8.5 8.1 6.4 % 4.3 % Difference not exceeding nonferiority margin 2.1 % 0.0 % Fractional flow reserve guidance Intravascular ultrasound guidance Difference not exceeding nonferiority margin in composite outcome of death, myocardial infarction, or revascularization at 24 months (8.1% vs. 8.5%; ARD -0.4, 95% CI -0.7 to -0.1) Secondary outcomes No significant difference in composite outcome of death, myocardial infarction, or revascularization at 12 months (4.6% vs. 3.4%; AD 1.1%, 95% CI -0.8 to 3) No significant difference in composite outcome of death from cardiac cause, target-vessel myocardial infarction, or target-lesion revascularization (3.3% vs. 3%; AD 0.3%, 95% CI -1.4 to 1.9) Significant decrease in the percentage of patients who had undergone PCI (44.4% vs. 65.3%; ARD -20.9, 95% CI -25.7 to -16.1) Conclusion In adult patients being evaluated for PCI for the treatment of intermediate stenosis, fractional flow reserve guidance was noninferior to intravascular ultrasound guidance with respect to the composite outcome of death, myocardial infarction, or revascularization at 24 months. Reference Bon-Kwon Koo, Xinyang Hu, Jeehoon Kang et al. Fractional Flow Reserve or Intravascular Ultrasonography to Guide PCI. N Engl J Med. 2022 Sep 1;387(9):779-789. Open reference URL https://web.pathway.md/studies/recg0XhuHwuREAQtQ 2/2

6/28/23, 10:39 PM FOCUS Pathway Feedback Search Clinical Topics Home Studies FOCUS FOCUS Disease Hip fracture Trial question What is the role of liberal transfusion strategy in high-risk patients after hip surgery? Study design Multi-center Open label RCT Population Characteristics of study participants 76.0% female N = 2016 24.0% male 2016 patients (1527 female, 489 male) Inclusion criteria: patients 50 years of age with a history of or risk factors for CVD who had Hgb level < 10 g/dL after hip-fracture surgery Key exclusion criteria: unable to walk without human assistance before hip fracture, declined blood transfusions, had multiple trauma, pathologic hip fracture associated with cancer, history of clinically recognized acute myocardial infarction within 30 days before randomization, or actively bleeding at the time of potential randomization Interventions N=1007 liberal use of transfusions (a Hgb threshold of 10 g/dL) N=1009 restrictive use of transfusion (symptoms of anemia or at physician discretion for a Hgb level of < 8 g/dL) Primary outcome Death or an inability to walk across a room without human assistance at 60 days https://web.pathway.md/studies/recaSL8g5CJvdGXAU 1/2 6/28/23, 10:39 PM FOCUS Pathway 35.2 % 35.2 34.7 26.4 % 17.6 % 8.8 % No significant difference 0.0 % Liberal use of transfusions Restrictive use of transfusion No significant difference in death or an inability to walk across a room without human assistance at 60 days (35.2% vs. 34.7%; OR 1.01, 95% CI 0.84 to 1.22) Secondary outcomes No significant difference in in-hospital acute coronary syndrome or death (4.3% vs. 5.2%; OR 0.82, 99% CI 0.48 to 1.42) No significant difference in death at 60 days (7.6% vs. 6.6%; OR 1.17, 99% CI 0.75 to 1.83) Safety outcomes No significant difference in serious adverse events and in-hospital clinical events. Conclusion In patients 50 years of age with a history of or risk factors for CVD who had Hgb level < 10 g/dL after hip-fracture surgery, liberal use of transfusions were not superior to restrictive use of transfusion with respect to death or an inability to walk across a room without human assistance at 60 days. Reference Carson JL, Terrin ML, Noveck H et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011 Dec 29;365(26):2453-62. Open reference URL https://web.pathway.md/studies/recaSL8g5CJvdGXAU 2/2

6/28/23, 10:40 PM FOREST Pathway Feedback Search Clinical Topics Home Studies FOREST FOREST Disease Disease Disease Acute cystitis Acute pyelonephritis Recurre Trial question Is fosfomycin noninferior to ceftriaxone or meropenem in patients with bacteremic UTI due to multidrug-resistant E. coli? Study design Multi-center Open label RCT Population Characteristics of study participants 51.0% female N = 143 49.0% male 143 patients (73 female, 70 male) Inclusion criteria: adult patients with bacteremic UTIs due to multidrug-resistant E. coli Key exclusion criteria: septic shock, prostatitis; kidney transplantation; polycystic kidney disease; > 48 hours delay in abscess drainage or obstruction release; palliative care; liver cirrhosis; hemodialysis; allergy to study drugs; active empirical treatment > 72 hours at randomization Interventions N=70 fosfomycin (an intravenous dose of 4 g every 6 hours with an option to switch to oral dose after 4 days) N=73 comparator antibiotics (intravenous ceftriaxone 1 g daily or meropenem 1 g every 8 hours, could switch to an oral agent or IV ertapenem after 4 days) Primary outcome https://web.pathway.md/studies/recCPJqdZcTJ8yZaT 1/2 6/28/23, 10:40 PM FOREST Pathway Rate of clinical and microbiological cure 5 to 7 days after administration 78.1 % 78.1 68.6 58.6 % 39.0 % Difference exceeding nonferiority margin 19.5 % 0.0 % Fosfomycin Comparator antibiotics Difference exceeding nonferiority margin in the rate of clinical and microbiological cure 5 to 7 days after administration (68.6% vs. 78.1%; ARD -9.4, 95% CI -21.5 to Infinity) Secondary outcomes No significant difference in clinical or microbiological failure (14.3% vs. 19.7%; ARD -5.4, 95% CI -Infinity to 4.9) No significant difference in death at day 30 (3.2% vs. 2.8%; AD 0.4%, 95% CI -Infinity to 5.2) No significant difference in relapse (13.1% vs. 8.4%; AD 4.7%, 95% CI -Infinity to 13.5) Safety outcomes No significant difference in adverse events and serious adverse events. Significant difference in adverse event-related discontinuations (8.5% vs. 0%). Conclusion In adult patients with bacteremic UTIs due to multidrug-resistant E. coli, fosfomycin was not noninferior to comparator antibiotics with respect to the rate of clinical and microbiological cure 5 to 7 days after administration. Reference Jes s Sojo-Dorado, Inmaculada L pez-Hern ndez, Clara Rosso-Fernandez et al. Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections: A Randomized Clinical Trial. JAMA Netw Open. 2022 Jan 4;5(1):e2137277. Open reference URL https://web.pathway.md/studies/recCPJqdZcTJ8yZaT 2/2

6/28/23, 10:40 PM FOURIER-OLE Pathway Feedback Search Clinical Topics Home Studies FOURIER OLE FOURIER OLE Disease Disease Coronary artery disease Dyslipidemia Trial question What is the role of long-term use of evolocumab in patients with established ASCVD? Study design Multi-center Open label RCT Population Characteristics of study participants 23.0% female N = 6635 77.0% male 6635 patients (1549 female, 5086 male) Inclusion criteria: patients with a history of established ASCVD and a fasting low-density lipoprotein cholesterol level 70 mg/dL while on statin Key exclusion criteria: permanent medication discontinual due to adverse effects in the parent study; participation in another study; not being able to complete follow-up for the duration of the extension program; pregnancy Interventions N=3355 evolocumab (continuous receipt, from FOURIER study, of subcutaneous injections of either 140 mg every 2 weeks or 420 mg every month) N=3280 placebo in parent study (receipt of placebo in parent study and evolocumab in this extension study) Primary outcome https://web.pathway.md/studies/recN2ZXdvdYnS5dqB 1/2 6/28/23, 10:40 PM FOURIER-OLE Pathway Composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization 4.0 % 3.96 3.36 3.0 % 2.0 % Significant decrease 1.0 % NNT = 167 0.0 % Evolocumab Placebo in parent study Significant decrease in composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization (3.36% vs. 3.96%; HR 0.85, 95% CI 0.75 to 0.96) Secondary outcomes Significant decrease in cardiovascular death, myocardial infarction or stroke (2.05% vs. 2.58%; HR 0.8, 95% CI 0.68 to 0.93) Significant decrease in cardiovascular death (0.68% vs. 0.9%; HR 0.77, 95% CI 0.6 to 0.99) Significant decrease in coronary heart disease death or myocardial infarction (1.3% vs. 1.82%; HR 0.72, 95% CI 0.6 to 0.86) Safety outcomes No significant differences in low-density lipoprotein cholesterol levels, adverse events. Significant difference in injection site reactions (0.81% vs. 0.65%). Conclusion In patients with a history of established ASCVD and a fasting low-density lipoprotein cholesterol level 70 mg/dL while on statin, evolocumab was superior to placebo in parent study with respect to the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. Reference Michelle L O'Donoghue, Robert P Giugliano, Stephen D Wiviott et al. Long-Term Evolocumab in Patients with Established Atherosclerotic Cardiovascular Disease. Circulation. 2022 Oct 11;146(15):1109-1119. Open reference URL https://web.pathway.md/studies/recN2ZXdvdYnS5dqB 2/2

6/28/23, 10:40 PM FOURIER Pathway Feedback Search Clinical Topics Home Studies FOURIER FOURIER Disease Disease Coronary artery disease Dyslipidemia Trial question What is the role of evolocumab in patients with ASCVD and LDL cholesterol levels 70 mg/dL who were receiving statin therapy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 25.0% female N = 27564 75.0% male 27564 patients (6769 female, 20795 male) Inclusion criteria: patients with ASCVD and LDL cholesterol 70 mg/dL (1.8 mmol/L) who were receiving statin therapy Key exclusion criteria: known hemorrhagic stroke, uncontrolled or recurrent VT, uncontrolled hypertension, planned or expected cardiac surgery or revascularization within 3 months, severe renal dysfunction, pregnant or breastfeeding women Interventions N=13784 evolocumab (either 140 mg every 2 weeks or 420 mg monthly SC) N=13780 placebo (subcutaneous injections) Primary outcome Major cardiovascular events 11.3 % 11.3 https://web.pathway.md/studies/recTB7IuvQL1jb5rb 1/2 6/28/23, 10:40 PM FOURIER Pathway 9.8 8.5 % 5.7 % Significant decrease 2.8 % NNT = 67 0.0 % Evolocumab Placebo Significant decrease in major cardiovascular events (9.8% vs. 11.3%; HR 0.85, 95% CI 0.79 to 0.92) Secondary outcomes Significant decrease in cardiovascular death, myocardial infarction, or stroke (5.9% vs. 7.4%; HR 0.8, 95% CI 0.73 to 0.88) Safety outcomes No significant differences in overall adverse events, with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). Conclusion In patients with ASCVD and LDL cholesterol 70 mg/dL (1.8 mmol/L) who were receiving statin therapy, evolocumab was superior to placebo with respect to major cardiovascular events. Reference Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. Open reference URL https://web.pathway.md/studies/recTB7IuvQL1jb5rb 2/2

6/28/23, 10:40 PM FRAN Pathway Feedback Search Clinical Topics Home Studies FRAN FRAN Disease Menopause Trial question What is the effect of continuous transdermal nitroglycerin patches in women with menopause- related hot flashes? Study design Single center Double blinded RCT Population 134 female patients Inclusion criteria: perimenopausal or postmenopausal women reporting 7 hot flashes per day Key exclusion criteria: use of nitroglycerin or other nitrate-containing medications during the past 4 weeks; vaginal estrogen or progestins during the past 4 weeks or systemic estrogen during the past 12 weeks; other medications with potential efficacy for hot flashes during the past 4 weeks Interventions N=65 nitroglycerin (transdermal nitroglycerin participant-directed dose titration from 0.2-0.6 mg/hour) N=69 placebo (matching placebo patches) Primary outcome Reduction in hot flash frequency per day at week 5 4.5 4.5 3.6 3.4 2.3 1.1 No significant difference 0.0 https://web.pathway.md/studies/recELByEqDefeNPp6 1/2 6/28/23, 10:40 PM FRAN Pathway Nitroglycerin Placebo No significant difference in reduction in hot flash frequency per day at week 5 (4.5 vs. 3.6; AD 0.9, 95% CI -2.1 to 0.3) Secondary outcomes Borderline significant increase in reduction in moderate-to-severe hot flashes per day at week 5 (3.3 vs. 2.2; AD 1.1, 95% CI 0 to 2.2) No significant difference in reduction in total daily diary-based hot flash severity score at week 5 (8.3 vs. 6.1; AD 2.2, 95% CI -0.4 to 4.7) No significant difference in reduction in hot flash frequency per day at week 12 (4.6 vs. 4.7; AD -0.1, 95% CI -1.2 to 1.4) Safety outcomes No significant differences in adverse event, headache. Significant difference in headache at week 1 (65.7% vs. 5.6%). Conclusion In perimenopausal or postmenopausal women reporting 7 hot flashes per day, nitroglycerin was not superior to placebo with respect to reduction in hot flash frequency per day at week 5. Reference Alison J Huang, Steven R Cummings, Peter Ganz et al. Efficacy of Continuous Transdermal Nitroglycerin for Treating Hot Flashes by Inducing Nitrate Cross-tolerance in Perimenopausal and Postmenopausal Women: A Randomized Clinical Trial. JAMA Intern Med. 2023 Jun 5;e231977. Open reference URL https://web.pathway.md/studies/recELByEqDefeNPp6 2/2

6/28/23, 10:42 PM Franklin Pathway Feedback Search Clinical Topics Home Studies Franklin Franklin Disease Bronchiolitis Trial question What is the role of high-flow oxygen therapy among infants with bronchiolitis who were treated outside an ICU? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 1472 63.0% male 1472 patients (547 female, 925 male) Inclusion criteria: infants younger than 12 months of age who had bronchiolitis and a need for supplemental oxygen therapy Key exclusion criteria: critically illness with an immediate need for respiratory support; cyanotic heart disease, basal skull fracture, upper airway obstruction, or craniofacial malformation; and receipt of oxygen therapy at home Interventions N=739 high-flow (heated and humidified oxygen delivered at a rate of 2 L/kg of body weight per minute by Optiflow Junior cannula and Airvo 2 high-flow system) N=733 standard therapy (supplemental oxygen through a nasal cannula, up to a maximum of 2 L/min) Primary outcome https://web.pathway.md/studies/recSyMH4vLuaZun1Y 1/2 6/28/23, 10:42 PM Franklin Pathway Escalation of care due to treatment failure 23.0 % 23 17.3 % 12 11.5 % Significant decrease 5.8 % NNT = 9 0.0 % High-flow Standard therapy Significant decrease in escalation of care due to treatment failure (12% vs. 23%; ARD -11, 95% CI -15 to -7) Secondary outcomes No significant difference in duration of hospital stay (3.12 days vs. 2.94 days; AD 0.18 days, 95% CI -0.09 to 0.44) No significant difference in duration of ICU stay (2.63 days vs. 2.72 days; AD -0.09 days, 95% CI -0.74 to 0.55) No significant difference in duration of oxygen therapy (1.81 days vs. 1.87 days; AD -0.06 days, 95% CI -0.28 to 0.16) Safety outcomes No significant difference in adverse events. Significant difference in the respiratory rate at the time of escalation of care (62.6 breaths/min vs. 54.6 breaths/min). Conclusion In infants younger than 12 months of age who had bronchiolitis and a need for supplemental oxygen therapy, high-flow was superior to standard therapy with respect to escalation of care due to treatment failure. Reference Donna Franklin, Franz E Babl, Luregn J Schlapbach et al. A Randomized Trial of High-Flow Oxygen Therapy in Infants with Bronchiolitis. N Engl J Med. 2018 Mar 22;378(12):1121-1131. Open reference URL https://web.pathway.md/studies/recSyMH4vLuaZun1Y 2/2

6/28/23, 10:40 PM FREEDOM Pathway Feedback Search Clinical Topics Home Studies FREEDOM FREEDOM Disease Disease Disease Coronary artery disease Diabetes mellitus type 1 Diabete Trial question What is the role of PCI with drug-eluting stents in patients with diabetes and multivessel coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 29.0% female N = 1900 71.0% male 1900 patients (544 female, 1356 male) Inclusion criteria: patients with diabetes and multivessel coronary artery disease Key exclusion criteria: severe congestive HF, prior CABG surgery, prior cardiac valve surgery, prior PCI with stent implantation within 6 months, previous stroke within 6 months, history of significant bleeding, or dementia Interventions N=953 percutaneous coronary artery intervention (sirolimus-eluting and paclitaxel-eluting stents plus aspirin and clopidogrel for at least 12 months) N=947 CABG (on/off pump surgery with arterial revascularization plus aspirin and clopidogrel for at least 12 months) Primary outcome Death from any cause, nonfatal myocardial infarction, or nonfatal stroke at 5 years https://web.pathway.md/studies/recLVhOw5JqWMqsN5 1/2 6/28/23, 10:40 PM FREEDOM Pathway 26.6 % 26.6 20.0 % 18.7 13.3 % Significant increase 6.7 % NNH = 13 0.0 % Percutaneous coronary artery intervention Coronary artery bypass graft Significant increase in death from any cause, nonfatal myocardial infarction, or nonfatal stroke at 5 years (26.6% vs. 18.7%; AD 7.9%, 95% CI 3.3 to 12.5) Secondary outcomes Significant increase in major adverse cardiovascular and cerebrovascular events at 1 year (16.8% vs. 11.8%; RR 1.42, 95% CI 0.45 to 2.39) No significant difference in death at 1 year (3.4% vs. 4.2%; RR 0.81, 95% CI -0.87 to 2.49) Significant increase in repeat revascularization at 1 year (12.6% vs. 4.8%; RR 2.63, 95% CI 1.07 to 4.19) Safety outcomes No significant difference in major bleeding event within 30 days after index revascularization. Significant difference in acute renal failure requiring hemodialysis within 30 days after index revascularization (0.1% vs. 0.8%). Conclusion In patients with diabetes and multivessel coronary artery disease, percutaneous coronary artery intervention was inferior to CABG with respect to death from any cause, nonfatal myocardial infarction, or nonfatal stroke at 5 years. Reference Farkouh ME, Domanski M, Sleeper LA et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012 Dec 20;367(25):2375-84. Open reference URL https://web.pathway.md/studies/recLVhOw5JqWMqsN5 2/2

6/28/23, 10:41 PM FRISC-II Pathway Feedback Search Clinical Topics Home Studies FRISC II FRISC II Disease Disease Disease Coronary artery disease Non-ST-elevation myocardial inf ST-elev Trial question Is early invasive treatment strategy superior to non-invasive treatment strategy in patients with unstable coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 30.0% female N = 2457 70.0% male 2457 patients (749 female, 1708 male) Inclusion criteria: patients with unstable coronary artery disease Key exclusion criteria: on waiting list for coronary revascularization, other acute or severe cardiac disease, renal or hepatic insufficiency, osteoporosis, hypersensitivity to randomized drugs, previous open-heart surgery, or advanced age (eg, > 75 years) Interventions N=1222 early invasive treatment (target to perform all invasive procedures, aiming for revascularization, within 7 days of starting open-label dalteparin) N=1235 non-invasive treatment (coronary angiography in patients with refractory or recurrent symptoms, despite maximum medical treatment, or severe ischemia on a symptom-limited exercise test before discharge) Primary outcome https://web.pathway.md/studies/recE4aT6TtWKDjWwD 1/2 6/28/23, 10:41 PM FRISC-II Pathway Death or MI 12.1 % 12.1 9.4 9.1 % 6.0 % Significant decrease 3.0 % NNT = 37 0.0 % Early invasive treatment Non-invasive treatment Significant decrease in death or MI (12.1% vs. 9.4%; RR 0.78, 95% CI 0.62 to 0.98) Secondary outcomes Significant decrease in myocardial infarction (10.1% vs. 7.8%; RR 0.77, 95% CI 0.6 to 0.99) No significant difference in death (1.9% vs. 2.9%; RR 0.65, 95% CI 0.39 to 1.09) Safety outcomes No significant difference in stroke (0.2% vs. 0.2%) and thrombocytopenia (0.1% vs. 0.1%). Significant difference in serious adverse events (3.8% vs. 1.6%) and major bleeding (1.6% vs. 0.7%). Conclusion In patients with unstable coronary artery disease, early invasive treatment was superior to non- invasive treatment with respect to death or MI. Reference FRISC II Investigators. Invasive compared with non-invasive treatment in unstable coronary- artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet. 1999 Aug 28;354(9180):708-15. Open reference URL https://web.pathway.md/studies/recE4aT6TtWKDjWwD 2/2

6/28/23, 10:55 PM GALA-RIF Pathway Feedback Search Clinical Topics Home Studies GALA RIF GALA RIF Disease Disease Alcohol-related liver disease Alcoholic hepatitis Trial question What is the role of rifaximin-alpha in patients with ALD? Study design Single center Double blinded RCT Population Characteristics of study participants 16.0% female N = 136 84.0% male 136 patients (22 female, 114 male) Inclusion criteria: adults, aged 18-75 years, who had current or previous alcohol overuse, biopsy-proven ALD, and no previous hepatic decompensation Key exclusion criteria: known allergy to rifaximin; antibiotic treatment in the previous 4 weeks; contraindications for liver biopsy; cancer or other debilitating disease with a life expectancy < 1 year Interventions N=68 rifaximin-alpha (an oral dose of 550 mg BID for 18 months) N=68 placebo (matching placebo for 18 months) Primary outcome Regression of liver fibrosis per-protocol analysis 28.0 % 28 26 21 0 % https://web.pathway.md/studies/rec4QzOKopZmwjVZx 1/2 6/28/23, 10:55 PM 21.0 % GALA-RIF Pathway 14.0 % 7.0 % No significant difference 0.0 % Rifaximin-alpha Placebo No significant difference in regression of liver fibrosis the per-protocol analysis (26% vs. 28%; OR 1.1, 95% CI 0.45 to 2.68) Secondary outcomes Significant decrease in progression of liver fibrosis in the per-protocol analysis (24% vs. 43%; OR 0.42, 95% CI 0.18 to 0.98) No significant difference in regression of hepatic lobular inflammation (50% vs. 33%; OR 0.5, 95% CI 0.22 to 1.11) No significant difference in progression of hepatic steatosis (26% vs. 35%; OR 0.64, 95% CI 0.28 to 1.47) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In adults, aged 18-75 years, who had current or previous alcohol overuse, biopsy-proven ALD, and no previous hepatic decompensation, rifaximin-alpha was not superior to placebo with respect to regression of liver fibrosis the per-protocol analysis. Reference Mads Israelsen, Bj rn St hr Madsen, Nikolaj Torp et al. Rifaximin- for liver fibrosis in patients with alcohol-related liver disease (GALA-RIF): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol. 2023 Jun;8(6):523-532. Open reference URL https://web.pathway.md/studies/rec4QzOKopZmwjVZx 2/2

6/28/23, 10:56 PM GastroPOC Pathway Feedback Search Clinical Topics Home Studies GastroPOC GastroPOC Disease Disease Acute diarrhea Clostridioides difficile infection Trial question What is the role of syndromic molecular point-of-care testing in patients hospitalized with suspected gastroenteritis? Study design Single center Open label RCT Population Characteristics of study participants 49.0% female N = 277 51.0% male 277 patients (137 female, 140 male) Inclusion criteria: adult patients hospitalized with suspected gastroenteritis Key exclusion criteria: palliative approach being taken by treating clinician, previously included in the study and re-presenting within 30 days after hospital discharge, declination of stool sample or rectal swab Interventions N=137 molecular point-of-care testing (syndromic molecular point-of-care testing of stool or rectal samples) N=140 routine clinical care (stool testing done by standard laboratory testing at the discretion of clinical team) Primary outcome Duration of single-occupancy room isolation https://web.pathway.md/studies/recrPULNQqZeQQ3ua 1/2 6/28/23, 10:56 PM GastroPOC Pathway 2.6 days 2.6 2.0 days 1.8 1.3 days 0.7 days Significant decrease 0.0 days Molecular point-of-care testing Routine clinical care Significant decrease in duration of single-occupancy room isolation (1.8 days vs. 2.6 days; AD -0.8 days, 95% CI -1.3 to -0.3) Secondary outcomes Significant decrease in time to study results (1.7 hours vs. 44.7 hours; AD -43.9 hours, 95% CI -49.3 to -38.4) Significant decrease in time to de-isolation (0.6 days vs. 2.2 days; AD -1.5 days, 95% CI -2.2 to -0.8) Significant increase in antibiotic use (65% vs. 47%; AD 18%, 95% CI 6 to 29) Safety outcomes No significant differences in ICU admission, hospital deaths, readmission and re-presentation within 30 days. Conclusion In adult patients hospitalized with suspected gastroenteritis, molecular point-of-care testing was superior to routine clinical care with respect to duration of single-occupancy room isolation. Reference Nathan J Brendish, Kate R Beard, Ahalya K Malachira et al. Clinical impact of syndromic molecular point-of-care testing for gastrointestinal pathogens in adults hospitalised with suspected gastroenteritis (GastroPOC): a pragmatic, open-label, randomised controlled trial. Lancet Infect Dis. 2023 Apr 25;S1473-3099(23)00066-X. Open reference URL https://web.pathway.md/studies/recrPULNQqZeQQ3ua 2/2

6/28/23, 10:55 PM GEMINI 1 Pathway Feedback Search Clinical Topics Home Studies GEMINI 1 GEMINI 1 Trial question What is the role of pilocarpine hydrochloride ophthalmic solution in patients with presbyopia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 73.0% female N = 323 27.0% male 323 patients (235 female, 88 male) Inclusion criteria: patients aged 40-55 years with presbyopia Key exclusion criteria: severe dry eye disease; history of intraocular surgery; history of glaucoma or ocular hypertension; anisocoria of > 1 mm between pupils under mesopic conditions Interventions N=163 pilocarpine hydrochloride (one drop of pilocarpine hydrochloride 1.25% in each eye, once daily, for up to 30 days) N=160 placebo (one drop of vehicle in each eye, once daily, for up to 30 days) Primary outcome Rate of the percentage of patients with improved mesopic, high-contrast, binocular distance- corrected near visual acuity at hour 3 on day 30 30.7 % 30.7 23.0 % 15.3 % Significant increase 8.1 7.7 % https://web.pathway.md/studies/recfl3gyT5eNJxuci 1/2 6/28/23, 10:55 PM GEMINI 1 Pathway NNH = 4 0.0 % Pilocarpine hydrochloride Placebo Significant increase in the rate of the percentage of patients with improved mesopic, high- contrast, binocular distance-corrected near visual acuity at hour 3 on day 30 (30.7% vs. 8.1%; AD 22.5%, 95% CI 14.3 to 30.8) Secondary outcomes Significant increase in the rate of the percentage of patients with improved mesopic, high- contrast, binocular distance-corrected near visual acuity at hour 6 on day 30 (18.4% vs. 8.8%; AD 9.7%, 95% CI 2.3 to 17) Significant increase in the rate of the percentage of patients who achieved 20/40 or better photopic, high-contrast, binocular distance-corrected near visual acuity at hour 1 on day 30 (92.5% vs. 73.9%; AD 18.7%, 95% CI 10.6 to 26.7) Significant increase in mean improvement of mesopic, high-contrast, binocular distance- corrected near visual acuity at hour 0.5 on day 30 (9.3 vs. 4.2; MD 5.1, 95% CI 3.7 to 6.5) Safety outcomes No significant difference in adverse events. Conclusion In patients aged 40-55 years with presbyopia, pilocarpine hydrochloride was superior to placebo with respect to the rate of the percentage of patients with improved mesopic, high-contrast, binocular distance-corrected near visual acuity at hour 3 on day 30. Reference George O Waring th, Francis W Price Jr, David Wirta et al. Safety and Efficacy of AGN-190584 in Individuals With Presbyopia: The GEMINI 1 Phase 3 Randomized Clinical Trial. JAMA Ophthalmol. 2022 Mar 3;e220059. Open reference URL https://web.pathway.md/studies/recfl3gyT5eNJxuci 2/2

6/28/23, 10:55 PM GLUCONTROL Pathway Feedback Search Clinical Topics Home Studies GLUCONTROL GLUCONTROL Disease In-hospital hyperglycemia Trial question Is intensive glucose control superior to intermediate glucose control in patients in the ICU? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 1078 63.0% male 1078 patients (400 female, 678 male) Inclusion criteria: adult patients admitted to medical or surgical ICUs Key exclusion criteria: life expectancy below 24 hours; absence of informed consent Interventions N=536 intensive glucose control (blood glucose target 4.4-6.1 mmol/L) N=542 intermediate glucose control (blood glucose target 7.8-10.0 mmol/L) Primary outcome Death from any cause in intensive care unit 17.2 % 17.2 15.3 12.9 % 8.6 % https://web.pathway.md/studies/rec1pl3YPjZYp0sii 1/2 6/28/23, 10:55 PM GLUCONTROL Pathway 4.3 % No significant difference 0.0 % Intensive glucose control Intermediate glucose control No significant difference in death from any cause in the ICU (17.2% vs. 15.3%; AD 1.9%, 95% CI -2.55 to 6.35) Secondary outcomes No significant difference in death from any cause at day 28 (18.7% vs. 15.3%; AD 3.4%, 95% CI -1.11 to 7.91) No significant difference in death in the hospital at day 28 (23.3% vs. 19.4%; AD 3.9%, 95% CI -0.88 to 8.68) Safety outcomes Significant difference in hypoglycemia (8.7% vs. 2.7%). Conclusion In adult patients admitted to medical or surgical ICUs, intensive glucose control was not superior to intermediate glucose control with respect to death from any cause in the ICU. Reference Jean-Charles Preiser, Philippe Devos, Sergio Ruiz-Santana et al. A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study. Intensive Care Med. 2009 Oct;35(10):1738-48. Open reference URL https://web.pathway.md/studies/rec1pl3YPjZYp0sii 2/2

6/28/23, 10:56 PM GRACE-VAP Pathway Feedback Search Clinical Topics Home Studies GRACE VAP GRACE VAP Disease Ventilator-associated pneumonia Trial question Is Gram stain-guided antibiotic therapy noninferior to guideline-based antibiotic therapy in patients with ventilator-associated pneumonia? Study design Multi-center Open label RCT Population Characteristics of study participants 32.0% female N = 206 68.0% male 206 patients (65 female, 141 male) Inclusion criteria: patients with ventilator-associated pneumonia in the ICU Key exclusion criteria: known allergy to study medications; discharge from ICU; HF; atelectasis; receipt of antibiotics for > 24 hours; withdrawal or withholding of life support; COVID-19 infection Interventions N=103 Gram stain-guided antibiotic therapy (selection of antibiotics guided by Gram staining of the endotracheal aspirate) N=103 guideline-based antibiotic therapy (combination of an anti-pseudomonal agent and anti- MRSA agent) Primary outcome Clinical response https://web.pathway.md/studies/recSj8dxIZWD0L9G8 1/2 6/28/23, 10:56 PM GRACE-VAP Pathway 76.7 % 76.7 71.8 57.5 % 38.4 % Difference not exceeding nonferiority margin 19.2 % 0.0 % Gram stain-guided antibiotic therapy Guideline-based antibiotic therapy Difference not exceeding nonferiority margin in clinical response (76.7% vs. 71.8%; AD 5%, 95% CI -7 to 17) Secondary outcomes No significant difference in death at day 28 (13.6% vs. 17.5%; HR 0.74, 95% CI 0.37 to 1.48) Significant decrease in the use of antipseudomonal agents (69.9% vs. 100%; ARD -30.1, 95% CI -21.5 to -39.9) Significant decrease in the use of anti-MRSA agents (61.2% vs. 100%; AD -38.8%, 95% CI -29.4 to -48.9) Safety outcomes No significant differences in adverse events, ICU-free days, ventilator-free days. Conclusion In patients with ventilator-associated pneumonia in the ICU, Gram stain-guided antibiotic therapy was noninferior to guideline-based antibiotic therapy with respect to clinical response. Reference Jumpei Yoshimura, Kazuma Yamakawa, Yoshinori Ohta et al. Effect of Gram Stain-Guided Initial Antibiotic Therapy on Clinical Response in Patients With Ventilator-Associated Pneumonia: The GRACE-VAP Randomized Clinical Trial. JAMA Netw Open. 2022 Apr 1;5(4):e226136. Open reference URL https://web.pathway.md/studies/recSj8dxIZWD0L9G8 2/2

6/28/23, 10:56 PM GREAT Pathway Feedback Search Clinical Topics Home Studies GREAT GREAT Trial question Are second-generation hydrogel coils superior to bare platinum coils in patients with small-to- medium-sized intracranial aneurysms? Study design Multi-center Open label RCT Population Characteristics of study participants 69.0% female N = 484 31.0% male 484 patients (333 female, 151 male) Inclusion criteria: adult patients with untreated small-to-medium-sized intracranial aneurysms Key exclusion criteria: previous randomization in the trial; treatment of > 1 aneurysm in the same treatment episode; previous treatment of aneurysm by coiling or clipping Interventions N=243 hydrogel coil (endovascular embolization with second-generation hydrogel coils) N=241 bare platinum coil (endovascular embolization with bare platinum coils) Primary outcome Percentage of patients with unfavorable angiographic and clinical events 28.7 % 28.7 21.5 % 19.9 14.3 % Significant decrease 7.2 % NNT = 11 0.0 % Hydrogel coil Bare platinum coil https://web.pathway.md/studies/recB7D4V9Voejk9PE 1/2 6/28/23, 10:56 PM GREAT Pathway Significant decrease in the percentage of patients with unfavorable angiographic and clinical events (19.9% vs. 28.7%; ARD -8.4, 95% CI -16.2 to -0.5) Secondary outcomes Significant increase in the achievement of a greater aneurysm packing density (39% vs. 31%; AD 8%, 95% CI 3.25 to 12.75) No significant difference in death from any cause at day 14 (2% vs. 2.1%; ARD -0.1, 95% CI -3.1 to 3.2) Safety outcomes No significant difference in procedural complications; adverse events at 18 months. Conclusion In adult patients with untreated small-to-medium-sized intracranial aneurysms, hydrogel coil was superior to bare platinum coil with respect to the percentage of patients with unfavorable angiographic and clinical events. Reference Christian A Taschner, Ren Chapot, Vincent Costalat et al. Second-Generation Hydrogel Coils for the Endovascular Treatment of Intracranial Aneurysms: A Randomized Controlled Trial. Stroke. 2018 Mar;49(3):667-674. Open reference URL https://web.pathway.md/studies/recB7D4V9Voejk9PE 2/2

6/28/23, 10:56 PM GRECCO-19 Pathway Feedback Search Clinical Topics Home Studies GRECCO 19 GRECCO 19 Disease COVID 19 infection Trial question What is the effect of colchicine in patients hospitalized with COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 42.0% female N = 105 58.0% male 105 patients (44 female, 61 male) Inclusion criteria: patients hospitalized with COVID-19 Key exclusion criteria: pregnancy or lactation, known hypersensitivity to colchicine, known hepatic failure, eGFR < 20 mL/min/1.73 m , corrected QT interval > 450 milliseconds Interventions N=55 colchicine (1.5-mg loading dose followed by 0.5 mg after 60 min and maintenance doses of 0.5 mg BID with standard medical treatment for as long as 3 weeks) N=50 control (standard medical treatment) Primary outcome Time to clinical deterioration rate 14.0 % 14 10 5 % https://web.pathway.md/studies/recgB7LEatPrdQqd2 1/2 6/28/23, 10:56 PM 10.5 % GRECCO-19 Pathway 7.0 % Significant decrease 3.5 % NNT = 8 1.8 0.0 % Colchicine Control Significant decrease in time to clinical deterioration rate (1.8% vs. 14%; OR 0.11, 95% CI 0.01 to 0.96) Secondary outcomes Significant decrease in median maximum CRP levels (3.1 mg/dL vs. 4.5 mg/dL; AD -4.75 mg/dL, 95% CI -19.1 to -9.6) Significant decrease in median peak high-sensitivity cardiac troponin values (0.008 ng/mL vs. 0.011 ng/mL; AD -0.0017 ng/mL, 95% CI 0 to 0) Significant increase in the rate of cumulative event-free 10 day survival (97% vs. 83%; AD 14%, 95% CI 1.34 to 26.66) Safety outcomes No significant differences in adverse events, vomiting, diarrhea requiring study discontinuation, nausea, muscle spasm, headache. Significant difference in diarrhea (45.5% vs. 18.0%). Conclusion In patients hospitalized with COVID-19, colchicine was superior to control with respect to time to clinical deterioration rate. Reference Spyridon G Deftereos, Georgios Giannopoulos, Dimitrios A Vrachatis et al. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial. JAMA Netw Open. 2020 Jun 1;3(6):e2013136. Open reference URL https://web.pathway.md/studies/recgB7LEatPrdQqd2 2/2

6/28/23, 10:57 PM Gujjar Pathway Feedback Search Clinical Topics Home Studies Gujjar Gujjar Disease Status epilepticus Trial question What is the role of intravenous levetiracetam in patients with status epilepticus and cluster seizures? Study design Single center Open label RCT Population Characteristics of study participants 32.0% female N = 115 68.0% male 115 patients (37 female, 78 male) Inclusion criteria: adult patients with status epilepticus or cluster seizures, following an initial dose of IV benzodiazepine to control ongoing seizure Key exclusion criteria: known allergy to drugs used, requiring immediate neurosurgery, hemodynamic compromise, serious arrhythmias, pregnancy, cardiac failure or pulmonary edema, in pre-terminal states, or having pseudo-seizures Interventions N=22 + 38 levetiracetam (intravenous dosage of 30 mg/kg over 30 min for status epilepticus and cluster seizures) N=30 + 25 phenytoin (intravenous dosage of 20 mg/kg over 30 min for status epilepticus and cluster seizures) Primary outcome https://web.pathway.md/studies/reck4zFlasiYQFPzL 1/2 6/28/23, 10:57 PM Gujjar Pathway Seizure control over 24 hour 82.0 % 82 73.3 61.5 % 41.0 % 20.5 % No significant difference 0.0 % Levetiracetam Phenytoin No significant difference in seizure control over 24 hour (82% vs. 73.3%; RR 1.12, 95% CI -1.11 to 3.35) Secondary outcomes No significant difference in poor outcome with modified Rankin score 4-6 (45% vs. 60%; RR 0.75, 95% CI -0.63 to 2.13) Safety outcomes No significant difference in adverse events. Conclusion In adult patients with status epilepticus or cluster seizures, following an initial dose of IV benzodiazepine to control ongoing seizure, levetiracetam was not superior to phenytoin with respect to seizure control over 24 hour. Reference Arunodaya R Gujjar, Ramachandiran Nandhagopal, Poovathoor C Jacob et al. Intravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study. Seizure. 2017 Jul;49:8-12. Open reference URL https://web.pathway.md/studies/reck4zFlasiYQFPzL 2/2

6/28/23, 11:00 PM HACA Pathway Feedback Search Clinical Topics Home Studies HACA HACA Disease Disease Cardiac arrest Ventricular arrhythmias Trial question Is hypothermia superior to normothermia in patients who have been successfully resuscitated after cardiac arrest due to VF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 24.0% female N = 275 76.0% male 275 patients (65 female, 210 male) Inclusion criteria: patients who have been successfully resuscitated after cardiac arrest due to VF Key exclusion criteria: a tympanic-membrane temperature below 30 C on admission, a comatose state before the cardiac arrest, pregnancy, a terminal illness that preceded the arrest, or a known preexisting coagulopathy Interventions N=136 therapeutic hypothermia (target temperature, 32 C to 34 C, measured in the bladder over a period of 24 hours) N=137 normothermia (standard treatment and maintenance of normothermia) Primary outcome Favorable neurologic outcome https://web.pathway.md/studies/recxZlYVGmaXmSngO 1/2 6/28/23, 11:00 PM HACA Pathway 55.0 % 55 41.3 % 39 27.5 % Significant increase 13.8 % NNT = 6 0.0 % Therapeutic hypothermia Normothermia Significant increase in favorable neurologic outcome (55% vs. 39%; RR 1.4, 95% CI 1.08 to 1.81) Secondary outcomes Significant decrease in death at 6 months (41% vs. 55%; RR 0.74, 95% CI 0.58 to 0.95) Safety outcomes No significant difference in complication rate. Conclusion In patients who have been successfully resuscitated after cardiac arrest due to VF, therapeutic hypothermia was superior to normothermia with respect to favorable neurologic outcome. Reference HACA Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002 Feb 21;346(8):549-56. Open reference URL https://web.pathway.md/studies/recxZlYVGmaXmSngO 2/2

6/28/23, 11:01 PM HALT-IT Pathway Feedback Search Clinical Topics Home Studies HALT IT HALT IT Disease Disease Disease Lower gastrointestinal bleeding Non-variceal upper gastrointesti Varicea Trial question What is the effect of a high-dose 24-hour infusion of tranexamic acid in patients with acute gastrointestinal bleeding? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 12009 64.0% male 12009 patients (4266 female, 7743 male) Inclusion criteria: adult patients with significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding Key exclusion criteria: the responsible clinician's 'uncertainty' as to whether or not to use an antifibrinolytic agent in a particular patient with upper or lower gastrointestinal bleeding Interventions N=5994 tranexamic acid (slow intravenous infusion of a 1 g loading dose followed by a maintenance dose of 3 g for 24 hours) N=6015 placebo (matching intravenous infusion of sodium chloride 0.9%) Primary outcome Rate of death due to bleeding within 5 days 3.8 3.8 % 3.7 https://web.pathway.md/studies/recXvWfP4jGec0hyO 1/2 6/28/23, 11:01 PM HALT-IT Pathway 3 2.8 % 1.9 % 0.9 % No significant difference 0.0 % Tranexamic acid Placebo No significant difference in the rate of death due to bleeding within 5 days (3.7% vs. 3.8%; RR 0.99, 99% CI 0.82 to 1.18) Secondary outcomes No significant difference in arterial thromboembolic events (myocardial infarction or stroke) (0.7% vs. 0.8%; RR 0.92, 95% CI 0.6 to 1.39) Borderline significant increase in venous thromboembolic events (deep vein thrombosis or PE) (0.8% vs. 0.4%; RR 1.85, 95% CI 1.15 to 2.98) No significant difference in the rate of death from all-causes within 28 days (9.5% vs. 9.2%; RR 1.03, 95% CI 0.92 to 1.16) Safety outcomes No significant differences in renal failure, liver failure, respiratory failure, cardiac events, sepsis, pneumonia, days in ICU, and Katz score. Significant differences in seizure (0.6% vs. 0.4%), deep vein thrombosis (0.4% vs. 0.2%), pulmonary thrombosis (0.5% vs.s 0.3%). Conclusion In adult patients with significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding, tranexamic acid was not superior to placebo with respect to the rate of death due to bleeding within 5 days. Reference HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020 Jun 20;395(10241):1927-1936. Open reference URL https://web.pathway.md/studies/recXvWfP4jGec0hyO 2/2

6/28/23, 11:08 PM HandiCAP Pathway Feedback Search Clinical Topics Home Studies HandiCAP HandiCAP Trial question What is the effect of intraoperative handovers of anesthesia care in adults undergoing extended surgical procedures? Study design Multi-center Single blinded RCT Population Characteristics of study participants 44.0% female N = 1772 56.0% male 1772 patients (775 female, 997 male) Inclusion criteria: adult patients scheduled for major inpatient surgery expected to last at least 2 hours Key exclusion criteria: pregnancy; previous surgery by the same specialty within 6 months; participation in another interventional trial within the last 3 months Interventions N=891 handover of care (at least one complete transition of care from 1 anesthesiologist to another during surgery) N=881 no handover of care (same anesthesiologist from anesthesia induction to end of surgical procedure) Primary outcome Composite of death, hospital readmission, or serious postoperative complications at day 30 32.5 % 32.5 30.1 24.4 % 16.3 % 8.1 % No significant difference 0.0 % https://web.pathway.md/studies/recJu1uio1YZxxxnK 1/2 6/28/23, 11:08 PM HandiCAP Pathway 0 0 % Handover of care No handover of care No significant difference in composite of death, hospital readmission, or serious postoperative complications at day 30 (30.1% vs. 32.5%; OR 0.89, 95% CI 0.72 to 1.1) Secondary outcomes No significant difference in death from all causes at day 30 (2.1% vs. 3.4%; OR 0.61, 95% CI 0.34 to 1.1) No significant difference in hospital readmission at day 30 (13% vs. 15.6%; OR 0.8, 95% CI 0.61 to 1.05) No significant difference in the rate of serious postoperative complications within 30 days (21.9% vs. 21.6%; OR 1.02, 95% CI 0.81 to 1.28) Conclusion In adult patients scheduled for major inpatient surgery expected to last at least 2 hours, handover of care was not superior to no handover of care with respect to the composite of death, hospital readmission, or serious postoperative complications at day 30. Reference Melanie Meersch, Raphael Weiss, Mira K llmar et al. Effect of Intraoperative Handovers of Anesthesia Care on Mortality, Readmission, or Postoperative Complications Among Adults: The HandiCAP Randomized Clinical Trial. JAMA. 2022 Jun 28;327(24):2403-2412. Open reference URL https://web.pathway.md/studies/recJu1uio1YZxxxnK 2/2

6/28/23, 11:01 PM HARP-2 (secondary analysis) Pathway Feedback Search Clinical Topics Home Studies HARP 2 (secondary analysis) HARP 2 (secondary analysis) Disease Acute respiratory distress syndr Trial question What is the role of simvastatin in patients with ARDS? Study design Multi-center Double blinded RCT Population Characteristics of study participants 43.0% female N = 511 57.0% male 511 patients (220 female, 291 male) Inclusion criteria: patients with acute lung injury or ARDS admitted to the ICU within the previous 48 hours Key exclusion criteria: assessed > 48 hours after onset of ARDS, pregnancy, receipt of statins within the previous 2 weeks, severe liver disease, severe renal impairment without receipt of RRT Interventions N=247 simvastatin (at a dose of 80 mg/day for up to 28 days) N=264 placebo (matching placebo for 28 days) Primary outcome Death at day 28 in group with high baseline plasma interleukin-18 36.8 % 36.8 https://web.pathway.md/studies/recA4NuARFylY4Rba 1/2 6/28/23, 11:01 PM HARP-2 (secondary analysis) Pathway 27.6 % 24 18.4 % Significant decrease 9.2 % NNT = 8 0.0 % Simvastatin Placebo Significant decrease in death at day 28 in group with high baseline plasma IL-18 (24% vs. 36.8%; RR 0.65, 95% CI 0.16 to 1.14) Secondary outcomes No significant difference in death at day 28 in group with low baseline plasma IL-18 (17.8% vs. 17.2%; RR 1.04, 95% CI -5.03 to 7.11) Conclusion In patients with acute lung injury or ARDS admitted to the ICU within the previous 48 hours, simvastatin was superior to placebo with respect to death at day 28 in group with high baseline plasma IL-18. Reference Andrew James Boyle, Peter Ferris, Ian Bradbury et al. Baseline plasma IL-18 may predict simvastatin treatment response in patients with ARDS: a secondary analysis of the HARP-2 randomised clinical trial. Crit Care. 2022 Jun 7;26(1):164. Open reference URL https://web.pathway.md/studies/recA4NuARFylY4Rba 2/2

6/28/23, 11:01 PM HEARTMATE II Pathway Feedback Search Clinical Topics Home Studies HEARTMATE II HEARTMATE II Disease Heart failure Trial question What is the role of continuous-flow LV assist device in patients with advanced HF? Study design Multi-center Open label RCT Population Characteristics of study participants 15.8% female N = 200 84.2% male 200 patients (31 female, 169 male) Inclusion criteria: patients with advanced HF who were ineligible for transplantation Key exclusion criteria: irreversible, severe renal, pulmonary, or hepatic dysfunction or active infection Interventions N=134 continuous flow LVAD (continuous-flow HeartMate II) N=66 pulsatile-flow LVAD (pulsatile-flow HeartMate XVE) Primary outcome Death, disabling stroke, or reoperation to repair or replace device at 2 years 89.0 % 89 66.8 % 54 https://web.pathway.md/studies/recx1Bq38rDHR1Tlv 1/2 6/28/23, 11:01 PM HEARTMATE II Pathway 44.5 % Significant decrease 22.3 % NNT = 3 0.0 % Continuous flow LVAD Pulsatile-flow LVAD Significant decrease in death, disabling stroke, or reoperation to repair or replace the device at 2 years (54% vs. 89%; HR 0.38, 95% CI 0.27 to 0.54) Secondary outcomes Significant decrease in the rate of death 2 years (42% vs. 76%; RR 0.54, 95% CI 0.34 to 0.86) Safety outcomes No significant differences in stroke (17% vs. 14%, p=0.21). Significant differences in sepsis (36% vs. 44%, p < 0.001), pump replacement (9% vs. 34%, p < 0.001), respiratory failure (38% vs. 41%, p < 0.001), renal failure (16% vs. 24%, p < 0.001), cardiac arrhythmia (56% vs. 59%, p = 0.006). Conclusion In patients with advanced HF who were ineligible for transplantation, continuous flow LVAD was superior to pulsatile-flow LVAD with respect to death, disabling stroke, or reoperation to repair or replace the device at 2 years. Reference Slaughter MS, Rogers JG, Milano CA et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med. 2009 Dec 3;361(23):2241-51. Open reference URL https://web.pathway.md/studies/recx1Bq38rDHR1Tlv 2/2

6/28/23, 11:02 PM HEAT (acetaminophen) Pathway Feedback Search Clinical Topics Home Studies HEAT (acetaminophen) HEAT (acetaminophen) Disease Sepsis and septic shock Trial question What is the role of acetaminophen in fever among critically ill patients with suspected infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 35.4% female N = 700 64.6% male 700 patients (242 female, 449 male) Inclusion criteria: patients with fever (body temperature, 38 C) and known or suspected infection Key exclusion criteria: pregnancy, clinically significant rhabdomyolysis, moribund, requirement for ongoing use of non-steroidal anti-inflammatory drugs, AST or ALT > 5 times the ULN, or bilirubin > 2 times the ULN, or any other contraindication to 4 g acetaminophen/day Interventions N=352 acetaminophen (an infusion containing 1 g of intravenous acetaminophen, every 6 hours) N=348 placebo (an infusion of 5% dextrose in water, every 6 hours) Primary outcome Rate of death by 90 days 16.6 16.6 % 15 9 https://web.pathway.md/studies/recxJlJNsNF7nukEe 1/2 6/28/23, 11:02 PM 16.6 % HEAT (acetaminophen) Pathway 15.9 12.5 % 8.3 % 4.2 % No significant difference 0.0 % Acetaminophen Placebo No significant difference in the rate of death by 90 days (15.9% vs. 16.6%; RR 0.96, 96% CI 0.66 to 1.39) Secondary outcomes No significant difference in length of ICU stay (4.1 days vs. 4.2 days; AD -0.1 days, 95% CI -0.7 to 0.4) No significant difference in hospital length of stay (13.7 days vs. 13.8 days; AD -0.01 days, 95% CI -1.6 to 1.6) Safety outcomes No significant difference in liver dysfunction leading to discontinuation of the drug. Conclusion In patients with fever (body temperature, 38 C) and known or suspected infection, acetaminophen was not superior to placebo with respect to the rate of death by 90 days. Reference Young P, Saxena M, Bellomo R et al. Acetaminophen for Fever in Critically Ill Patients with Suspected Infection. N Engl J Med. 2015 Dec 3;373(23):2215-24. Open reference URL https://web.pathway.md/studies/recxJlJNsNF7nukEe 2/2

6/28/23, 11:02 PM HEAT (intracranial aneurysm) Pathway Feedback Search Clinical Topics Home Studies HEAT (intracranial aneurysm) HEAT (intracranial aneurysm) Trial question Is second-generation hydrocoil embolic system superior to bare platinum coil in patients with small-to-medium-sized intracranial aneurysms? Study design Multi-center Open label RCT Population Characteristics of study participants 79.0% female N = 600 21.0% male 600 patients (474 female, 126 male) Inclusion criteria: adult patients with untreated 3-to-14-mm intracranial aneurysms Key exclusion criteria: concurrent intracranial pathologies; serious comorbidities Interventions N=297 hydrogel coil (aneurysm treatment using the HydroCoil Embolization System) N=303 bare platinum (aneurysm treatment using bare platinum coil(s)) Primary outcome Aneurysm recurrence 15.4 % 15.4 11.6 % 7.7 % Significant decrease 4.4 3.9 % NNT = 9 0.0 % https://web.pathway.md/studies/rec7laTFHmiKza2ar 1/2 6/28/23, 11:02 PM HEAT (intracranial aneurysm) Pathway Hydrogel coil Bare platinum Significant decrease in aneurysm recurrence (4.4% vs. 15.4%; OR 0.29, 95% CI 0.11 to 0.47) Secondary outcomes Significant decrease in aneurysm occlusion stability (13% vs. 27%; OR 0.48, 95% CI 0.2 to 0.76) Significant decrease in minor recurrence (1% vs. 5%; OR 0.2, 95% CI 0.06 to 0.34) Significant decrease in major recurrence (12.8% vs. 20.7%; OR 0.62, 95% CI 0.12 to 1.12) Safety outcomes No significant difference in adverse events. Conclusion In adult patients with untreated 3-to-14-mm intracranial aneurysms, hydrogel coil was superior to bare platinum with respect to aneurysm recurrence. Reference Bernard R Bendok, Karl R Abi-Aad, Jennifer D Ward et al. The Hydrogel Endovascular Aneurysm Treatment Trial (HEAT): A Randomized Controlled Trial of the Second-Generation Hydrogel Coil. Neurosurgery. 2020 May 1;86(5):615-624. Open reference URL https://web.pathway.md/studies/rec7laTFHmiKza2ar 2/2

6/28/23, 11:02 PM HEP-COVID Pathway Feedback Search Clinical Topics Home Studies HEP COVID HEP COVID Disease COVID 19 infection Trial question Is therapeutic-dose heparin superior to standard-dose heparin in high-risk hospitalized patients with COVID-19? Study design Multi-center Double blinded RCT Population Characteristics of study participants 46.0% female N = 253 54.0% male 253 patients (117 female, 136 male) Inclusion criteria: hospitalized adult patients with COVID-19 and D-dimer levels > 4 times the ULN Key exclusion criteria: physician-determined need for full-dose anticoagulation or dual antiplatelet therapy; bleeding within the past month; active gastrointestinal or intracranial cancer; hepatic dysfunction; platelet count < 25,000/ L Interventions N=129 therapeutic-dose heparin (enoxaparin, 0.5 or 1 mg/kg subcutaneous, BID based on CrCl) N=124 standard-dose heparin (prophylactic or intermediate-dose low-molecular-weight heparin or UFH) Primary outcome https://web.pathway.md/studies/recCPXMNCvuVBJ8KB 1/2 6/28/23, 11:02 PM HEP-COVID Pathway Venous thromboembolism, arterial thromboembolism, or death from any cause at day 30 41.9 % 41.9 31.4 % 28.7 20.9 % Significant decrease 10.5 % NNT = 8 0.0 % Therapeutic-dose heparin Standard-dose heparin Significant decrease in VTE, arterial thromboembolism, or death from any cause at day 30 (28.7% vs. 41.9%; RR 0.68, 95% CI 0.49 to 0.96) Secondary outcomes Significant decrease in VTE, arterial thromboembolism, or death from any cause at day 14 (23.3% vs. 36.3%; RR 0.64, 95% CI 0.43 to 0.95) Significant decrease in VTE, arterial thromboembolism, or death in non-ICU patients (16.7% vs. 36.1%; RR 0.46, 95% CI 0.27 to 0.81) No significant difference in VTE, arterial thromboembolism, or death in ICU patients (51.1% vs. 55.3%; RR 0.92, 95% CI 0.62 to 1.39) Safety outcomes No significant difference in major bleeding. Conclusion In hospitalized adult patients with COVID-19 and D-dimer levels > 4 times the ULN, therapeutic- dose heparin was superior to standard-dose heparin with respect to VTE, arterial thromboembolism, or death from any cause at day 30. Reference Alex C Spyropoulos, Mark Goldin, Dimitrios Giannis et al. Efficacy and Safety of Therapeutic- Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial. JAMA Intern Med. 2021 Dec 1;181(12):1612-1620. Open reference URL https://web.pathway.md/studies/recCPXMNCvuVBJ8KB 2/2

6/28/23, 11:03 PM HERA Pathway Feedback Search Clinical Topics Home Studies HERA HERA Trial question Is one year of treatment with trastuzumab after adjuvant chemotherapy superior to observation in female patients with HER2-positive breast cancer? Study design Multi-center Open label RCT Population 3387 female patients Inclusion criteria: female patients with HER2-positive breast cancer Key exclusion criteria: distant metastases, a previous invasive breast carcinoma, clinical stage T4 tumors, including inflammatory breast cancers or involvement of supraclavicular nodes Interventions N=1694 trastuzumab (at a dose of 8 mg/kg of body weight IV once, then at a dose of 6 mg/kg every three weeks for 1 year) N=1693 observation alone (no treatment) Primary outcome Recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant cancer, or death 13.0 % 13 9.8 % 7.5 6.5 % Significant decrease 3.3 % NNT = 18 0.0 % Trastuzumab Observation alone Significant decrease in recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant cancer, or death (7.5% vs. 13%; HR 0.54, 95% CI 0.43 to 0.67) Secondary outcomes No significant difference in death from any cause (1.7% vs. 2.2%; HR 0.76, 95% CI 0.47 to 1.23) https://web.pathway.md/studies/recmy5vQHAkMIT6iQ 1/2 6/28/23, 11:03 PM HERA Pathway Significant decrease in distant recurrence (5% vs. 9.1%; HR 0.49, 95% CI 0.38 to 0.63) Safety outcomes Significant differences in severe congestive HF (0.54% vs. 0%, p = 0.002). Conclusion In female patients with HER2-positive breast cancer, trastuzumab was superior to observation alone with respect to recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant cancer, or death. Reference Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-72. Open reference URL https://web.pathway.md/studies/recmy5vQHAkMIT6iQ 2/2

6/28/23, 11:03 PM HERCULES Pathway Feedback Search Clinical Topics Home Studies HERCULES HERCULES Disease Thrombotic thrombocytopenic p Trial question What is the effect of caplacizumab in patients with acquired TTP? Study design Multi-center Double blinded RCT Population Characteristics of study participants 69.0% female N = 145 31.0% male 145 patients (100 female, 45 male) Inclusion criteria: patients with acquired TTP Key exclusion criteria: severe ADAMTS13 deficiency, thrombotic microangiopathies unassociated with TTP, such as HUS, or congenital TTP Interventions N=72 caplacizumab (10 mg IV bolus, then 10 mg SC daily during PLEX and for 30 days thereafter) N=73 placebo (standard of care, including PLEX, with matching placebo) Primary outcome Platelet count normalization 90.3 % 90.3 87.7 67.7 % https://web.pathway.md/studies/rec6gG92da5Vxed2B 1/2 6/28/23, 11:03 PM HERCULES Pathway 45.1 % Significant increase 22.6 % NNH = 38 0.0 % Caplacizumab Placebo Significant increase in platelet count normalization (90.3% vs. 87.7%; RR 1.55, 95% CI 1.09 to 2.19) Secondary outcomes Significant decrease in death due to TTP, recurrence, or thromboembolism (12% vs. 49%; RR 0.24, 95% CI 0.1 to 0.38) Significant decrease in recurrence of TTP during trial (12% vs. 38%; RR 0.32, 95% CI 0.13 to 0.51) Safety outcomes No significant differences in bleeding-related adverse events (65% vs. 48%), death during the trial (1 vs. 3 patients). Conclusion In patients with acquired TTP, caplacizumab was superior to placebo with respect to platelet count normalization. Reference Scully M, Cataland SR, Peyvandi F et al. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2019 Jan 24;380(4):335-346. Open reference URL https://web.pathway.md/studies/rec6gG92da5Vxed2B 2/2

6/28/23, 11:08 PM Hi-Light Vitiligo Pathway Feedback Search Clinical Topics Home Studies Hi-Light Vitiligo Hi-Light Vitiligo Disease Vitiligo Trial question Is combination treatment with narrowband UV-B light plus topical corticosteroids superior to topical corticosteroids alone in patients with vitiligo? Study design Multi-center Double blinded RCT Population Characteristics of study participants 48.0% female N = 348 52.0% male 348 patients (168 female, 180 male) Inclusion criteria: adults and children with active vitiligo affecting < 10% of skin Key exclusion criteria: segmental or universal vitiligo; vitiligo limited to areas contraindicated for treatment with potent topical corticosteroid or evidence of marked Koebner phenomenon; history of skin cancer; radiotherapy use or photosensitivity; pregnancy Interventions N=175 combination therapy (topical corticosteroid ointment plus narrowband UV-B light) N=173 topical corticosteroid (topical corticosteroid plus dummy narrowband UV-B light) Primary outcome Target patch treatment success at 9 months 27.0 % 27 https://web.pathway.md/studies/recb7FleffsCYpOz1 1/2 6/28/23, 11:08 PM Hi-Light Vitiligo Pathway 20.3 % 17 13.5 % Significant increase 6.8 % NNT = 10 0.0 % Combination therapy Topical corticosteroid Significant increase in target patch treatment success at 9 months (27% vs. 17%; OR 1.93, 95% CI 1.02 to 3.68) Secondary outcomes Borderline significant increase in treatment success as assessed by blinded patient and public involvement assessors at 9 months (28% vs. 11%; OR 3.52, 95% CI 1.8 to 6.89) Borderline significant increase in repigmentation as assessed by blinded dermatologist using digital images of target patch at 9 months (15% vs. 3%; OR 4.62, 95% CI 1.5 to 14.2) Conclusion In adults and children with active vitiligo affecting < 10% of skin, combination therapy was superior to topical corticosteroid with respect to target patch treatment success at 9 months. Reference K S Thomas, J M Batchelor, P Akram et al. Randomized controlled trial of topical corticosteroid and home-based narrowband ultraviolet B for active and limited vitiligo: results of the HI-Light Vitiligo Trial. Br J Dermatol. 2021 May;184(5):828-839. Open reference URL https://web.pathway.md/studies/recb7FleffsCYpOz1 2/2

6/28/23, 11:09 PM HiFlo-COVID Pathway Feedback Search Clinical Topics Home Studies HiFlo-COVID HiFlo-COVID Disease COVID 19 infection Trial question Is high-flow oxygen therapy through a nasal cannula superior to conventional oxygen therapy in patients with severe COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 33.0% female N = 199 67.0% male 199 patients (65 female, 134 male) Inclusion criteria: adult patients with respiratory distress and a ratio of partial pressure of arterial oxygen to FiO2 < 200 due to COVID-19 Key exclusion criteria: indication for immediate orotracheal intubation, pregnancy, chronic liver disease, active bacterial or fungal infection, history of COPD Interventions N=99 high-flow oxygen therapy (breathing support with high-flow oxygen therapy through a nasal cannula) N=100 conventional oxygen therapy (oxygen therapy by conventional nasal cannula/prongs, venturi mask, or mask with reservoir) Primary outcome Rate of intubation within 28 days https://web.pathway.md/studies/recbaMCybDEXJiR4R 1/2 6/28/23, 11:09 PM HiFlo-COVID Pathway 51.0 % 51 38.3 % 34.3 25.5 % Significant decrease 12.8 % NNT = 6 0.0 % High-flow oxygen therapy Conventional oxygen therapy Significant decrease in the rate of intubation within 28 days (34.3% vs. 51%; HR 0.62, 95% CI 0.39 to 0.96) Secondary outcomes Significant increase in the rate of clinical recovery within 28 days (77.8% vs. 71%; HR 1.39, 95% CI 1 to 1.92) Significant increase in ventilator-free days at day 28 (28 days vs. 24 days; OR 2.08, 95% CI 1.18 to 3.64) No significant difference in death at day 28 (8.1% vs. 16%; HR 0.49, 95% CI 0.21 to 1.16) Safety outcomes No significant differences in suspected bacterial pneumonia, bacteremia. Conclusion In adult patients with respiratory distress and a ratio of partial pressure of arterial oxygen to FiO2 < 200 due to COVID-19, high-flow oxygen therapy was superior to conventional oxygen therapy with respect to the rate of intubation within 28 days. Reference Gustavo A Ospina-Tasc n, Luis Eduardo Calder n-Tapia, Alberto F Garc a et al. Effect of High- Flow Oxygen Therapy vs Conventional Oxygen Therapy on Invasive Mechanical Ventilation and Clinical Recovery in Patients With Severe COVID-19: A Randomized Clinical Trial. JAMA. 2021 Dec 7;326(21):2161-2171. Open reference URL https://web.pathway.md/studies/recbaMCybDEXJiR4R 2/2

6/28/23, 11:03 PM HIGH Pathway Feedback Search Clinical Topics Home Studies HIGH HIGH Trial question Is high-flow nasal oxygen superior to standard oxygen in immunocompromised patients with acute respiratory failure? Study design Multi-center Open label RCT Population Characteristics of study participants 33.3% female N = 778 66.7% male 778 patients (259 female, 517 male) Inclusion criteria: adult immunocompromised patients with acute hypoxemic respiratory failure Key exclusion criteria: imminent death; anatomical factors precluding the use of a nasal cannula; hypercapnia and isolated cardiogenic pulmonary edema indicating noninvasive ventilation; and surgery within the last 6 days Interventions N=388 high-flow oxygen therapy (initiated at 50 L/min and 100% FiO2, with a subsequent flow rate increase up to 60 L/min as needed to achieve SpO2 95%) N=388 standard oxygen therapy (oxygen delivered via nasal prongs or mask with or without a reservoir bag and with or without a Venturi system to achieve SpO2 95%) Primary outcome Rate of death by day 28 36.1 % 36.1 35.6 27.1 % 18.1 % 9.0 % No significant difference 0.0 % https://web.pathway.md/studies/recahdbINIRRssoNA 1/2 6/28/23, 11:03 PM HIGH Pathway High-flow oxygen therapy Standard oxygen therapy No significant difference in the rate of death by day 28 (35.6% vs. 36.1%; HR 0.98, 95% CI 0.77 to 1.24) Secondary outcomes No significant difference in invasive mechanical ventilation (38.7% vs. 43.8%; HR 0.85, 95% CI 0.68 to 1.06) No significant difference in ICU acquired infection (10% vs. 10.6%; HR 1.01, 95% CI 0.96 to 1.06) No significant difference in death in the hospital (41.2% vs. 41.7%; RR 0.99, 99% CI 0.84 to 1.17) Safety outcomes No significant difference in patient comfort and dyspnea scores. Significant differences in respiratory rate after 6 hours (25/min vs. 26/min), the ratio of the partial pressure of oxygen and FiO2 until day 4 (150 vs. 119). Conclusion In adult immunocompromised patients with acute hypoxemic respiratory failure, high-flow oxygen therapy was not superior to standard oxygen therapy with respect to the rate of death by day 28. Reference Elie Azoulay, Virginie Lemiale, Djamel Mokart et al. Effect of High-Flow Nasal Oxygen vs Standard Oxygen on 28-Day Mortality in Immunocompromised Patients With Acute Respiratory Failure: The HIGH Randomized Clinical Trial. JAMA. 2018 Nov 27;320(20):2099-2107. Open reference URL https://web.pathway.md/studies/recahdbINIRRssoNA 2/2

6/28/23, 11:04 PM HIMALAYA (durvalumab) Pathway Feedback Search Clinical Topics Home Studies HIMALAYA (durvalumab) HIMALAYA (durvalumab) Disease Hepatocellular carcinoma Trial question Is durvalumab noninferior to sorafenib in patients with unresectable HCC? Study design Multi-center Open label RCT Population Characteristics of study participants 15.0% female N = 778 85.0% male 778 patients (118 female, 660 male) Inclusion criteria: patients with unresectable HCC and no previous systemic treatment Key exclusion criteria: hepatic encephalopathy within past 12 months; clinically meaningful ascites; main portal vein tumor thrombosis; active or prior documented gastrointestinal bleeding Interventions N=389 durvalumab (at a dose of 1,500 mg every 4 weeks) N=389 sorafenib (at a dose of 400 mg BID) Primary outcome Median overall survival 16.6 months 16.56 13.77 12.4 months https://web.pathway.md/studies/rechwCye3ATBS8fWP 1/2 6/28/23, 11:04 PM HIMALAYA (durvalumab) Pathway 8.3 months Difference not exceeding nonferiority margin 4.1 months 0.0 months Durvalumab Sorafenib Difference not exceeding nonferiority margin in median overall survival (16.56 months vs. 13.77 months; HR 0.86, 95% CI 0.73 to 1.03) Secondary outcomes No significant difference in median progression-free survival (3.65 months vs. 4.07 months; HR 1.02, 95% CI 0.88 to 1.19) Safety outcomes No significant difference in adverse events and grade 3 or 4 adverse events. Conclusion In patients with unresectable HCC and no previous systemic treatment, durvalumab was noninferior to sorafenib with respect to median overall survival. Reference Ghassan K. Abou-Alfa, M.D., M.B.A. et al. Tremelimumab Plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022;1(8). Open reference URL https://web.pathway.md/studies/rechwCye3ATBS8fWP 2/2

6/28/23, 11:03 PM HIMALAYA (STRIDE) Pathway Feedback Search Clinical Topics Home Studies HIMALAYA STRIDE HIMALAYA STRIDE Disease Hepatocellular carcinoma Trial question Is tremelimumab plus durvalumab superior to sorafenib in patients with unresectable HCC? Study design Multi-center Open label RCT Population Characteristics of study participants 15.0% female N = 782 85.0% male 782 patients (118 female, 664 male) Inclusion criteria: patients with unresectable HCC and no previous systemic treatment Key exclusion criteria: hepatic encephalopathy within past 12 months; clinically meaningful ascites; main portal vein tumor thrombosis; active or prior documented gastrointestinal bleeding Interventions N=393 STRIDE (300 mg tremelimumab for one dose plus 1,500 mg of durvalumab every 4 weeks) N=389 sorafenib (at a dose of 400 mg BID) Primary outcome Median overall survival 16.43 16.4 months 13.77 https://web.pathway.md/studies/recWNect8xPyZMfmU 1/2 6/28/23, 11:03 PM HIMALAYA (STRIDE) Pathway 12.3 months 8.2 months 4.1 months Significant increase 0.0 months STRIDE Sorafenib Significant increase in median overall survival (16.43 months vs. 13.77 months; HR 1.28, 96% CI 1.07 to 1.53) Secondary outcomes No significant difference in median progression-free survival (3.78 months vs. 4.07 months; HR 0.9, 95% CI 0.77 to 1.05) Safety outcomes No significant difference in adverse events and grade 3 or 4 adverse events. Conclusion In patients with unresectable HCC and no previous systemic treatment, STRIDE was superior to sorafenib with respect to median overall survival. Reference Ghassan K. Abou-Alfa, M.D., M.B.A. et al. Tremelimumab Plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evid. 2022;1(8). Open reference URL https://web.pathway.md/studies/recWNect8xPyZMfmU 2/2

6/28/23, 11:09 PM Hokusai VTE Cancer Pathway Feedback Search Clinical Topics Home Studies Hokusai VTE Cancer Hokusai VTE Cancer Disease Disease Disease Cancer-associated thrombosis Deep vein thrombosis Pulmon Trial question Is edoxaban noninferior to dalteparin for the management of VTE in patients with cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 48.5% female N = 1050 51.5% male 1050 patients (506 female, 540 male) Inclusion criteria: patients with cancer who had acute symptomatic or incidental VTE Key exclusion criteria: basal cell or squamous cell skin cancer, a history of VTE, previous treatment dose of anticoagulant or > 75 mg aspirin per day, clinically significant liver disease, active bleeding or high risk of bleeding, or uncontrolled hypertension Interventions N=522 edoxaban (LMWH for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily) N=524 dalteparin (subcutaneous dose of 200 IU/kg of body weight once daily for 1 month followed by a dose of 150 IU/kg once daily) Primary outcome Recurrent venous thromboembolism or major bleeding 13.5 13 5 % 12 8 https://web.pathway.md/studies/recmIlnWz7o5W9ffl 1/2 6/28/23, 11:09 PM 13.5 % Hokusai VTE Cancer Pathway 12.8 10.1 % 6.8 % Difference not exceeding nonferiority margin 3.4 % 0.0 % Edoxaban Dalteparin Difference not exceeding nonferiority margin in recurrent VTE or major bleeding (12.8% vs. 13.5%; HR 0.97, 95% CI 0.7 to 1.36) Secondary outcomes No significant difference in recurrent VTE (7.9% vs. 11.3%; HR 0.71, 95% CI 0.48 to 1.06) Significant increase in major bleeding (6.9% vs. 4%; HR 1.77, 95% CI 1.03 to 3.04) No significant difference in death from any cause (39.5% vs. 36.6%; HR 1.12, 95% CI 0.92 to 1.37) Safety outcomes No significant differences in adverse events, including progression of neoplasm and pneumonia. Conclusion In patients with cancer who had acute symptomatic or incidental VTE, edoxaban was noninferior to dalteparin with respect to recurrent VTE or major bleeding. Reference Raskob GE, van Es N, Verhamme P et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624. Open reference URL https://web.pathway.md/studies/recmIlnWz7o5W9ffl 2/2

6/28/23, 11:10 PM Home Sleep and Metabolism Pathway Feedback Search Clinical Topics Home Studies Home Sleep and Metabolism Home Sleep and Metabolism Disease Obesity Trial question What is the effect of sleep extension among adults with overweight who habitually decreased their sleep duration? Study design Single center Open label RCT Population Characteristics of study participants 49.0% female N = 80 51.0% male 80 patients (39 female, 41 male) Inclusion criteria: overweight adults with habitual sleep duration < 6.5 hours per night Key exclusion criteria: obstructive sleep apnea; insomnia or history of any other sleep disorder; night shift; rotating shift work; participants following a weight-loss regimen Interventions N=40 sleep extension (sleep hygiene counseling aiming to extend sleep duration to 8.5 hours for 2 weeks) N=40 habitual sleep (continued habitual sleep without intervention for 2 weeks) Primary outcome Significant decrease in energy intake (-155.5 kcal/d vs. 114.9 kcal/d; AD -270.4 kcal/d, 95% CI -393.4 to -147.4) t https://web.pathway.md/studies/recKbsSr56idt7elq S d 1/2 6/28/23, 11:10 PM Home Sleep and Metabolism Pathway Secondary outcomes No significant difference in total energy expenditure (-46.7 kcal/d vs. 7.2 kcal/d; AD -53.9 kcal/d, 95% CI -134.9 to 27.1) Significant decrease in weight (-0.48 kg vs. 0.39 kg; AD -0.87 kg, 95% CI -1.39 to -0.35) Significant decrease in fat-free mass (-0.36 kg vs. 0.26 kg; AD -0.62 kg, 95% CI -1.02 to -0.23) Conclusion In overweight adults with habitual sleep duration < 6.5 hours per night, sleep extension was superior to habitual sleep with respect to energy intake. Reference Esra Tasali, Kristen Wroblewski, Eva Kahn et al. Effect of Sleep Extension on Objectively Assessed Energy Intake Among Adults With Overweight in Real-life Settings: A Randomized Clinical Trial. JAMA Intern Med. 2022 Apr 1;182(4):365-374. Open reference URL https://web.pathway.md/studies/recKbsSr56idt7elq 2/2

6/28/23, 11:05 PM HOPE-ICU Pathway Feedback Search Clinical Topics Home Studies HOPE ICU HOPE ICU Disease ICU delirium Trial question What is the effect of IV haloperidol in critically ill patients? Study design Single center Double blinded RCT Population Characteristics of study participants 42.0% female N = 141 58.0% male 141 patients (59 female, 82 male) Inclusion criteria: critically ill adult patients needing mechanical ventilation within 72 hours of admission Key exclusion criteria: allergy to haloperidol, moderate to severe dementia, Parkinson's disease, structural brain damage, chronic antipsychotic use, moribund state Interventions N=71 haloperidol (at a dose of 2.5 mg IV every 8 hours) N=70 placebo (an equal volume of 0.9% saline IV every 8 hours) Primary outcome Days alive without delirium and without coma in first 14 days 6.0 days 6 5 4.5 days https://web.pathway.md/studies/recAajrQLj9AatYDD 1/2 6/28/23, 11:05 PM HOPE-ICU Pathway 3.0 days 1.5 days No significant difference 0.0 days Haloperidol Placebo No significant difference in days alive without delirium and without coma in the first 14 days (5 days vs. 6 days; AD -0.48 days, 95% CI -2.08 to 1.21) Secondary outcomes No significant difference in ventilator-free days in the first 28 days (21 days vs. 17 days; AD 0.25 days, 95% CI -3.26 to 4.16) No significant difference in death at 28 days (28.2% vs. 27.1%; RR 1.04, 95% CI 0.61 to 1.77) No significant difference in length of critical care stay (9.5 days vs. 9 days; AD -1.45 days, 95% CI -5.42 to 2.52) Safety outcomes No significant differences in use of individual sedative or opioid drugs, QTc prolongation > 500 ms. Significant difference in risk of needing additional antipsychotics (11% vs. 26%). Conclusion In critically ill adult patients needing mechanical ventilation within 72 hours of admission, haloperidol was not superior to placebo with respect to days alive without delirium and without coma in the first 14 days. Reference Valerie J Page, E Wesley Ely, Simon Gates et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2013 Sep;1(7):515-23. Open reference URL https://web.pathway.md/studies/recAajrQLj9AatYDD 2/2

6/28/23, 11:04 PM HOPE Pathway Feedback Search Clinical Topics Home Studies HOPE HOPE Disease Disease Disease Acute ischemic stroke Coronary artery disease Diabete Trial question What is the role of ramipril in patients who were at high-risk for cardiovascular events but are not known to have a low ejection fraction or HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 27.0% female N = 9297 73.0% male 9297 patients (2480 female, 6817 male) Inclusion criteria: patients who were at high-risk for cardiovascular events but are not known to have a low ejection fraction or HF Key exclusion criteria: HF, low ejection fraction (< 0.40), taking angiotensin-converting-enzyme inhibitor or vitamin E, uncontrolled hypertension or overt nephropathy, or myocardial infarction or stroke within four weeks before the study Interventions N=4645 ramipril (10 mg once per day PO) N=4652 placebo (matching placebo PO daily) Primary outcome Death, myocardial infarction, or stroke 17.8 % 17.8 https://web.pathway.md/studies/recS8JjaWx0r4ueeF 1/2 6/28/23, 11:04 PM HOPE Pathway 14 13.4 % 8.9 % Significant decrease 4.5 % NNT = 26 0.0 % Ramipril Placebo Significant decrease in death, myocardial infarction, or stroke (14% vs. 17.8%; RR 0.78, 95% CI 0.7 to 0.86) Secondary outcomes Significant decrease in cardiovascular death (6.1% vs. 8.1%; RR 0.74, 95% CI 0.64 to 0.87) Significant decrease in death from myocardial infarction (9.9% vs. 12.3%; RR 0.8, 95% CI 0.7 to 0.9) Significant decrease in death from stroke (3.4% vs. 4.9%; RR 0.68, 95% CI 0.56 to 0.84) Conclusion In patients who were at high-risk for cardiovascular events but are not known to have a low ejection fraction or HF, ramipril was superior to placebo with respect to death, myocardial infarction, or stroke. Reference Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Sleight P et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000 Jan 20;342(3):145-53. Open reference URL https://web.pathway.md/studies/recS8JjaWx0r4ueeF 2/2

6/28/23, 11:06 PM HOT-ICU Pathway Feedback Search Clinical Topics Home Studies HOT ICU HOT ICU Disease Acute respiratory distress syndr Trial question Is lower oxygenation target superior to higher oxygenation target in patients with acute hypoxemic respiratory failure? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 2910 64.0% male 2910 patients (1039 female, 1871 male) Inclusion criteria: adult patients with acute hypoxemic respiratory failure in the ICU Key exclusion criteria: not randomized within 12 hours of ICU admission; receives chronic mechanical ventilation; use of home oxygenation; previous treatment with bleomycin; pregnancy Interventions N=1453 lower oxygenation target (partial pressure of oxygen in arterial blood 60 mmHg) N=1457 higher oxygenation target (partial pressure of oxygen in arterial blood 90 mmHg) Primary outcome Death at day 90 42.9 % 42.9 42.4 32 2 % https://web.pathway.md/studies/rec2C5I1SQxLcdbEA 1/2 6/28/23, 11:06 PM 32.2 % HOT-ICU Pathway 21.4 % 10.7 % No significant difference 0.0 % Lower oxygenation target Higher oxygenation target No significant difference in death at day 90 (42.9% vs. 42.4%; RR 1.02, 95% CI 0.94 to 1.11) Secondary outcomes No significant difference in the percentage of days alive within life support (87.8% vs. 84.4%; AD 3.4%, 95% CI -0.65 to 7.45) No significant difference in the percentage of days alive after hospital discharge (55.6% vs. 50%; AD 5.6%, 95% CI -19.12 to 30.32) Safety outcomes No significant difference in serious adverse events. Conclusion In adult patients with acute hypoxemic respiratory failure in the ICU, lower oxygenation target was not superior to higher oxygenation target with respect to death at day 90. Reference Olav L Schj rring, Thomas L Klitgaard, Anders Perner et al. Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure. N Engl J Med. 2021 Apr 8;384(14):1301-1311. Open reference URL https://web.pathway.md/studies/rec2C5I1SQxLcdbEA 2/2

6/28/23, 11:06 PM HPS2-THRIVE Pathway Feedback Search Clinical Topics Home Studies HPS2 THRIVE HPS2 THRIVE Disease Disease Disease Acute ischemic stroke Coronary artery disease Diabete Trial question What is the effect of ER niacin with laropiprant in patients with atherosclerotic vascular disease? Study design Multi-center Double blinded RCT Population Characteristics of study participants 17.0% female N = 25673 83.0% male 25673 patients (4444 female, 21229 male) Inclusion criteria: adult patients with a history of myocardial infarction, cerebrovascular disease, peripheral arterial disease, or diabetes mellitus with evidence of symptomatic coronary disease Key exclusion criteria: clinically significant hepatic, renal, muscle-related, or other disease, receiving concurrent treatment with potentially interacting drugs, or receiving LDL cholesterol- lowering treatment that was more effective than simvastatin at a dose of 40 mg plus ezetimibe at a dose of 10 mg daily Interventions N=12838 niacin-laropiprant (e 2 g of ER niacin and 40 mg of laropiprant daily) N=12835 placebo (matching placebo daily) Primary outcome Major vascular event https://web.pathway.md/studies/rec6Otyb52e4mfUhE 1/2 6/28/23, 11:06 PM HPS2-THRIVE Pathway 13.7 % 13.7 13.2 10.3 % 6.8 % 3.4 % No significant difference 0.0 % Niacin-laropiprant Placebo No significant difference in major vascular event (13.2% vs. 13.7%; RR 0.96, 96% CI 0.9 to 1.03) Secondary outcomes No significant difference in major vascular events excluding hemorrhagic stroke (12.4% vs. 13.1%; RR 0.95, 95% CI 0.88 to 1.01) No significant difference in major vascular events excluding both hemorrhagic stroke and revascularization procedures (7.9% vs. 8.4%; RR 0.95, 95% CI 0.87 to 1.03) No significant difference in death from any cause (6.2% vs. 5.7%; RR 1.09, 95% CI 0.99 to 1.21) Safety outcomes Significant differences in fatal or nonfatal serious adverse events (55.6% vs. 52.7%, p < 0.001), disturbance in diabetes leading to hospitalization (11.1% vs. 7.5%, p < 0.001), proportional increase in diabetes diagnosis (5.7% vs. 4.3%, p < 0.001), excess of gastrointestinal serious adverse events (4.8% vs. 3.8%, p < 0.001), excess of musculoskeletal serious adverse events (3.7% vs. 3.0%, p < 0.001), skin-related serious adverse events (0.7% vs. 0.4%, p = 0.003), excess infections (8.0% vs. 6.6%, p < 0.001), and excess of bleeding events (2.5% vs. 1.9%, p < 0.001). Conclusion In adult patients with a history of myocardial infarction, cerebrovascular disease, peripheral arterial disease, or diabetes mellitus with evidence of symptomatic coronary disease, niacin- laropiprant was not superior to placebo with respect to major vascular event. Reference HPS-THRIVE Collaborative Group, Landray MJ, Haynes R et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014 Jul 17;371(3):203-12. Open reference URL https://web.pathway.md/studies/rec6Otyb52e4mfUhE 2/2

6/28/23, 11:06 PM HPTN 052 Pathway Feedback Search Clinical Topics Home Studies HPTN 052 HPTN 052 Disease Human immunodeficiency virus i Trial question What is the role of early antiretroviral therapy in HIV-1 serodiscordant couples? Study design Multi-center Open label RCT Population Characteristics of study participants 50.0% female N = 1763 50.0% male 1763 patients (873 female, 890 male) Inclusion criteria: HIV-1 serodiscordant couples (one partner HIV-1-positive and the other HIV- 1-negative) with CD4 counts between 350 and 550 cells/mm Key exclusion criteria: history of injection drug use within the last 5 years, AIDS-defining illness, use of ART drugs, acute hepatitis within 30 days prior to enrollment, acute therapy for serious medical illnesses, or allergy/sensitivity to any study drug or their formulations Interventions N=886 early antiretroviral therapy (immediate antiretroviral therapy) N=877 delayed antiretroviral therapy (after decline in the CD4 count or the onset of HIV-1- related symptoms) Primary outcome HIV-1 transmission in HIV-1-negative partners 1.7 % 1.7 https://web.pathway.md/studies/recdCfZkTjjU4CBFw 1/2 6/28/23, 11:06 PM HPTN 052 Pathway 1.3 % 0.8 % Significant decrease 0.4 % NNT = 63 0.1 0.0 % Early antiretroviral therapy Delayed antiretroviral therapy Significant decrease in HIV-1 transmission in HIV-1-negative partners (0.1% vs. 1.7%; HR 0.04, 95% CI 0.01 to 0.27) Secondary outcomes Significant decrease in HIV-1-related clinical event or death (2.4% vs. 4%; HR 0.59, 95% CI 0.4 to 0.88) No significant difference in death (10 vs. 13; HR 0.77, 95% CI 0.34 to 1.76) Safety outcomes No significant differences in grade 3 or 4 severe or life-threatening adverse events (14% vs. 14%, p=0.64). Significant differences in grade 3 or 4 laboratory abnormalities (27% vs. 18%, p < 0.001). Conclusion In HIV-1 serodiscordant couples (one partner HIV-1-positive and the other HIV-1-negative) with CD4 counts between 350 and 550 cells/mm , early antiretroviral therapy was superior to delayed antiretroviral therapy with respect to a HIV-1 transmission in HIV-1-negative partners. Reference Cohen MS, Chen YQ, McCauley M et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011 Aug 11;365(6):493-505. Open reference URL https://web.pathway.md/studies/recdCfZkTjjU4CBFw 2/2

6/28/23, 11:10 PM Hung Pathway Feedback Search Clinical Topics Home Studies Hung Hung Disease COVID 19 infection Trial question What is the effect of the triple combination of interferon -1b, lopinavir-ritonavir, and ribavirin in the treatment of patients hospitalized with COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 46.0% female N = 127 54.0% male 127 patients (59 female, 68 male) Inclusion criteria: adult hospitalized patients with COVID-19 Key exclusion criteria: inability to comprehend and to follow all required study procedures, allergy or severe reactions to the study drugs, known prolonged QT or PR interval, second- or third-degree heart block, or ventricular cardiac arrhythmias, known history of severe depression, pregnant or lactating women Interventions N=86 combination (lopinavir 400 mg and ritonavir 100 mg every 12 hours, ribavirin 400 mg every 12 hours, and three doses of 8 million IUs of interferon -1b on alternate days for a total of 14 days) N=41 control (lopinavir 400 mg and ritonavir 100 mg every 12 hours for 14 days) Primary outcome https://web.pathway.md/studies/rec6YWTsCLGFZ4iR5 1/2 6/28/23, 11:10 PM Hung Pathway Time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 12.0 days, 12 9.0 days, 7 6.0 days, 3.0 days, Significant decrease 0.0 days, Combination Control Significant decrease in time to providing a nasopharyngeal swab negative for SARS-CoV-2 (7 days, vs. 12 days,; HR 0.22, 95% CI 0.09 to 0.53) Secondary outcomes Significant decrease in time to complete alleviation of symptoms (4 days vs. 8 days; HR 0.255, 95% CI 0.1 to 0.6) Significant decrease in time to Sequential Organ Failure Assessment score of 0 (3 days vs. 8 days; HR 0.52, 95% CI 0.28 to 0.97) Significant decrease in median hospital stay (9 days vs. 14.5 days; HR 0.36, 95% CI 0.16 to 0.83) Safety outcomes No significant differences in adverse events, self-limiting nausea and diarrhea. Conclusion In adult hospitalized patients with COVID-19, combination was superior to control with respect to time to providing a nasopharyngeal swab negative for SARS-CoV-2. Reference Ivan Fan-Ngai Hung, Kwok-Cheung Lung, Eugene Yuk-Keung Tso et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020 May 30;395(10238):1695-1704. Open reference URL https://web.pathway.md/studies/rec6YWTsCLGFZ4iR5 2/2

6/28/23, 11:10 PM Hungarian Prenatal Vitamin Trial Pathway Feedback Search Clinical Topics Home Studies Hungarian Prenatal Vitamin Trial Hungarian Prenatal Vitamin Trial Disease Disease Myelomeningocele Vitamins, minerals, and dietary s Trial question Is periconceptional supplementation of vitamins superior to trace-element supplement in women planning a pregnancy? Study design Multi-center Open label RCT Population 4156 female patients Inclusion criteria: women planning a pregnancy Key exclusion criteria: delayed conception or infertility, currently pregnant, age of > 35 years, and a history of previous unwanted pregnancy Interventions N=2104 vitamin supplementation (a single tablet containing 12 vitamins, including 0.8 mg of folic acid; 4 minerals; and 3 trace elements daily for at least one month before conception and until the date of the second missed menstrual period or later) N=2052 trace-element supplementation (a single tablet containing copper, manganese, zinc, and a very low dose of vitamin C daily for at least one month before conception and until the date of the second missed menstrual period or later) Primary outcome Congenital malformations 22.9 % 22.9 17.2 % 13.3 11.4 % Significant decrease 5.7 % https://web.pathway.md/studies/recfc8MyqFCDMmi5A 1/2 6/28/23, 11:10 PM Hungarian Prenatal Vitamin Trial Pathway NNT = 10 0.0 % Vitamin supplementation Trace-element supplementation Significant decrease in congenital malformations (13.3% vs. 22.9%; RR 0.58, 95% CI 0.09 to 1.07) Secondary outcomes Significant decrease in neural-tube defects (ARD -6, 95% CI -11.39 to -0.61) Safety outcomes No significant difference in prevalence of cleft lip with or without cleft palate (4 vs. 3). Conclusion In women planning a pregnancy, vitamin supplementation was superior to trace-element supplementation with respect to congenital malformations. Reference Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992 Dec 24;327(26):1832-5. Open reference URL https://web.pathway.md/studies/recfc8MyqFCDMmi5A 2/2

6/28/23, 11:06 PM HYBRID II Pathway Feedback Search Clinical Topics Home Studies HYBRID II HYBRID II Disease Cardiac arrest Trial question What is the role of inhaled hydrogen gas in patients with coma following cardiogenic out-of- hospital cardiac arrest? Study design Multi-center Double blinded RCT Population Characteristics of study participants 19.0% female N = 73 81.0% male 73 patients (14 female, 59 male) Inclusion criteria: patients aged 20-80 years with coma following cardiogenic out-of-hospital cardiac arrest Key exclusion criteria: known pre-arrest cerebral performance category score of 3 or 4; known treatment limitations; do not resuscitate order; trauma-associated out-of-hospital cardiac arrest; oxygen saturation < 94% with 50% oxygen inhalation Interventions N=39 hydrogen gas (inhalation of 2% hydrogen gas for 18 hours) N=34 control (inhalation of titrated oxygen gas for 18 hours) Primary outcome Cerebral performance category of 1 or 2 at day 90 56.0 % 56 https://web.pathway.md/studies/recO2mVzype2pkozx 1/2 6/28/23, 11:06 PM HYBRID II Pathway 42.0 % 39 28.0 % 14.0 % No significant difference 0.0 % Hydrogen gas Control No significant difference in cerebral performance category of 1 or 2 at day 90 (56% vs. 39%; RR 0.72, 95% CI 0.46 to 1.13) Secondary outcomes Significant decrease in median mRS score at day 90 (1 vs. 5; AD -4, 95% CI -7.04 to -0.96) Significant increase in survival at day 90 (85% vs. 61%; RR 2.5, 95% CI 1.09 to 5.88) Significant increase in mRS score of 0 (46% vs. 21%; RR 2.18, 95% CI 1.04 to 4.56) Safety outcomes No significant difference in adverse events and serious adverse events. Conclusion In patients aged 20-80 years with coma following cardiogenic out-of-hospital cardiac arrest, hydrogen gas were not superior to control with respect to cerebral performance category of 1 or 2 at day 90. Reference Tomoyoshi Tamura, Masaru Suzuki, Koichiro Homma et al. Efficacy of inhaled hydrogen on neurological outcome following brain ischaemia during post-cardiac arrest care (HYBRID II): a multi-centre, randomised, double-blind, placebo-controlled trial. EClinicalMedicine. 2023 Mar 17;58:101907. Open reference URL https://web.pathway.md/studies/recO2mVzype2pkozx 2/2

6/28/23, 11:10 PM Hydrocortisone, Vitamin C, and Thiamine in Severe Sepsis and Septic Shock Pathway Feedback Search Clinical Topics Home Studies Hydrocortisone, Vitamin C, and Thiamine in Severe Sepsis and Septic Shock Hydrocortisone, Vitamin C, and Thiamine in Severe Sepsis and Septic Shock Disease Sepsis and septic shock Trial question What is the composite effect of vitamin C, hydrocortisone, and thiamine treatment in patients with sepsis and septic shock? Study design Single center Open label Observational study Population Characteristics of study participants 47.0% female N = 94 53.0% male 94 patients (44 female, 50 male) Inclusion criteria: patients with consecutive sepsis or septic shock Key exclusion criteria: < 18 years of age, pregnant, and patients with limitations of care were Interventions N=47 treatment (intravenous vitamin C, hydrocortisone, and thiamine during a 7-month period) N=47 control (treated in ICU without vitamin C or thiamine during the preceding 7 months) Primary outcome Hospital death 40.4 % 40.4 30.3 % https://web.pathway.md/studies/recIVrqB95k0amAJ2 1/2 6/28/23, 11:10 PM Hydrocortisone, Vitamin C, and Thiamine in Severe Sepsis and Septic Shock Pathway 20.2 % Significant decrease 10.1 % NNT = 3 8.5 0.0 % Treatment Control Significant decrease in hospital death (8.5% vs. 40.4%; RR 0.21, 95% CI 0.09 to 0.33) Conclusion In patients with consecutive sepsis or septic shock, treatment was superior to control with respect to hospital death. Reference Marik PE, Khangoora V, Rivera R et al. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017 Jun;151(6):1229-1238. Open reference URL https://web.pathway.md/studies/recIVrqB95k0amAJ2 2/2

6/28/23, 11:10 PM Hydroxyurea versus anagrelide in high-risk ET Pathway Feedback Search Clinical Topics Home Studies Hydroxyurea versus anagrelide in high-risk ET Hydroxyurea versus anagrelide in high-risk ET Disease Essential thrombocythemia Trial question What is the role of hydroxyurea in patients with essential thrombocythemia? Study design Multi-center Open label RCT Population Characteristics of study participants 58.0% female N = 809 42.0% male 809 patients (467 female, 342 male) Inclusion criteria: patients with essential thrombocythemia who were at high-risk for vascular events and already receiving low-dose aspirin Key exclusion criteria: myelodysplasia or myelofibrosis, and known causes of reactive thrombocytosis, myocardial infarction within the previous three months, severe congestive HF, severe ventricular arrhythmia, pregnancy or lactation, or leg ulceration Interventions N=401 hydroxyurea (at a starting dose of 0.5-1.0 g daily, subsequent adjustment to maintain platelet count < 400,000 per m plus aspirin 75-100 mg daily) N=405 anagrelide (starting dose of 0.5 mg BID, subsequent adjustment to maintain platelet count < 400,000 per m plus aspirin 75-100 mg daily) Primary outcome Arterial or venous thrombosis, serious hemorrhage, or death from vascular causes https://web.pathway.md/studies/recqdKO9q1PVXZF6w 1/2 6/28/23, 11:10 PM Hydroxyurea versus anagrelide in high-risk ET Pathway 55.0 55 41.3 36 27.5 13.8 Significant increase 0.0 Hydroxyurea Anagrelide Significant increase in arterial or venous thrombosis, serious hemorrhage, or death from vascular causes (36 vs. 55; OR 1.57, 95% CI 1.04 to 2.37) Secondary outcomes Significant increase in arterial thrombosis (17 vs. 37; OR 2.16, 95% CI 1.27 to 3.69) Significant increase in serious hemorrhage (8 vs. 22; OR 2.61, 95% CI 1.27 to 5.33) Significant increase in transformation to myelofibrosis (5 vs. 16; OR 2.92, 95% CI 1.24 to 6.86) Safety outcomes Significant differences in study drug withdrawal due to side-effects (43 vs. 88, p < 0.001). Conclusion In patients with essential thrombocythemia who were at high-risk for vascular events and already receiving low-dose aspirin, hydroxyurea was superior to anagrelide with respect to arterial or venous thrombosis, serious hemorrhage, or death from vascular causes. Reference Harrison CN, Campbell PJ, Buck G et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005 Jul 7;353(1):33-45. Open reference URL https://web.pathway.md/studies/recqdKO9q1PVXZF6w 2/2

6/28/23, 11:06 PM HYPERION Pathway Feedback Search Clinical Topics Home Studies HYPERION HYPERION Disease Cardiac arrest Trial question What is the role of moderate therapeutic hypothermia in patients with cardiac arrest who have non-shockable rhythm? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 584 64.0% male 584 patients (208 female, 373 male) Inclusion criteria: patients with coma who had been admitted to the ICU after resuscitation from cardiac arrest with non-shockable rhythm Key exclusion criteria: a no-flow time of > 10 minutes; a low-flow time of > 60 minutes; major hemodynamic instability; time from cardiac arrest to a screening of > 300 minutes; moribund condition; severe hepatic dysfunction Interventions N=284 hypothermia (induction of a body temperature of 33 C with a window of +- 0.5 degree Celsius and maintained for 24 hours) N=297 normothermia (body temperature maintained at 36.5 to 37.5 C for 48 hours according to the standard protocol) Primary outcome https://web.pathway.md/studies/rec7k8Ua4aXAjauUx 1/2 6/28/23, 11:06 PM HYPERION Pathway Rate of survival with a favorable neurologic outcome, Cerebral Performance Category of 1 or 2, on day 90 10.2 % 10.2 7.6 % 5.7 5.1 % Significant increase 2.5 % NNT = 22 0.0 % Hypothermia Normothermia Significant increase in the rate of survival with a favorable neurologic outcome, Cerebral Performance Category of 1 or 2, on day 90 (10.2% vs. 5.7%; AD 4.5%, 95% CI 0.1 to 8.9) Secondary outcomes No significant difference in death at day 90 (81.3% vs. 83.2%; ARD -1.9, 95% CI -8 to 4.3) No significant difference in survival to ICU discharge (21.8% vs. 20.5%; HR 1.07, 95% CI 0.75 to 1.52) No significant difference in survival to hospital discharge (19.7% vs. 16.8%; HR 1.19, 95% CI 0.81 to 1.74) Safety outcomes No significant difference in prespecified serious adverse events. Conclusion In patients with coma who had been admitted to the ICU after resuscitation from cardiac arrest with non-shockable rhythm, hypothermia was superior to normothermia with respect to the rate of survival with a favorable neurologic outcome, Cerebral Performance Category of 1 or 2, on day 90. Reference Jean-Baptiste Lascarrou, Hamid Merdji, Am lie Le Gouge et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. 2019 Dec 12;381(24):2327-2337. Open reference URL https://web.pathway.md/studies/rec7k8Ua4aXAjauUx 2/2

6/28/23, 11:07 PM HYPRESS Pathway Feedback Search Clinical Topics Home Studies HYPRESS HYPRESS Disease Sepsis and septic shock Trial question What is the effect of hydrocortisone on the development of shock among patients with severe sepsis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 35.5% female N = 380 64.5% male 380 patients (124 female, 229 male) Inclusion criteria: patients with severe sepsis Key exclusion criteria: septic shock, younger than 18 years, known hypersensitivity to hydrocortisone or mannitol (placebo), history of corticosteroid medication with indication for continuation of therapy or other indications for treatment with corticosteroids Interventions N=190 hydrocortisone (continuous infusion at a dose of 200 mg for 5 days followed by dose tapering until day 11) N=190 placebo (lyophilized mannitol) Primary outcome Rate of septic shock within 14 days 22.9 22 9 % 21 2 https://web.pathway.md/studies/reczdwroms4DHgnNv 1/2 6/28/23, 11:07 PM 22.9 % HYPRESS Pathway 21.2 17.2 % 11.4 % 5.7 % No significant difference 0.0 % Hydrocortisone Placebo No significant difference in the rate of septic shock within 14 days (21.2% vs. 22.9%; AD -1.8%, 95% CI -10.7 to 7.2) Secondary outcomes No significant difference in death at 28 days (8.8% vs. 8.2%; AD 0.5%, 95% CI -5.6 to 6.7) No significant difference in death at 90 days (19.9% vs. 16.7%; AD 3.2%, 95% CI -5.1 to 11.4) No significant difference in death at 180 days (26.8% vs. 22.2%; AD 4.6%, 95% CI -4.6 to 13.7) Safety outcomes No significant differences in secondary infections, weaning failure, muscle weakness, hypernatremia, or other adverse events. Significant differences in hyperglycemia (90.9% vs. 81.5%), delirium (8.5% vs. 19.2%). Conclusion In patients with severe sepsis, hydrocortisone was not superior to placebo with respect to the rate of septic shock within 14 days. Reference Keh D, Trips E, Marx G et al. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA. 2016 Nov 1;316(17):1775-1785. Open reference URL https://web.pathway.md/studies/reczdwroms4DHgnNv 2/2

6/28/23, 11:07 PM HYVET Pathway Feedback Search Clinical Topics Home Studies HYVET HYVET Disease Hypertension Trial question What is the effect of indapamide treatment in patients 80 years of age with hypertension? Study design Multi-center Double blinded RCT Population Characteristics of study participants 60.0% female N = 3845 40.0% male 3845 patients (2326 female, 1519 male) Inclusion criteria: patients 80 years of age with a sustained systolic BP 160 mmHg Key exclusion criteria: a contraindication to use of the trial medications, accelerated hypertension, secondary hypertension, hemorrhagic stroke in the previous 6 months, HF requiring treatment with antihypertensive medication, gout, clinical dementia, and a requirement of nursing care Interventions N=1933 active-treatment (diuretic indapamide, sustained releases 1.5 mg, if necessary perindopril 2 or 4 mg to achieve the target BP 150/80 mmHg) N=1912 placebo (matching placebo of indapamide, if necessary matching placebo of perindopril) Primary outcome Incidence of stroke at 2 years https://web.pathway.md/studies/recSyBcdoGyXgb1DU 1/2 6/28/23, 11:07 PM HYVET Pathway 17.7/1000 py 17.7 13.3/1000 py 12.4 8.8/1000 py 4.4/1000 py No significant difference 0.0/1000 py Active-treatment Placebo No significant difference in the incidence of stroke at 2 years (12.4 /1000 py vs. 17.7 /1000 py; HR 0.7, 95% CI 0.49 to 1.01) Secondary outcomes Significant decrease in the incidence of death from stroke (6.5 /1000 py vs. 10.7 /1000 py; HR 0.61, 95% CI 0.38 to 0.99) Significant decrease in the incidence of death from any cause (47.2 /1000 py vs. 59.6 /1000 py; HR 0.79, 95% CI 0.65 to 0.95) Significant decrease in the incidence of HF (5.3 /1000 py vs. 14.8 /1000 py; HR 0.36, 95% CI 0.22 to 0.58) Safety outcomes Significant difference in serious adverse events (358 events vs. 448 events). Conclusion In patients 80 years of age with a sustained systolic BP 160 mmHg, active-treatment was not superior to placebo with respect to the incidence of stroke at 2 years. Reference Beckett NS, Peters R, Fletcher AE et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008 May 1;358(18):1887-98. Open reference URL https://web.pathway.md/studies/recSyBcdoGyXgb1DU 2/2

6/28/23, 11:31 PM I-PRESERVE Pathway Feedback Search Clinical Topics Home Studies I PRESERVE I PRESERVE Disease Heart failure Trial question What is the role of irbesartan in patients with HF and preserved ejection fraction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 60.0% female N = 4128 40.0% male 4128 patients (2491 female, 1637 male) Inclusion criteria: patients with HF and a preserved LVEF Key exclusion criteria: intolerance to an angiotensin-receptor blocker; an alternative cause of the patient's symptoms; previous LVEF < 40%; history of acute coronary syndrome, coronary revascularization, stroke within the previous 3 months Interventions N=2067 irbesartan (300 mg once daily) N=2061 placebo (matching placebo once daily) Primary outcome Incidence of death from any cause or hospitalization for a cardiovascular cause 105.4/1000 py 105.4 100.4 79.1/1000 py https://web.pathway.md/studies/recI41nO7uSO9gO0X 1/2 6/28/23, 11:31 PM I-PRESERVE Pathway 52.7/1000 py 26.4/1000 py No significant difference 0.0/1000 py Irbesartan Placebo No significant difference in the incidence of death from any cause or hospitalization for a cardiovascular cause (100.4 /1000 py vs. 105.4 /1000 py; HR 0.95, 95% CI 0.86 to 1.05) Secondary outcomes No significant difference in the incidence of death from any cause (52.6 /1000 py vs. 52.3 /1000 py; HR 1, 95% CI 0.88 to 1.14) No significant difference in the incidence of hospitalization for cardiovascular causes (70.6 /1000 py vs. 74.3 /1000 py; HR 0.95, 95% CI 0.85 to 1.08) No significant difference in the incidence of hospitalization for any cause (203.6 /1000 py vs. 199.8 /1000 py; HR 1.02, 95% CI 0.94 to 1.11) Safety outcomes No significant difference in serious adverse event. Conclusion In patients with HF and a preserved LVEF, irbesartan was not superior to placebo with respect to the incidence of death from any cause or hospitalization for a cardiovascular cause. Reference Barry M Massie, Peter E Carson, John J McMurray et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008 Dec 4;359(23):2456-67. Open reference URL https://web.pathway.md/studies/recI41nO7uSO9gO0X 2/2

6/28/23, 11:31 PM I-WOTCH Pathway Feedback Search Clinical Topics Home Studies I WOTCH I WOTCH Disease Opioids for pain Trial question What is the role of group-based educational intervention in patients taking strong opioids for chronic nonnmalignant pain? Study design Multi-center Open label RCT Population Characteristics of study participants 60.0% female N = 608 40.0% male 608 patients (362 female, 242 male) Inclusion criteria: adults taking strong opioids to treat chronic nonmalignant pain Key exclusion criteria: people living in chronic care facilities; unable to leave home without assistance; use of methadone not prescribed for chronic pain Interventions N=305 education and support (3-day-long group sessions on skill-based learning and education and 1-on-1 support for 12 months plus usual care) N=303 usual care (self-help booklet on pain, opioids, and opioid tapering plus a relaxation CD) Primary outcome Opioid discontinuation at 12 months 29.0 % 29 https://web.pathway.md/studies/rec3AJ1fDHRCwgOhO 1/2 6/28/23, 11:31 PM I-WOTCH Pathway 21.8 % 14.5 % Significant increase 7.3 % 7 NNH = 5 0.0 % Education and support Usual care Significant increase in opioid discontinuation at 12 months (29% vs. 7%; OR 5.55, 95% CI 2.8 to 10.99) Secondary outcomes No significant difference in Patient-Reported Outcomes Measurement Information System Pain Interference Short Form 8a score at 12 months (-4.1 vs. -3.17; MD -0.52, 95% CI -1.94 to 0.89) Significant increase in opioid discontinuation at 4 months (26% vs. 3%; OR 11.61, 95% CI 5.06 to 26.63) Significant increase in the percentage of patients achieving a 50% reduction in Morphine Equivalent Dose at 12 months (57% vs. 27%; OR 3.76, 95% CI 2.47 to 5.71) Safety outcomes No significant difference in serious adverse events. Conclusion In adults taking strong opioids to treat chronic nonmalignant pain, education and support were superior to usual care with respect to opioid discontinuation at 12 months. Reference Harbinder K Sandhu, Katie Booth, Andrea D Furlan et al. Reducing Opioid Use for Chronic Pain With a Group-Based Intervention: A Randomized Clinical Trial. JAMA. 2023 May 23;329(20):1745-1756. Open reference URL https://web.pathway.md/studies/rec3AJ1fDHRCwgOhO 2/2

6/28/23, 11:31 PM IABP-SHOCK II Pathway Feedback Search Clinical Topics Home Studies IABP SHOCK II IABP SHOCK II Disease Disease Disease Cardiogenic shock Non-ST-elevation myocardial inf ST-elev Trial question What is the role of intra-aortic balloon counterpulsation in patients with cardiogenic shock complicating acute myocardial infarction? Study design Multi-center Open label RCT Population Characteristics of study participants 31.0% female N = 600 69.0% male 600 patients (187 female, 413 male) Inclusion criteria: patients with cardiogenic shock complicating acute myocardial infarction who were expected to undergo early revascularization (by means of PCI or bypass surgery) and to receive the best available medical therapy Key exclusion criteria: undergone resuscitation for > 30 minutes; no intrinsic heart action; in a coma with fixed dilatation of pupils that was not induced by drugs; ventricular septal defect or papillary muscle rupture; onset of shock > 12 hours before screening; massive PE, or AR >grade II in severity Interventions N=301 IABP (intra-aortic balloon counterpulsation) N=299 control (no intra-aortic balloon counterpulsation) Primary outcome https://web.pathway.md/studies/recpVkqgtbkzO04fz 1/2 6/28/23, 11:31 PM IABP-SHOCK II Pathway Death at 30 days 41.3 % 41.3 39.7 31.0 % 20.6 % 10.3 % No significant difference 0.0 % IABP Control No significant difference in death at 30 days (39.7% vs. 41.3%; RR 0.96, 96% CI 0.79 to 1.17) Secondary outcomes No significant difference in reinfarction in hospital (3% vs. 1.3%; RR 2.24, 95% CI 0.7 to 7.18) No significant difference in stent thrombosis in hospital (1.3% vs. 1%; RR 1.32, 95% CI 0.3 to 5.87) Safety outcomes No significant differences in sepsis (15.7% vs. 20.5, p=0.15), major bleeding (3.3% vs. 4.4%, p=0.51), peripheral ischemic complications (4.3% vs. 3.4%, p=0.53), and stroke (0.7% vs. 1.7%, p=0.28). Conclusion In patients with cardiogenic shock complicating acute myocardial infarction who were expected to undergo early revascularization (by means of PCI or bypass surgery) and to receive the best available medical therapy, IABP was not superior to control with respect to death at 30 days. Reference Thiele H, Zeymer U, Neumann FJ et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. N Engl J Med. 2012 Oct 4;367(14):1287-96. Open reference URL https://web.pathway.md/studies/recpVkqgtbkzO04fz 2/2

6/28/23, 11:31 PM ICAP Pathway Feedback Search Clinical Topics Home Studies ICAP ICAP Disease Acute pericarditis Trial question What is the effect of colchicine in patients with acute pericarditis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 40.0% female N = 240 60.0% male 240 patients (95 female, 145 male) Inclusion criteria: adults with acute pericarditis who were receiving conventional treatment Key exclusion criteria: tuberculous, neoplastic, or purulent pericarditis; severe liver disease, skeletal myopathy; blood dyscrasia; IBD; hypersensitivity to colchicine or other contraindication to its use; current treatment with colchicine; and life expectancy < 18 months; pregnant or lactating women Interventions N=120 colchicine (at a dose of 0.5 mg BID for 3 months for patients weighing > 70 kg or 0.5 mg once daily for patients weighting 70 kg) N=120 placebo (identical placebo for 3 months) Primary outcome Incessant or recurrent pericarditis 37.5 % 37.5 https://web.pathway.md/studies/rech5UryaqePukKjw 1/2 6/28/23, 11:31 PM ICAP Pathway 28.1 % 18.8 % 16.7 Significant decrease 9.4 % NNT = 5 0.0 % Colchicine Placebo Significant decrease in incessant or recurrent pericarditis (16.7% vs. 37.5%; RR 0.44, 95% CI 0.28 to 0.7) Secondary outcomes Significant decrease in symptom persistence at 72 hours (19.2% vs. 40%; RR 0.48, 95% CI 0.2 to 0.76) Significant decrease in hospitalization (5% vs. 14.2%; RR 0.35, 95% CI 0.05 to 0.65) Significant increase in remission at 1 week (85% vs. 58.3%; RR 1.46, 95% CI 0.59 to 2.33) Safety outcomes No significant difference in overall adverse effects and rates of study-drug discontinuation. Conclusion In adults with acute pericarditis who were receiving conventional treatment, colchicine was superior to placebo with respect to incessant or recurrent pericarditis. Reference Imazio M, Brucato A, Cemin R et al. A randomized trial of colchicine for acute pericarditis. N Engl J Med. 2013 Oct 17;369(16):1522-8. Open reference URL https://web.pathway.md/studies/rech5UryaqePukKjw 2/2

6/28/23, 11:40 PM Icatibant in ACEI-Induced Angioedema Pathway Feedback Search Clinical Topics Home Studies Icatibant in ACEI Induced Angioedema Icatibant in ACEI Induced Angioedema Disease Hypertension Trial question What is the role of icatibant in patients who had ACE-inhibitor-induced angioedema? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 27 63.0% male 27 patients (10 female, 17 male) Inclusion criteria: patients who had ACE-inhibitor-induced angioedema of the upper aerodigestive tract Key exclusion criteria: causes other than ACE inhibitors, history of angioedema before the initiation of ACE-inhibitor therapy, acute urticaria, unstable angina, acute myocardial ischemia, acute HF with a NYHA class of III or IV, pregnancy, and lactation Interventions N=13 icatibant (at a dose of 30 mg SC) N=14 standard therapy (intravenous 500 mg prednisolone plus 2 mg clemastine) Primary outcome Median time to complete resolution of edema 27.1 hours 27.1 https://web.pathway.md/studies/recr8fuzeWK1rXZTe 1/2 6/28/23, 11:40 PM Icatibant in ACEI-Induced Angioedema Pathway 20.3 hours 13.6 hours 8 6.8 hours Significant decrease 0.0 hours Icatibant Standard therapy Significant decrease in median time to complete resolution of edema (8 hours vs. 27.1 hours; AD -19.1 hours, 95% CI -31.18 to -7.02) Secondary outcomes Significant increase in complete resolution within 4 hours (AD 38%, 95% CI 5.95 to 70.05) Significant decrease in median time to the onset of symptom relief (2 hours vs. 11.7 hours; AD -9.7 hours, 95% CI -18.47 to -0.93) Safety outcomes No significant difference in drug-related adverse event. Significant differences in adverse events (7% vs. 27%), redness at injection site (80% vs. 27%), swelling at injection site (53% vs. 20%), pain at injection site (47% vs. 13%). Conclusion In patients who had ACE-inhibitor-induced angioedema of the upper aerodigestive tract, icatibant was superior to standard therapy with respect to median time to complete resolution of edema. Reference Bas M, Greve J, Stelter K et al. A randomized trial of icatibant in ACE-inhibitor-induced angioedema. N Engl J Med. 2015 Jan 29;372(5):418-25. Open reference URL https://web.pathway.md/studies/recr8fuzeWK1rXZTe 2/2

6/28/23, 11:41 PM iCBT (secondary analysis, guided iCBT vs. self-guided iCBT) Pathway Feedback Search Clinical Topics Home Studies iCBT (secondary analysis, guided iCBT vs. self-guided iCBT iCBT (secondary analysis, guided iCBT vs. self-guided iCBT Disease Disease Generalized anxiety disorder Major depressive disorder Trial question Is clinician-guided iCBT superior to self-guided iCBT among university students with anxiety and depression? Study design Multi-center Open label RCT Population 884 patients Inclusion criteria: university students with anxiety and/or depression Key exclusion criteria: positive screens for lifetime bipolar disorder or nonaffective psychosis or recent suicidal ideation with intent Interventions N=445 clinician-guided iCBT (guides sent online weekly messages to users designed to create personalized experiences and provide feedback) N=439 self-guided iCBT (no personalized messages received from clinicians) Primary outcome Joint remission of anxiety and depression at 3 months 51.8 % 51.8 38.8 % 37.8 25.9 % Significant increase 12.9 % NNT = 7 0.0 % Clinician-guided internet-delivered cognitive behavioral therapy Self-guided internet-delivered cognitive behavioral therapy https://web.pathway.md/studies/recOhJ6PE1nktRNyg 1/2 6/28/23, 11:41 PM iCBT (secondary analysis, guided iCBT vs. self-guided iCBT) Pathway Significant increase in joint remission of anxiety and depression at 3 months (51.8% vs. 37.8%; AD 14%, 95% CI 4.77 to 23.23) Secondary outcomes No significant difference in anxiety remission (62.7% vs. 50.2%; AD 12.5%, 95% CI -4.09 to 29.09) Conclusion In university students with anxiety and/or depression, clinician-guided iCBT was superior to self- guided iCBT with respect to joint remission of anxiety and depression at 3 months. Reference Corina Benjet, Nur Hani Zainal, Yesica Albor et al. A Precision Treatment Model for Internet- Delivered Cognitive Behavioral Therapy for Anxiety and Depression Among University Students: A Secondary Analysis of a Randomized Clinical Trial. JAMA Psychiatry. 2023 Jun 7;e231675. Online ahead of print. Open reference URL https://web.pathway.md/studies/recOhJ6PE1nktRNyg 2/2

6/28/23, 11:41 PM iCBT (secondary analysis, guided iCBT vs. usual treatment) Pathway Feedback Search Clinical Topics Home Studies iCBT (secondary analysis, guided iCBT vs. usual treatment) iCBT (secondary analysis, guided iCBT vs. usual treatment) Disease Disease Generalized anxiety disorder Major depressive disorder Trial question What is the effect of clinician-guided iCBT on university students with anxiety and depression? Study design Multi-center Open label RCT Population 880 patients Inclusion criteria: university students with anxiety and/or depression Key exclusion criteria: positive screens for lifetime bipolar disorder or nonaffective psychosis or recent suicidal ideation with intent Interventions N=445 clinician-guided iCBT (guides sent online weekly messages to users designed to create personalized experiences and provide feedback) N=435 treatment as usual (informal counseling services provided by the faculty or referrals to the clinic) Primary outcome Joint remission of anxiety and depression at 3 months 51.8 % 51.8 40 38.8 % 25.9 % Significant increase 12.9 % NNT = 8 0.0 % Clinician-guided internet-delivered cognitive behavioral therapy Treatment as usual https://web.pathway.md/studies/recRQt42kgHzbNItQ 1/2 6/28/23, 11:41 PM iCBT (secondary analysis, guided iCBT vs. usual treatment) Pathway Significant increase in joint remission of anxiety and depression at 3 months (51.8% vs. 40%; AD 11.8%, 95% CI 4.8 to 18.8) Secondary outcomes No significant difference in anxiety remission (62.7% vs. 53%; AD 9.7%, 95% CI -6.73 to 26.13) Conclusion In university students with anxiety and/or depression, clinician-guided iCBT was superior to treatment as usual with respect to joint remission of anxiety and depression at 3 months. Reference Corina Benjet, Nur Hani Zainal, Yesica Albor et al. A Precision Treatment Model for Internet- Delivered Cognitive Behavioral Therapy for Anxiety and Depression Among University Students: A Secondary Analysis of a Randomized Clinical Trial. JAMA Psychiatry. 2023 Jun 7;e231675. Online ahead of print. Open reference URL https://web.pathway.md/studies/recRQt42kgHzbNItQ 2/2

6/28/23, 11:32 PM ICTOC Pathway Feedback Search Clinical Topics Home Studies ICTOC ICTOC Disease Disease Cellulitis Peripheral edema Trial question What is the role of leg compression therapy in patients with chronic edema of the leg and recurrent cellulitis? Study design Single center Open label RCT Population Characteristics of study participants 49.0% female N = 84 51.0% male 84 patients (41 female, 43 male) Inclusion criteria: patients with chronic edema of the leg and recurrent cellulitis Key exclusion criteria: younger than 18 years of age, already wearing effective compression garments 5 days per week, receiving end-of-life care, clinically unstable condition, chronic wound or a wound requiring specialist treatment, or compression therapy contraindicated Interventions N=41 compression (leg compression therapy plus education on cellulitis prevention) N=43 control (education alone) Primary outcome Recurrence of cellulitis 40.0 % 40 https://web.pathway.md/studies/recvWh46eEAzo4Jdi 1/2 6/28/23, 11:32 PM ICTOC Pathway 30.0 % 20.0 % 15 Significant decrease 10.0 % NNT = 4 0.0 % Compression Control Significant decrease in recurrence of cellulitis (15% vs. 40%; HR 0.23, 95% CI 0.09 to 0.59) Secondary outcomes No significant difference in hospitalization for cellulitis (7% vs. 14%; HR 0.38, 95% CI 0.09 to 1.59) Significant decrease in change in leg volume at 12 months (-181 ml vs. 60 ml; AD -241 ml, 95% CI -365 to -117) Significant decrease in combined quality-of-life measure for limb lymphedema (LYMQOL) at 12 months (-0.5 vs. -0.2; AD -0.3, 95% CI -0.6 to -0.1) Safety outcomes No significant difference in quality of life assessment. Conclusion In patients with chronic edema of the leg and recurrent cellulitis, compression was superior to control with respect to recurrence of cellulitis. Reference Elizabeth Webb, Teresa Neeman, Francis J Bowden et al. Compression Therapy to Prevent Recurrent Cellulitis of the Leg. N Engl J Med. 2020 Aug 13;383(7):630-639. Open reference URL https://web.pathway.md/studies/recvWh46eEAzo4Jdi 2/2

6/28/23, 11:32 PM ICU-diary Pathway Feedback Search Clinical Topics Home Studies ICU-diary ICU-diary Disease Posttraumatic stress disorder Trial question What is the effect of an ICU diary on posttraumatic stress disorder symptoms among patients receiving mechanical ventilation? Study design Multi-center Open label RCT Population Characteristics of study participants 37.3% female N = 657 62.7% male 657 patients (126 female, 213 male) Inclusion criteria: adult patients (with 1 family member each) who received mechanical ventilation within 48 hours after ICU admission for at least 2 days Key exclusion criteria: no family members visitation, a preadmission diagnosis of psychosis or dementia, acute neurologic diseases, cardiac arrest at admission, mute or deaf, moribund or imminent death Interventions N=355 intervention (an ICU diary filled in by clinicians and family members) N=354 control (usual ICU care without an ICU diary) Primary outcome Significant posttraumatic stress disorder symptoms 34.3 % 34.3 https://web.pathway.md/studies/recPqFhCDfBDQb7hQ 1/2 6/28/23, 11:32 PM ICU-diary Pathway 29.9 25.7 % 17.1 % 8.6 % No significant difference 0.0 % Intervention Control No significant difference in significant posttraumatic stress disorder symptoms (29.9% vs. 34.3%; ARD -4, 95% CI -15 to 6) Secondary outcomes No significant difference in Impact of Event Scale-Revised score (12 vs. 13; AD -1.47, 95% CI -1.93 to 4.87) No significant difference in Hospital Anxiety Depression Scale score among patients at 3- month follow-up (9 vs. 9; AD -0.75, 95% CI -2.27 to 0.78) No significant difference in Hospital Anxiety Depression Scale score among families at 3- month follow-up (14 vs. 14; AD 0.33, 95% CI -0.96 to 1.63) Safety outcomes No significant differences in symptoms of anxiety and depression, memories of ICU stay, delusional memories, emotional memories. Conclusion In adult patients (with 1 family member each) who received mechanical ventilation within 48 hours after ICU admission for at least 2 days, intervention was not superior to control with respect to significant posttraumatic stress disorder symptoms. Reference Mait Garrouste-Orgeas, C cile Flahault, Isabelle Vinatier et al. Effect of an ICU Diary on Posttraumatic Stress Disorder Symptoms Among Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial. JAMA. 2019 Jul 16;322(3):229-239. Open reference URL https://web.pathway.md/studies/recPqFhCDfBDQb7hQ 2/2

6/28/23, 11:32 PM ICU-ROX Pathway Feedback Search Clinical Topics Home Studies ICU ROX ICU ROX Trial question What is the effect of conservative oxygen therapy in adult patients undergoing mechanical ventilation in the ICU? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 965 63.0% male 965 patients (357 female, 608 male) Inclusion criteria: adult patients who were anticipated to require mechanical ventilation beyond the day after recruitment in the ICU Key exclusion criteria: life expectancy < 90 days due to a chronic or underlying medical condition; admitted following a drug overdose; long-term dependence on invasive ventilation prior to this acute illness; pregnancy Interventions N=484 conservative oxygen therapy (No supplemental oxygen use when the SpO2 is > 97%, and the FiO2 was decreased to 0.21 when the SpO2 was above the acceptable lower limit of 91%) N=481 usual oxygen therapy (no specific measures limiting supplemental oxygen use and the FiO2) Primary outcome Number of ventilator-free days at day 28 22.1 days 22.1 21.3 16.6 days 11.1 days 5 5 d https://web.pathway.md/studies/reclNFf9ZEq68sUdj 1/2 6/28/23, 11:32 PM 5.5 days ICU-ROX Pathway No significant difference 0.0 days Conservative oxygen therapy Usual oxygen therapy No significant difference in the number of ventilator-free days at day 28 (21.3 days vs. 22.1 days; AD -0.3 days, 95% CI -2.1 to 1.6) Secondary outcomes No significant difference in death at day 180 (35.7% vs. 34.5%; OR 1.05, 95% CI 0.81 to 1.37) No significant difference in time from randomization to ICU discharge (115 hours vs. 124 hours; AD -8.4 hours, 95% CI -27.7 to 10.9) No significant difference in the percentage of patients who received RRT in ICU (19.4% vs. 22.5%; OR 0.83, 95% CI 0.61 to 1.14) Safety outcomes No significant difference in adverse events. Significant differences in severe problems with walking around (2.8% vs. 8.7%), severe problems with washing or dressing (0.8% vs. 4%). Conclusion In adult patients who were anticipated to require mechanical ventilation beyond the day after recruitment in the ICU, conservative oxygen therapy was not superior to usual oxygen therapy with respect to number of ventilator-free days at day 28. Reference ICU-ROX Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Diane Mackle, Rinaldo Bellomo et al. Conservative Oxygen Therapy during Mechanical Ventilation in the ICU. N Engl J Med. 2020 Mar 12;382(11):989-998. Open reference URL https://web.pathway.md/studies/reclNFf9ZEq68sUdj 2/2

6/28/23, 11:32 PM IDEAL-ICU Pathway Feedback Search Clinical Topics Home Studies IDEAL ICU IDEAL ICU Disease Disease Acute kidney injury Sepsis and septic shock Trial question What is the role of early strategy for the initiation of RRT among patients with septic shock who had severe AKI? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 488 61.0% male 488 patients (192 female, 296 male) Inclusion criteria: patients with early-stage septic shock who had severe AKI at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease classification system but without life-threatening complications related to AKI Key exclusion criteria: requirement of emergency RRT before randomization, chronic renal at dialysis, moribund with life expectancy < 24 hours Interventions N=246 an early strategy (RRT within 12 hours after documentation of failure-stage AKI) N=242 a delayed strategy (RRT after a delay of 48 hours if renal recovery had not occurred) Primary outcome Death at 90 days 58 58 0 % 54 https://web.pathway.md/studies/recWjfQSTo5FzjHJy 1/2 6/28/23, 11:32 PM 58.0 % IDEAL-ICU Pathway 54 43.5 % 29.0 % 14.5 % No significant difference 0.0 % An early strategy A delayed strategy No significant difference in death at 90 days (58% vs. 54%; RR 1.07, 95% CI -1.29 to 3.43) Secondary outcomes Significant decrease in days free of RRT (12 days vs. 16 days; AD -4 days, 95% CI -6.85 to -1.15) No significant difference in days free of mechanical ventilation (2 days vs. 3 days; AD -1 days, 95% CI -2.49 to 0.49) No significant difference in median length of ICU stay (11 days vs. 10 days; AD 1 days, 95% CI -14.97 to 16.97) Safety outcomes No significant difference in other adverse events and fluid balance at any given time. Significant difference in hyperkalemia (0% vs. 4%). Conclusion In patients with early-stage septic shock who had severe AKI at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease classification system but without life- threatening complications related to AKI, an early strategy was not superior to a delayed strategy with respect to death at 90 days. Reference Saber D Barbar, Rapha l Clere-Jehl, Abderrahmane Bourredjem et al. Timing of Renal- Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018 Oct 11;379(15):1431-1442. Open reference URL https://web.pathway.md/studies/recWjfQSTo5FzjHJy 2/2

6/28/23, 11:32 PM IDEAL Pathway Feedback Search Clinical Topics Home Studies IDEAL IDEAL Disease Chronic kidney disease Trial question What is the role of early initiation of dialysis in patients with stage V CKD? Study design Multi-center Open label RCT Population Characteristics of study participants 35.0% female N = 828 65.0% male 828 patients (286 female, 542 male) Inclusion criteria: patients 18 years of age with progressive CKD and an eGFR between 10.0 and 15.0 mL/min/1.73 m of body-surface area Key exclusion criteria: younger than 18 years of age, estimated GFR < 10.0 mL/min, plans to receive a kidney transplant from a live donor within the next 12 months, recently diagnosed cancer that was likely to affect survival, or unable to provide written informed consent Interventions N=404 early dialysis initiation (initiation of dialysis when the estimated GFR was 10.0-14.0 mL/min) N=424 late dialysis initiation (initiation of dialysis when the estimated GFR was 5.0-7.0 mL/min) Primary outcome All-cause death 37.6 37.6 % 36.6 https://web.pathway.md/studies/rec5DwB34goo84j81 1/2 6/28/23, 11:32 PM IDEAL Pathway 36 6 28.2 % 18.8 % 9.4 % No significant difference 0.0 % Early dialysis initiation Late dialysis initiation No significant difference in all-cause death (37.6% vs. 36.6%; HR 1.04, 95% CI 0.83 to 1.3) Secondary outcomes No significant difference in the incidence of cardiovascular events (10.9 /100 py vs. 8.8 /100 py; HR 1.23, 95% CI 0.97 to 1.56) Safety outcomes No significant difference in frequency of adverse events. Conclusion In patients 18 years of age with progressive CKD and an eGFR between 10.0 and 15.0 mL/min/1.73 m of body-surface area, early dialysis initiation was not superior to late dialysis initiation with respect to a all-cause death. Reference Cooper BA, Branley P, Bulfone L et al. A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med. 2010 Aug 12;363(7):609-19. Open reference URL https://web.pathway.md/studies/rec5DwB34goo84j81 2/2

6/28/23, 11:42 PM iDIAPASON Pathway Feedback Search Clinical Topics Home Studies iDIAPASON iDIAPASON Disease Ventilator-associated pneumonia Trial question Is short duration of antibiotic therapy noninferior to prolonged antibiotic therapy in patients with P. aeruginosa ventilator-associated pneumonia? Study design Multi-center Open label RCT Population Characteristics of study participants 24.0% female N = 186 76.0% male 186 patients (45 female, 141 male) Inclusion criteria: adult patients with P. aeruginosa ventilator-associated pneumonia Key exclusion criteria: current antibiotic therapy active on P. aeruginosa for extra-pulmonary infection; chronic pulmonary colonization with P. aeruginosa; immunosuppression Interventions N=88 short-duration therapy (antibiotic treatment for 8 days) N=98 long-duration therapy (antibiotic treatment for 15 days) Primary outcome Composite outcome of death and recurrence in intensive care unit at day 90 35.2 % 35.2 26.4 % 25.5 https://web.pathway.md/studies/recyJY8M0sjfCxpz5 1/2 6/28/23, 11:42 PM iDIAPASON Pathway 17.6 % Difference not exceeding nonferiority margin 8.8 % 0.0 % Short-duration therapy Long-duration therapy Difference not exceeding nonferiority margin in composite outcome of death and recurrence in the ICU at day 90 (35.2% vs. 25.5%; AD 9.7%, 90% CI 0 to 21.2) Secondary outcomes Borderline significant increase in recurrence in the ICU at day 90 (17% vs. 9.2%; AD 7.9%, 90% CI 0 to 16.8) No significant difference in duration of mechanical ventilation (22 days vs. 25 days; AD -3 days, 95% CI -9 to 5) Conclusion In adult patients with P. aeruginosa ventilator-associated pneumonia, short-duration therapy was noninferior to long-duration therapy with respect to the composite outcome of death and recurrence in the ICU at day 90. Reference Adrien Bougl , Sophie Tuffet, Laura Federici et al. Comparison of 8 versus 15 days of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia in adults: a randomized, controlled, open-label trial. Intensive Care Med. 2022 Jul;48(7):841-849. Open reference URL https://web.pathway.md/studies/recyJY8M0sjfCxpz5 2/2

6/28/23, 11:33 PM IFR-SWEDEHEART Pathway Feedback Search Clinical Topics Home Studies IFR SWEDEHEART IFR SWEDEHEART Disease Coronary artery disease Trial question Is instantaneous wave-free ratio guided revascularization strategy noninferior to fractional flow reserve guided revascularization with respect to the rate of major adverse cardiac events in patients with stable angina or an acute coronary syndrome? Study design Multi-center Open label RCT Population Characteristics of study participants 25.0% female N = 2037 75.0% male 2037 patients (515 female, 1522 male) Inclusion criteria: patients with stable angina or an acute coronary syndrome who had an indication for physiologically guided assessment of coronary artery stenosis Key exclusion criteria: previous CABG with patent grafts to the interrogated vessel, known terminal disease with a life expectancy of less than a year, multi-vessel disease, unstable hemodynamics, inability to tolerate adenosine, heavily calcified or tortuous vessels Interventions N=1012 iFR-guided revascularization (measurement with coronary-pressure guidewire; iFR 0.89) N=1007 FFR-guided revascularization (measurement with coronary-pressure guidewire and hyperemia induction with the administration of intracoronary or intravenous adenosine; FFR 0.80) https://web.pathway.md/studies/recEeRRN2xiwl0LEl 1/2 6/28/23, 11:33 PM IFR-SWEDEHEART Pathway Primary outcome Death from any cause, nonfatal myocardial infarction, or unplanned revascularization at 12 months 6.7 % 6.7 6.1 5.0 % 3.4 % Difference not exceeding nonferiority margin 1.7 % 0.0 % IFR-guided revascularization FFR-guided revascularization Difference not exceeding nonferiority margin in death from any cause, nonfatal myocardial infarction, or unplanned revascularization at 12 months (6.7% vs. 6.1%; HR 1.12, 95% CI 0.79 to 1.58) Secondary outcomes No significant difference in death from any cause at 12 months (1.5% vs. 1.2%; HR 1.25, 95% CI 0.58 to 2.66) Conclusion In patients with stable angina or an acute coronary syndrome who had an indication for physiologically guided assessment of coronary artery stenosis, iFR-guided revascularization was noninferior to FFR-guided revascularization with respect to death from any cause, nonfatal myocardial infarction, or unplanned revascularization at 12 months. Reference Gotberg M, Christiansen EH, Gudmundsdottir IJ et al. Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI. N Engl J Med. 2017 May 11;376(19):1813-1823. Open reference URL https://web.pathway.md/studies/recEeRRN2xiwl0LEl 2/2

6/28/23, 11:34 PM IIHTT Pathway Feedback Search Clinical Topics Home Studies IIHTT IIHTT Disease Idiopathic intracranial hypertens Trial question What is the effect of acetazolamide in patients with idiopathic intracranial hypertension and mild visual loss? Study design Multi-center Double blinded RCT Population Characteristics of study participants 98.0% female N = 165 2.0% male 165 patients (161 female, 4 male) Inclusion criteria: patients with idiopathic intracranial hypertension and mild visual loss who received a low-sodium weight-reduction diet Key exclusion criteria: total treatment of idiopathic intracranial hypertension > 2 weeks; previous surgery for idiopathic intracranial hypertension; abnormal cerebrovascular fluid contents; abnormalities on neurologic examination aside from papilledema Interventions N=86 acetazolamide (maximally tolerated dosage of up to 4 g/day for 6 months) N=79 placebo (matching placebo for 6 months) Primary outcome Improvement in perimetric mean deviation in most affected eye at 6 months 1.4 dB 1.43 https://web.pathway.md/studies/recoxGsf65OfOisqv 1/2 6/28/23, 11:34 PM IIHTT Pathway 1.1 dB 0.7 dB 0.71 0.4 dB Borderline significant increase 0.0 dB Acetazolamide Placebo Borderline significant increase in improvement in perimetric mean deviation in the most affected eye at 6 months (1.43 dB vs. 0.71 dB; AD 0.71 dB, 95% CI 0 to 1.43) Secondary outcomes Significant decrease in improvement in papilledema grade (-1.31 vs. -0.61; AD -0.7, 95% CI -0.99 to -0.41) Significant increase in vision-related quality of life (8.33 vs. 1.98; AD 6.35, 95% CI 2.22 to 10.47) Significant increase in weight reduction (7.5 kg vs. 3.45 kg; AD 4.05 kg, 95% CI 1.83 to 6.27) Safety outcomes No significant differences in dizziness, dyspnea, headache. Significant differences in diarrhea (14.0% vs. 3.8%), vomiting (14.0% vs. 3.8%), dysgeusia (15.1% vs. 0%), paresthesia (47.7% vs. 6.3%), reduction in CO2 level (10.5% vs. 0%). Conclusion In patients with idiopathic intracranial hypertension and mild visual loss who received a low- sodium weight-reduction diet, acetazolamide was superior to placebo with respect to improvement in perimetric mean deviation in the most affected eye at 6 months. Reference NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee, Michael Wall, Michael P McDermott et al. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA. 2014 Apr 23-30;311(16):1641-51. Open reference URL https://web.pathway.md/studies/recoxGsf65OfOisqv 2/2

6/28/23, 11:40 PM Imatinib-IPF Pathway Feedback Search Clinical Topics Home Studies Imatinib-IPF Imatinib-IPF Disease Idiopathic pulmonary fibrosis Trial question What is the role of imatinib in patients with idiopathic pulmonary fibrosis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 29.0% female N = 119 71.0% male 119 patients (35 female, 84 male) Inclusion criteria: patients with idiopathic pulmonary fibrosis Key exclusion criteria: an alternate explanation for the presence of fibrotic lung disease or known connective tissue disease, women of childbearing age or breast-feeding, obstructive lung disease, active infection, unstable or deteriorating cardiac or neurologic disease, Interventions N=59 imatinib (Gleevec 600 mg, six tablets PO once daily for a period of 96 weeks) N=60 placebo (matching placebo for 96 weeks) Primary outcome No significant difference in change in diffusing capacity of CO at 96 weeks (-1.1 vs. -1.6; ARD 0.5, 95% CI -0.7 to 1.7) Secondary outcomes https://web.pathway.md/studies/recPTzRPPUps2JKZd 1/2 6/28/23, 11:40 PM Imatinib-IPF Pathway Significant increase in change in resting Pa(O2) at 96 weeks (0.3 vs. -5.6; ARD 5.9, 95% CI 5.9 to 5.9) Safety outcomes No significant differences in deaths (p=0.64), discontinuation of study drug (32% vs. 27%, p=0.51), and serious adverse events (18 vs. 19). Conclusion In patients with idiopathic pulmonary fibrosis, imatinib was not superior to placebo with respect to change in diffusing capacity of CO at 96 weeks. Reference Daniels CE, Lasky JA, Limper AH et al. Imatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial results. Am J Respir Crit Care Med. 2010 Mar 15;181(6):604-10. Open reference URL https://web.pathway.md/studies/recPTzRPPUps2JKZd 2/2

6/28/23, 11:35 PM IMbrave 150 Pathway Feedback Search Clinical Topics Home Studies IMbrave 150 IMbrave 150 Disease Hepatocellular carcinoma Trial question What is the effect of atezolizumab plus bevacizumab in patients with unresectable HCC? Study design Multi-center Open label RCT Population Characteristics of study participants 17.0% female N = 501 83.0% male 501 patients (87 female, 414 male) Inclusion criteria: patients with unresectable HCC who had not previously received systemic treatment Key exclusion criteria: history of autoimmune disease; coinfection with HBV or HCV; untreated or incompletely treated esophageal or gastric varices with bleeding or high risk of bleeding Interventions N=336 atezolizumab-bevacizumab (intravenous administration of 1,200 mg and 15 mg/kg, respectively, on day 1 of each 21-day cycle) N=165 sorafenib (at a dose of 400 mg BID, on days 1-21 of each 21-day cycle) Primary outcome Overall survival at 12 months 67.2 67.2 % 54 6 https://web.pathway.md/studies/rec4AdMf2EIHPFj0V 1/2 6/28/23, 11:35 PM IMbrave 150 Pathway 54.6 50.4 % 33.6 % Significant increase 16.8 % NNT = 8 0.0 % Atezolizumab-bevacizumab Sorafenib Significant increase in overall survival at 12 months (67.2% vs. 54.6%; AD 12.6%, 95% CI 5.12 to 20.08) Secondary outcomes Significant increase in median progression-free survival (6.8 months vs. 4.3 months; AD 2.5 months, 95% CI 1.02 to 3.98) Significant increase in confirmed objective response (27.3% vs. 11.9%; AD 15.4%, 95% CI 6.26 to 24.54) Safety outcomes No significant differences in adverse events, grade 3 or 4 adverse events. Conclusion In patients with unresectable HCC who had not previously received systemic treatment, atezolizumab-bevacizumab was superior to sorafenib with respect to overall survival at 12 months. Reference Richard S Finn, Shukui Qin, Masafumi Ikeda et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. Open reference URL https://web.pathway.md/studies/rec4AdMf2EIHPFj0V 2/2

6/28/23, 11:34 PM IMPACT Pathway Feedback Search Clinical Topics Home Studies IMPACT IMPACT Disease Chronic obstructive pulmonary Reference Lipson DA, Barnhart F, Brealey N et al. Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD. N Engl J Med. 2018 May 3;378(18):1671-1680. Open reference URL https://web.pathway.md/studies/recpmv6UBoWflYVnV 1/1

6/28/23, 11:40 PM ImpresU Pathway Feedback Search Clinical Topics Home Studies ImpresU ImpresU Disease Disease Disease Acute cystitis Acute pyelonephritis Recurre Trial question What is the role of multifaceted antibiotic stewardship intervention in frail older adults with suspected UTIs? Study design Multi-center Open label RCT Population Characteristics of study participants 71.0% female N = 1041 29.0% male 1041 patients (738 female, 303 male) Inclusion criteria: frail older adults aged 70 of age Key exclusion criteria: participation for < 2 months; in hospice-care; limited life expectancy of 1 month; on antibiotic prophylaxis Interventions N=502 antibiotic stewardship intervention (participatory-action-research approach used for implementation, with sessions for education, evaluation, and local tailoring of the intervention) N=539 usual care (no intervention) Primary outcome Number of antibiotic prescriptions for suspected urinary tract infections 0.6/ p-y 0.58 https://web.pathway.md/studies/reca674ffNONknNJg 1/2 6/28/23, 11:40 PM ImpresU Pathway 0.4/ p-y 0.3/ p-y 0.27 0.1/ p-y Significant decrease 0.0/ p-y Antibiotic stewardship intervention Usual care Significant decrease in the number of antibiotic prescriptions for suspected UTIs (0.27 / p-y vs. 0.58 / p-y; RR 0.42, 95% CI 0.26 to 0.68) Secondary outcomes Significant decrease in antibiotic prescriptions in office hours on day of suspected UTI (0.19 / p-y vs. 0.36 / p-y; RR 0.33, 95% CI 0.19 to 0.57) Significant decrease in suspected UTIs (0.32 / p-y vs. 0.72 / p-y; RR 0.51, 95% CI 0.34 to 0.77) No significant difference in death from all causes (0.26 / p-y vs. 0.26 / p-y; RR 1.03, 95% CI 0.48 to 2.21) Conclusion In frail older adults aged 70 of age, antibiotic stewardship intervention was superior to usual care with respect to number of antibiotic prescriptions for suspected UTIs. Reference Esther A R Hartman, Alma C van de Pol, Silje Rebekka Heltveit-Olsen et al. Effect of a multifaceted antibiotic stewardship intervention to improve antibiotic prescribing for suspected urinary tract infections in frail older adults (ImpresU): pragmatic cluster randomised controlled trial in four European countries. BMJ. 2023 Feb 22;380:e072319. Open reference URL https://web.pathway.md/studies/reca674ffNONknNJg 2/2

6/28/23, 11:35 PM IMPROVE-IT Pathway Feedback Search Clinical Topics Home Studies IMPROVE IT IMPROVE IT Disease Disease Disease Dyslipidemia Non-ST-elevation myocardial inf ST-elev Trial question What is the effect of the addition of ezetimibe to statin therapy in patients who have been hospitalized for an acute coronary syndrome? Study design Multi-center Double blinded RCT Population Characteristics of study participants 24.0% female N = 18144 76.0% male 18144 patients (4416 female, 13728 male) Inclusion criteria: patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg/dL Key exclusion criteria: planned CABG for the acute coronary syndrome event, CrCl of < 30 mL/min, active liver disease, or use of statin therapy that had LDL cholesterol-lowering potency > 40 mg of simvastatin Interventions N=9067 simvastatin-ezetimibe (simvastatin at a dose of 40 mg plus ezetimibe at a dose of 10 mg, once daily) N=9077 simvastatin monotherapy once daily (simvastatin at a dose of 40 mg plus placebo) Primary outcome https://web.pathway.md/studies/rec5r6HSU3d2QP2kO 1/2 6/28/23, 11:35 PM IMPROVE-IT Pathway Death from cardiovascular causes, major coronary event, or nonfatal stroke, Kaplan-Meier event rate at 7 years 34.7 % 34.7 32.7 26.0 % 17.4 % Significant decrease 8.7 % NNT = 50 0.0 % Simvastatin-ezetimibe Simvastatin monotherapy once daily Significant decrease in death from cardiovascular causes, major coronary event, or nonfatal stroke, Kaplan-Meier event rate at 7 years (32.7% vs. 34.7%; HR 0.936, 95% CI 0.89 to 0.99) Secondary outcomes Significant increase in median time-weighted average LDL cholesterol level (53.2 vs. 69.9; difference 16.7, 95% CI -17.49 to -16.02) Safety outcomes No significant differences in rates of prespecified muscle, gallbladder, and hepatic adverse events and cancer. Conclusion In patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg/dL, simvastatin-ezetimibe was superior to simvastatin monotherapy once daily with respect to death from cardiovascular causes, major coronary event, or nonfatal stroke, Kaplan-Meier event rate at 7 years. Reference Cannon CP, Blazing MA, Giugliano RP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97. Open reference URL https://web.pathway.md/studies/rec5r6HSU3d2QP2kO 2/2

6/28/23, 11:35 PM INDIGO Pathway Feedback Search Clinical Topics Home Studies INDIGO INDIGO Disease Diffuse glioma Trial question What is the role of vorasidenib in patients with grade 2 IDH-mutant glioma? Study design Multi-center Double blinded RCT Population Characteristics of study participants 44.0% female N = 331 56.0% male 331 patients (144 female, 187 male) Inclusion criteria: patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery Key exclusion criteria: prior anticancer therapy other than surgery, presence of features assessed by the investigator as high risk, HR-corrected QT interval of at least 450 msec on the basis of Fridericia's formula Interventions N=168 vorasidenib (an oral dose of 40 mg/day in 28-day cycles) N=163 placebo (matching placebo oral tablets in 28-day cycles) Primary outcome Median progression-free survival 27.7 months 27.7 https://web.pathway.md/studies/recCbGqKxtZxlof1U 1/2 6/28/23, 11:35 PM INDIGO Pathway 20.8 months 13.8 months 11.1 6.9 months Significant increase 0.0 months Vorasidenib Placebo Significant increase in median progression-free survival (27.7 months vs. 11.1 months; AD 16.6 months, 95% CI 6.75 to 26.45) Safety outcomes No significant difference in adverse events. Significant differences in increased ALT (38.9% vs. 14.7%), increased AST (28.7% vs. 8.0%). Conclusion In patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery, vorasidenib was superior to placebo with respect to median progression-free survival. Reference Ingo K Mellinghoff, Martin J van den Bent, Deborah T Blumenthal et al. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N Engl J Med. 2023 Jun 4. Online ahead of print. Open reference URL https://web.pathway.md/studies/recCbGqKxtZxlof1U 2/2

6/28/23, 11:35 PM INPULSIS Pathway Feedback Search Clinical Topics Home Studies INPULSIS INPULSIS Disease Idiopathic pulmonary fibrosis Trial question What is the effect of nintedanib in patients with idiopathic pulmonary fibrosis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 21.0% female N = 1066 79.0% male 1066 patients (220 female, 841 male) Inclusion criteria: patients with idiopathic pulmonary fibrosis Key exclusion criteria: liver transaminases or bilirubin above 1.5-fold ULN, myocardial infarction within 6 months or unstable angina within 1 month of randomization, taking full-dose anticoagulant therapy or high-dose antiplatelet therapy at screening, or treatment with NAC or prednisone > 15 mg/day or equivalent within 2 weeks of screening Interventions N=638 nintedanib (150 mg BID for 52 weeks) N=423 placebo (matching placebo for 52 weeks) Primary outcome Significant increase in the incidence of decline in FVC, in INPULSIS-1 (-114.7 mL/year vs. -239.9 mL/year; AD 125.3 mL/year, 95% CI 77.7 to 172.8) t https://web.pathway.md/studies/reccMJuaoyLd2h3t2 S d 1/2 6/28/23, 11:35 PM INPULSIS Pathway Secondary outcomes Significant increase in the incidence of change in FVC, in INPULSIS-2 (-113.6 mL/year vs. 207.3 mL/year; AD 93.7 mL/year, 95% CI 44.8 to 142.7) Safety outcomes Significant difference in adverse event related to diarrhea in INPULSIS-1 (61.5% vs. 18.6%) and INPULSIS-2 (63.2% vs. 18.3%). Conclusion In patients with idiopathic pulmonary fibrosis, nintedanib was superior to placebo with respect to the incidence of decline in FVC, in INPULSIS-1. Reference Richeldi L, du Bois RM, Raghu G et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2071-82. Open reference URL https://web.pathway.md/studies/reccMJuaoyLd2h3t2 2/2

6/28/23, 11:35 PM INSIGHT START Pathway Feedback Search Clinical Topics Home Studies INSIGHT START INSIGHT START Disease Human immunodeficiency virus i Trial question What is the role of initiation of antiretroviral therapy in patients with early asymptomatic HIV infection? Study design Multi-center Open label RCT Population Characteristics of study participants 27.0% female N = 4685 73.0% male 4685 patients (1257 female, 3428 male) Inclusion criteria: HIV-positive adults who had a CD4+ count > 500 cells/mm Key exclusion criteria: pregnant or breastfeeding women, prior use of ART, or any prior immunomodulatory therapy, history of any AIDS-defining condition; presence of symptoms consistent with HIV disease progression; or a history of myocardial infarction, angioplasty or bypass surgery, stroke, dialysis, renal transplantation, decompensated liver disease, or non- AIDS-defining cancer within 6 months before randomization Interventions N=2326 immediate-initiation (CD4+ count > 500 cells/mm ) N=2359 deferred-initiation (CD4+ count < 350 cells/mm or until the development of the AIDS or another condition that dictated the use of antiretroviral therapy) Primary outcome https://web.pathway.md/studies/recBrLFOMYMdZap8Z 1/2 6/28/23, 11:35 PM INSIGHT START Pathway Any serious AIDS-related event, serious non-AIDS-related event, or death 4.1 % 4.1 3.1 % 2.0 % 1.8 Significant decrease 1.0 % NNT = 43 0.0 % Immediate-initiation Deferred-initiation Significant decrease in any serious AIDS-related event, serious non-AIDS-related event, or death (1.8% vs. 4.1%; HR 0.43, 95% CI 0.3 to 0.62) Secondary outcomes Significant decrease in serious AIDS-related events (100-person yr) (0.2 vs. 0.7; HR 0.28, 95% CI 0.15 to 0.5) Significant decrease in serious non-AIDS-related events (0.42 vs. 0.67; HR 0.61, 95% CI 0.38 to 0.97) No significant difference in death from any cause (0.17 vs. 0.3; HR 0.58, 95% CI 0.28 to 1.17) Safety outcomes No significant differences in grade 4 event (HR 1.01, 95% CI 0.73-1.39, p=0.97) and unscheduled hospitalization (HR 0.91, 95% CI 0.77-1.08, p=0.28). Conclusion In HIV-positive adults who had a CD4+ count > 500 cells/mm , immediate-initiation was superior to deferred-initiation with respect to any serious AIDS-related event, serious non-AIDS-related event, or death. Reference INSIGHT START Study Group, Lundgren JD, Babiker AG et al. Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N Engl J Med. 2015 Aug 27;373(9):795-807. Open reference URL https://web.pathway.md/studies/recBrLFOMYMdZap8Z 2/2