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6/28/23, 11:22 PM NOBLE Pathway Feedback Search Clinical Topics Home Studies NOBLE NOBLE Disease Coronary artery disease Trial question What is the role of PCI in patients with left main coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 21.4% female N = 1201 78.6% male 1201 patients (256 female, 928 male) Inclusion criteria: patients with stable angina, unstable angina, or non-ST elevation myocardial infarction and left main coronary artery disease Key exclusion criteria: STEMI within 24 h, too high risk for CABG or PCI, or expected survival of < 1 year Interventions N=598 PCI (PCI with drug-eluting stents) N=603 CABG (CABG according to present clinical practice) Primary outcome Rate of Kaplan-Meier 5 year estimates of major adverse cardiac or cerebrovascular events https://web.pathway.md/studies/recf3dXyXUkIUDi1j 1/2 6/28/23, 11:22 PM NOBLE Pathway 29.0 % 29 21.8 % 19 14.5 % Difference exceeding nonferiority margin 7.3 % 0.0 % PCI CABG Difference exceeding nonferiority margin in the rate of Kaplan-Meier 5 year estimates of major adverse cardiac or cerebrovascular events (29% vs. 19%; HR 1.48, 95% CI 1.11 to 1.96) Secondary outcomes No significant difference in death from any cause (12% vs. 9%; HR 1.07, 95% CI 0.67 to 1.72) Conclusion In patients with stable angina, unstable angina, or non-ST elevation myocardial infarction and left main coronary artery disease, PCI was not noninferior to CABG with respect to the rate of Kaplan- Meier 5 year estimates of major adverse cardiac or cerebrovascular events. Reference Makikallio T, Holm NR, Lindsay M et al. Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial. Lancet. 2016 Dec 3;388(10061):2743-2752. Open reference URL https://web.pathway.md/studies/recf3dXyXUkIUDi1j 2/2

6/28/23, 11:22 PM NONS Pathway Feedback Search Clinical Topics Home Studies NONS NONS Disease COVID 19 infection Trial question What is the role of novel nitric oxide nasal spray in patients with recent COVID-19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 306 64.0% male 306 patients (109 female, 197 male) Inclusion criteria: adult patients with mild symptomatic COVID-19 Key exclusion criteria: requirement of oxygen support and hospitalization; pneumonia; pregnancy; allergy to nitric oxide nasal spray; asthma Interventions N=153 nitric oxide nasal spray (self-administered 6 times a day as 2 sprays per nostril for 7 days) N=153 placebo (matching placebo nasal spray for 7 days) Primary outcome Reduction in viral ribonucleic acid load at day 8 2.6 log10 2.62 https://web.pathway.md/studies/recrX82ZpjhPHV9JP 1/2 6/28/23, 11:22 PM NONS Pathway g 6 2.1 2.0 log10 1.3 log10 0.7 log10 Significant increase 0.0 log10 Nitric oxide nasal spray Placebo Significant increase in reduction in viral RNA load at day 8 (2.62 log10 copies/mL vs. 2.1 log10 copies/mL; AD 0.52 log10 copies/mL, 95% CI 0.12 to 0.92) Secondary outcomes Significant increase in the percentage of patients with negative conversion of RT-PCR at day 8 (82.8% vs. 66.7%; AD 16.1%, 95% CI 0.2 to 32.1) Significant decrease in time to negative conversion of RT-PCR (3 days vs. 7 days; AD -4 days, 95% CI -7.9 to -0.1) No significant difference in the percentage of patients with 2% improvement in the WHO Clinical Progression Scale score at day 8 (78.1% vs. 62.3%; AD 15.8%, 95% CI -1 to 32.6) Safety outcomes No significant differences in metHgb levels, nasal vasodilation symptoms, systemic vasodilation signs. Conclusion In adult patients with mild symptomatic COVID-19, nitric oxide nasal spray was superior to placebo with respect to reduction in viral RNA load at day 8. Reference Monika Tandon, Wen Wu, Keith Moore et al. SARS-CoV-2 accelerated clearance using a novel nitric oxide nasal spray (NONS) treatment: A randomised trial. Lancet Reg Health Southeast Asia. 2022 Jun 29;3:100036. Open reference URL https://web.pathway.md/studies/recrX82ZpjhPHV9JP 2/2

6/28/23, 11:22 PM NONSEDA Pathway Feedback Search Clinical Topics Home Studies NONSEDA NONSEDA Trial question Is nonsedation superior to light sedation in mechanically ventilated patients? Study design Multi-center Open label RCT Population Characteristics of study participants 46.2% female N = 700 53.8% male 700 patients (126 female, 147 male) Inclusion criteria: patients undergoing mechanical ventilation in the ICU Key exclusion criteria: severe head trauma, therapeutic hypothermia, status epilepticus, sedation anticipated to be necessary for oxygenation Interventions N=349 no sedation (no regular sedatives) N=351 light sedation (target RASS -2 to -3) Primary outcome Death at 90 days 42.4 % 42.4 37 31.8 % 21.2 % 10.6 % No significant difference 0.0 % https://web.pathway.md/studies/reclbA9aL2DF3CyBw 1/2 6/28/23, 11:22 PM NONSEDA Pathway No sedation Light sedation No significant difference in death at 90 days (42.4% vs. 37%; ARD 5.4, 95% CI -2.2 to 12.2) Secondary outcomes No significant difference in days alive at 90 days (13 days vs. 12 days; ARD 1, 95% CI -2 to 5) Borderline significant increase in coma and delirium-free days (27 days vs. 26 days; ARD 1, 95% CI 0 to 2) No significant difference in ventilator-free days (20 days vs. 19 days; ARD 1, 95% CI -3 to 3) Safety outcomes No significant differences in accidental extubation leading to intubation within 1 hour (1.1% vs. 0.3%, p=0.20). Conclusion In patients undergoing mechanical ventilation in the ICU, no sedation was not superior to light sedation with respect to death at 90 days. Reference Hanne T Olsen, Helene K Nedergaard, Thomas Str m et al. Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients. N Engl J Med. 2020 Mar 19;382(12):1103-1111. Open reference URL https://web.pathway.md/studies/reclbA9aL2DF3CyBw 2/2

6/28/23, 11:22 PM NordICC Pathway Feedback Search Clinical Topics Home Studies NordICC NordICC Disease Disease Colon cancer Rectal cancer Trial question What is the effect of colonoscopy screening on the risks of colorectal cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 50.0% female N = 84585 50.0% male 84585 patients (42186 female, 42399 male) Inclusion criteria: healthy men and women 55 to 64 years of age who had previously not undergone screening Key exclusion criteria: death or diagnosis of colorectal cancer before trial entry Interventions N=28220 colonoscopy screening (one-time colonoscopy screening) N=56365 usual care (no screening or intervention within the trial) Primary outcome Colorectal cancer at 10 years 1.2 % 1.2 https://web.pathway.md/studies/rec1VvshqMhnPObfl 1/2 6/28/23, 11:22 PM NordICC Pathway 0.98 0.9 % 0.6 % 0.3 % Borderline significant decrease 0.0 % Colonoscopy screening Usual care Borderline significant decrease in colorectal cancer at 10 years (0.98% vs. 1.2%; RR 0.82, 95% CI 0.7 to 0.93) Secondary outcomes No significant difference in death from colorectal cancer at 10 years (0.28% vs. 0.31%; RR 0.9, 95% CI 0.64 to 1.16) No significant difference in death from any cause at 10 years (11.03% vs. 11.04%; RR 0.99, 99% CI 0.96 to 1.04) Conclusion In healthy men and women 55 to 64 years of age who had previously not undergone screening, colonoscopy screening was superior to usual care with respect to colorectal cancer at 10 years. Reference Michael Bretthauer, Magnus L berg, Paulina Wieszczy et al. Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death. N Engl J Med. 2022 Oct 27;387(17):1547-1556. Open reference URL https://web.pathway.md/studies/rec1VvshqMhnPObfl 2/2

6/28/23, 11:22 PM Norfloxacin for primary SBP prophylaxis Pathway Feedback Search Clinical Topics Home Studies Norfloxacin for primary SBP prophylaxis Norfloxacin for primary SBP prophylaxis Disease Spontaneous bacterial peritonitis Trial question What is the role of norfloxacin in patients with cirrhosis and low ascitic fluid protein levels (< 15 g/L)? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 107 64.0% male 107 patients (38 female, 68 male) Inclusion criteria: patients with cirrhosis and low ascitic fluid protein levels (< 15 g/L) who had no history of infection and no active infection since cirrhosis diagnosis Key exclusion criteria: active gastrointestinal bleeding on admission, HCC or other life-threatening disease or failure to provide written informed consent Interventions N=53 norfloxacin (400 mg/day for 6 months) N=54 placebo (matching placebo daily for 6 months) Primary outcome https://web.pathway.md/studies/recbMMXeQNhkVwukY 1/2 6/28/23, 11:22 PM Norfloxacin for primary SBP prophylaxis Pathway Significant decrease in gram-negative infection (ARD -11, 95% CI -20.12 to -1.88) Safety outcomes No significant difference in mortality. Conclusion In patients with cirrhosis and low ascitic fluid protein levels (< 15 g/L) who had no history of infection and no active infection since cirrhosis diagnosis, norfloxacin was superior to placebo with respect to a gram-negative infection. Reference Grange JD, Roulot D, Pelletier G et al. Norfloxacin primary prophylaxis of bacterial infections in cirrhotic patients with ascites: a double-blind randomized trial. J Hepatol. 1998 Sep;29(3):430-6. Open reference URL https://web.pathway.md/studies/recbMMXeQNhkVwukY 2/2

6/28/23, 11:22 PM NORSTENT Pathway Feedback Search Clinical Topics Home Studies NORSTENT NORSTENT Disease Coronary artery disease Trial question What is the effect of drug-eluting stents in patients with stable or unstable coronary artery disease undergoing PCI? Study design Multi-center Open label RCT Population Characteristics of study participants 25.0% female N = 9013 75.0% male 9013 patients (2256 female, 6757 male) Inclusion criteria: patients who had stable or unstable coronary artery disease who were undergoing PCI Key exclusion criteria: previous treatment with coronary stent, bifurcation lesion requiring treatment with a two-stent technique, serious medical condition other than coronary artery disease with life expectancy < 5 years, intolerable side-effects to any drug in use during PCI or contraindications to long-term dual-antiplatelet therapy or had been prescribed warfarin Interventions N=4504 drug-eluting stents (everolumus- and zotarolumus-eluting stents) N=4509 bare-metal stents (contemporary devices with thin struts) https://web.pathway.md/studies/recPKoawdAkc4Jxrt 1/2 6/28/23, 11:22 PM NORSTENT Pathway Primary outcome All-cause death and nonfatal spontaneous myocardial infarction at 6 years 17.1 % 17.1 16.6 12.8 % 8.6 % 4.3 % No significant difference 0.0 % Drug-eluting stents Bare-metal stents No significant difference in all-cause death and nonfatal spontaneous myocardial infarction at 6 years (16.6% vs. 17.1%; HR 0.98, 95% CI 0.88 to 1.09) Secondary outcomes Significant decrease in any repeat revascularization at 6 years (16.5% vs. 19.8%; HR 0.76, 95% CI 0.69 to 0.85) Conclusion In patients who had stable or unstable coronary artery disease who were undergoing PCI, drug- eluting stents were not superior to bare-metal stents with respect to a all-cause death and nonfatal spontaneous myocardial infarction at 6 years. Reference Bonaa KH, Mannsverk J, Wiseth R et al. Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease. N Engl J Med. 2016 Sep 29;375(13):1242-52. Open reference URL https://web.pathway.md/studies/recPKoawdAkc4Jxrt 2/2

6/28/23, 11:22 PM NOTT Pathway Feedback Search Clinical Topics Home Studies NOTT NOTT Disease Disease Disease Chronic obstructive pulmonary Dyspnea in palliative care Home oxy Trial question What is the role of continuous oxygen therapy in patients with COPD and hypoxemia? Study design Multi-center Open label RCT Population Characteristics of study participants 2.5% female N = 203 97.5% male 203 patients (4 female, 160 male) Inclusion criteria: patients with COPD and hypoxemia Key exclusion criteria: previous oxygen therapy, other disease that might influence morbidity, mortality, compliance with therapy, or ability to give informed consent Interventions N=101 continuous oxygen therapy (by nasal prong at a measured flow rate of 1-4 L/min continuously for at least 12 months) N=102 nocturnal oxygen therapy (by nasal prong at a measured flow rate of 1-4 L/min at an interval of 12 hours for at least 12 months) Primary outcome https://web.pathway.md/studies/recSuwyvgh3TmeiBZ 1/2 6/28/23, 11:22 PM NOTT Pathway Death at 1 year 20.6 % 20.6 15.5 % 11.9 10.3 % Significant decrease 5.2 % NNT = 11 0.0 % Continuous oxygen therapy Nocturnal oxygen therapy Significant decrease in death at 1 year (11.9% vs. 20.6%; HR 0.52, 95% CI 0.31 to 0.85) Secondary outcomes Significant decrease in death, in patients with arterial partial pressure of CO2 43 mmHg (19.6% vs. 46%; RR 0.43, 95% CI 0.16 to 0.7) Conclusion In patients with COPD and hypoxemia, continuous oxygen therapy was superior to nocturnal oxygen therapy with respect to death at 1 year. Reference Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med. 1980 Sep;93(3):391-8. Open reference URL https://web.pathway.md/studies/recSuwyvgh3TmeiBZ 2/2

6/28/23, 11:22 PM NSABP B-32 Pathway Feedback Search Clinical Topics Home Studies NSABP B 32 NSABP B 32 Trial question What is the role of sentinel lymph node resection in women with invasive breast cancer and clinically negative lymph nodes? Study design Multi-center Open label RCT Population 5611 female patients Inclusion criteria: women with invasive breast cancer and clinically negative lymph nodes Key exclusion criteria: age < 18 years, positive ipsilateral axillary lymph nodes or prior removal of ipsilateral axillary lymph nodes, ulceration, erythema, infiltration of the skin or underlying chest wall, prior or concurrent breast implants, or prior breast malignancy Interventions N=1975 routine axillary node dissection (sentinel node resection with axillary dissection) N=2011 selective axillary node dissection (sentinel node resection with axillary dissection only if SLNs were positive) Primary outcome Overall survival, as per log-rank comparison 96.4 % 96.4 95 72.3 % 48.2 % 24.1 % No significant difference 0.0 % Routine axillary node dissection Selective axillary node dissection No significant difference in overall survival, as per log-rank comparison (96.4% vs. 95%; HR 1.2, 95% CI 0.96 to 1.5) Conclusion https://web.pathway.md/studies/rec6qeeKHWbkh4dgm 1/2 6/28/23, 11:22 PM NSABP B-32 Pathway In women with invasive breast cancer and clinically negative lymph nodes, routine axillary node dissection was not superior to selective axillary node dissection with respect to overall survival, as per log-rank comparison. Reference Krag DN, Anderson SJ, Julian TB et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol. 2010 Oct;11(10):927-33. Open reference URL https://web.pathway.md/studies/rec6qeeKHWbkh4dgm 2/2

6/28/23, 11:22 PM NSABP P-1 Pathway Feedback Search Clinical Topics Home Studies NSABP P 1 NSABP P 1 Trial question What is the role of tamoxifen in patients who were at increased risk for breast cancer? Study design Multi-center Double blinded RCT Population 13388 female patients Inclusion criteria: women who were at increased risk for breast cancer Key exclusion criteria: pregnancy, clinical evidence of breast cancer, receipt of estrogen or progesterone replacement therapy, oral contraceptives, or androgens within 3 months before randomization; and a history of deep vein thrombosis or PE Interventions N=6681 tamoxifen (20 mg/day for 5 years) N=6707 placebo (matching placebo daily for 5 years) Primary outcome Invasive breast cancer 43.4 43.4 32.5 21.7 22 10.8 Significant decrease 0.0 Tamoxifen Placebo Significant decrease in invasive breast cancer (22 vs. 43.4; RR 0.51, 95% CI 0.39 to 0.66) Secondary outcomes Significant decrease in noninvasive breast cancer (7.7 vs. 15.9; RR 0.5, 95% CI 0.33 to 0.77) https://web.pathway.md/studies/recap4ZINfl9MGXFf 1/2 6/28/23, 11:22 PM NSABP P-1 Pathway Safety outcomes Significant differences in endometrial cancer (2.30 vs. 0.91 per 1,000; RR 2.53, 95% CI 1.35-4.97), stroke (1.45 vs. 0.92 per 1,000 women), PE (0.69 vs. 0.23 per 1,000 women), and deep vein thrombosis (1.34 vs. 0.84 per 1,000 women). Conclusion In women who were at increased risk for breast cancer, tamoxifen was superior to placebo with respect to invasive breast cancer. Reference Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998 Sep 16;90(18):1371-88. Open reference URL https://web.pathway.md/studies/recap4ZINfl9MGXFf 2/2

6/28/23, 11:22 PM NUTRIREA-3 Pathway Feedback Search Clinical Topics Home Studies NUTRIREA 3 NUTRIREA 3 Trial question What is the role of early calorie and protein restriction in ventilated adults with shock? Study design Multi-center Open label RCT Population 3036 patients Inclusion criteria: adults receiving invasive mechanical ventilation and vasopressor support for shock Key exclusion criteria: specific nutritional needs; pregnancy; not-to-be-resuscitated order; department of corrections inmate Interventions N=1521 early calorie and protein restriction (6 kcal/kg/day and 0.2-0.4 g/kg/day protein during the first 7 days in the ICU) N=1515 standard calorie and protein targets (25 kcal/kg/day and 1.0-1.3 g/kg/day protein during the first 7 days in the ICU) Primary outcome Median time to readiness for intensive care unit discharge 9.0 days 9 8 6.8 days 4.5 days 2.3 days Significant decrease 0.0 days Early calorie and protein restriction Standard calorie and protein targets Significant decrease in median time to readiness for ICU discharge (8 days vs. 9 days; HR 0.89, 95% CI 0.82 to 0.98) Secondary outcomes https://web.pathway.md/studies/recb2wCgYQdGxPYee 1/2 6/28/23, 11:22 PM NUTRIREA-3 Pathway No significant difference in death from all causes at day 90 (41.3% vs. 42.8%; ARD -1.5, 95% CI -5 to 2) Conclusion In adults receiving invasive mechanical ventilation and vasopressor support for shock, early calorie and protein restriction were superior to standard calorie and protein targets with respect to median time to readiness for ICU discharge. Reference Jean Reignier, Gaetan Plantefeve, Jean-Paul Mira et al. Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel- group trial (NUTRIREA-3). Lancet Respir Med. 2023 Mar 20;S2213-2600(23)00092-9. Online ahead of print. Open reference URL https://web.pathway.md/studies/recb2wCgYQdGxPYee 2/2

6/28/23, 11:44 PM O2-ICU Pathway Feedback Search Clinical Topics Home Studies O2 ICU O2 ICU Trial question Is conservative oxygen therapy superior to conventional oxygen therapy in critically ill patients? Study design Single center Open label RCT Population Characteristics of study participants 43.0% female N = 434 57.0% male 434 patients (188 female, 246 male) Inclusion criteria: adult patients admitted to the ICU with an expected length of stay 72 hours Key exclusion criteria: readmission to ICU; decision to withhold life-sustaining treatment; immunosuppression or neutropenia; enrollment in other prospective studies Interventions N=216 conservative oxygen therapy (lowest possible FiO2 partial pressure of oxygen between 70 and 100 mmHg or SpO2 between 94% and 98%) N=218 conventional oxygen therapy (partial pressure of oxygen up to 150 mmHg or SpO2 > 97%) Primary outcome Death in intensive care unit 20.2 % 20.2 15.1 % 11.6 10.1 % Significant decrease 5.0 % https://web.pathway.md/studies/recesTQjmnafPy1Hy 1/2 6/28/23, 11:44 PM O2-ICU Pathway NNT = 12 0.0 % Conservative oxygen therapy Conventional oxygen therapy Significant decrease in death in the ICU (11.6% vs. 20.2%; RR 0.57, 95% CI 0.37 to 0.9) Secondary outcomes Significant decrease in the percentage of patients who developed shock (3.7% vs. 10.6%; RR 0.35, 95% CI 0.16 to 0.75) Significant decrease in the percentage of patients who developed liver failure (1.9% vs. 6.4%; RR 0.29, 95% CI 0.1 to 0.82) Significant decrease in bacteremia (5.1% vs. 10.1%; RR 0.5, 95% CI 0.25 to 1) Conclusion In adult patients admitted to the ICU with an expected length of stay 72 hours, conservative oxygen therapy was superior to conventional oxygen therapy with respect to death in the ICU. Reference Massimo Girardis, Stefano Busani, Elisa Damiani et al. Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016 Oct 18;316(15):1583-1589. Open reference URL https://web.pathway.md/studies/recesTQjmnafPy1Hy 2/2

6/28/23, 11:44 PM OAK Pathway Feedback Search Clinical Topics Home Studies OAK OAK Disease Non-small cell lung cancer Trial question What is the effect of atezolizumab in patients with previously treated non-small cell lung cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 39.1% female N = 1225 60.9% male 1225 patients (330 female, 520 male) Inclusion criteria: patients with squamous or non-squamous non-small cell lung cancer who had received one to two previous cytotoxic chemotherapy regimens for stage IIIB or IV non-small cell lung cancer Key exclusion criteria: history of autoimmune disease, previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway Interventions N=425 atezolizumab (intravenous 1200 mg fixed dose every 3 weeks) N=425 docetaxel (IV at 75 mg/m every 3 weeks) Primary outcome https://web.pathway.md/studies/recIQBTEFGYi7Qt6e 1/2 6/28/23, 11:44 PM OAK Pathway Overall survival in intention-to-treat population 13.8 months 13.8 10.4 months 9.6 6.9 months 3.5 months Significant increase 0.0 months Atezolizumab Docetaxel Significant increase in overall survival in the intention-to-treat population (13.8 months vs. 9.6 months; HR 1.37, 95% CI 1.15 to 1.61) Secondary outcomes No significant difference in progression-free survival in the intention-to-treat population (89% vs. 88%; HR 0.95, 95% CI 0.82 to 1.1) Safety outcomes Significant difference in treatment-related grade 3 or 4 adverse events (15% vs. 43%). Conclusion In patients with squamous or non-squamous non-small cell lung cancer who had received one to two previous cytotoxic chemotherapy regimens for stage IIIB or IV non-small cell lung cancer, atezolizumab was superior to docetaxel with respect to overall survival in the intention-to-treat population. Reference Rittmeyer A, Barlesi F, Waterkamp D et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. Open reference URL https://web.pathway.md/studies/recIQBTEFGYi7Qt6e 2/2

6/28/23, 11:44 PM OASIS-5 Pathway Feedback Search Clinical Topics Home Studies OASIS 5 OASIS 5 Disease Non-ST-elevation myocardial inf Trial question What is the effect of fondaparinux in patients with acute coronary syndromes? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.0% female N = 20078 62.0% male 20078 patients (7699 female, 12379 male) Inclusion criteria: patients with acute coronary syndromes Key exclusion criteria: contraindications to LMWH, recent hemorrhagic stroke, indications for anticoagulation other than an acute coronary syndrome, or a serum creatinine level of at least 3 mg/dL Interventions N=10057 fondaparinux (2.5 mg daily for a mean of 6 days) N=10021 enoxaparin (1 mg/kg body weight BID for a mean of 6 days) Primary outcome Death, myocardial infarction, or refractory ischemia at 9 days https://web.pathway.md/studies/recCIbYikm6e5O41G 1/2 6/28/23, 11:44 PM OASIS-5 Pathway 5.8 % 5.8 5.7 4.3 % 2.9 % Difference not exceeding nonferiority margin 1.4 % 0.0 % Fondaparinux Enoxaparin Difference not exceeding nonferiority margin in death, myocardial infarction, or refractory ischemia at 9 days (5.8% vs. 5.7%; HR 1.01, 95% CI 0.9 to 1.13) Secondary outcomes No significant difference in death or myocardial infarction at day 30 (6.2% vs. 6.8%; HR 0.9, 95% CI 0.81 to 1.01) Significant decrease in death at 30 days (2.9% vs. 3.5%; HR 0.83, 95% CI 0.71 to 0.97) Significant decrease in death, MI, refractory ischemia, or major bleeding at day 30 (10.2% vs. 12.4%; HR 0.82, 95% CI 0.75 to 0.89) Safety outcomes Significant differences in major bleeding at 9 days (2.2% vs. 4.1%), at 30 days (3.1% vs. 5.0%), and at 180 days (4.3% vs. 5.8%). Conclusion In patients with acute coronary syndromes, fondaparinux was noninferior to enoxaparin with respect to death, myocardial infarction, or refractory ischemia at 9 days. Reference Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, Yusuf S, Mehta SR et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006 Apr 6;354(14):1464-76. Open reference URL https://web.pathway.md/studies/recCIbYikm6e5O41G 2/2

6/28/23, 11:44 PM OAT Pathway Feedback Search Clinical Topics Home Studies OAT OAT Disease ST-elevation myocardial infarction Trial question What is the role of PCI in stable patients with occlusion of the infarct-related artery 3-28 days after myocardial infarction? Study design Multi-center Open label RCT Population Characteristics of study participants 22.0% female N = 2166 78.0% male 2166 patients (476 female, 1690 male) Inclusion criteria: stable patients who had total occlusion of the infarct-related artery 3 to 28 days after myocardial infarction and who met a high-risk criterion (an ejection fraction of < 50% or proximal occlusion) Key exclusion criteria: NYHA class III or IV HF, shock, a serum creatinine concentration > 2.5 mg/dL, angiographically significant left main or three-vessel coronary artery disease, angina at rest, and severe ischemia on stress testing Interventions N=1082 PCI (stent and optimal medical therapy) N=1084 medical therapy (conventional medical therapy alone) https://web.pathway.md/studies/recpjl2M37e6tLyPz 1/2 6/28/23, 11:44 PM OAT Pathway Primary outcome Death, myocardial infarction, or NYHA class IV heart failure at 4 years 17.2 % 17.2 15.6 12.9 % 8.6 % 4.3 % No significant difference 0.0 % Percutaneous coronary intervention Medical therapy No significant difference in death, myocardial infarction, or NYHA class IV HF at 4 years (17.2% vs. 15.6%; HR 1.16, 95% CI 0.92 to 1.45) Secondary outcomes No significant difference in myocardial infarction, both fatal and nonfatal (7% vs. 5.3%; HR 1.36, 95% CI 0.92 to 2) No significant difference in nonfatal reinfarction (6.9% vs. 5%; HR 1.44, 95% CI 0.96 to 2.16) Conclusion In stable patients who had total occlusion of the infarct-related artery 3 to 28 days after myocardial infarction and who met a high-risk criterion (an ejection fraction of < 50% or proximal occlusion), PCI was not superior to medical therapy with respect to death, myocardial infarction, or NYHA class IV HF at 4 years. Reference Hochman JS, Lamas GA, Buller CE et al. Coronary intervention for persistent occlusion after myocardial infarction. N Engl J Med. 2006 Dec 7;355(23):2395-407. Open reference URL https://web.pathway.md/studies/recpjl2M37e6tLyPz 2/2

6/28/23, 11:44 PM OCEAN(a)-DOSE (olpasiran 10 mg) Pathway Feedback Search Clinical Topics Home Studies OCEAN(a)-DOSE (olpasiran 10 mg) OCEAN(a)-DOSE (olpasiran 10 mg) Disease Disease Disease Acute ischemic stroke Coronary artery disease Dyslipidem Trial question What is the role of olpasiran in patients with established ASCVD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 27.0% female N = 112 73.0% male 112 patients (30 female, 82 male) Inclusion criteria: patients with established ASCVD and a lipoprotein(a) concentration > 150 nmol/L Key exclusion criteria: severe renal dysfunction or active liver disease Interventions N=58 olpasiran (at a dose of 10 mg every 12 week) N=54 placebo (matching placebo every 12 week) Primary outcome https://web.pathway.md/studies/reclihdmsvlRV9Z4c 1/2 6/28/23, 11:44 PM OCEAN(a)-DOSE (olpasiran 10 mg) Pathway Significant increase in percent reduction in lipoprotein A concentration at week 36 (66.9% vs. -3.6%; AD 70.5%, 95% CI 65.9 to 75.1) Secondary outcomes Significant increase in percent reduction in low-density lipoprotein cholesterol concentration at week 36 (17.4% vs. -6.3%; AD 23.7%, 95% CI 12.2 to 35.3) Significant increase in percent reduction in ApoB concentration at week 36 (11.5% vs. -7.4%; AD 18.9%, 95% CI 11.5 to 26.3) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In patients with established ASCVD and a lipoprotein(a) concentration > 150 nmol/L, olpasiran was superior to placebo with respect to percent reduction in lipoprotein A concentration at week 36. Reference Michelle L O'Donoghue, Robert S Rosenson, Baris Gencer et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Engl J Med. 2022 Nov 17;387(20):1855-1864. Open reference URL https://web.pathway.md/studies/reclihdmsvlRV9Z4c 2/2

6/28/23, 11:44 PM OCEAN(a)-DOSE (olpasiran 225 mg every 12 weeks) Pathway Feedback Search Clinical Topics Home Studies OCEAN(a)-DOSE (olpasiran 225 mg every 12 weeks) OCEAN(a)-DOSE (olpasiran 225 mg every 12 weeks) Disease Disease Disease Acute ischemic stroke Coronary artery disease Dyslipidem Trial question What is the role of olpasiran in patients with established ASCVD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 30.0% female N = 110 70.0% male 110 patients (33 female, 77 male) Inclusion criteria: patients with established ASCVD and a lipoprotein(a) concentration > 150 nmol/L Key exclusion criteria: severe renal dysfunction or active liver disease Interventions N=56 olpasiran (at a dose of 225 mg every 12 week) N=54 placebo (matching placebo every 12 week) Primary outcome https://web.pathway.md/studies/recpnfHi4ptuw8wQz 1/2 6/28/23, 11:44 PM OCEAN(a)-DOSE (olpasiran 225 mg every 12 weeks) Pathway Significant increase in percent reduction in lipoprotein(a) concentration at week 36 (97.5% vs. -3.6%; AD 101.1%, 95% CI 96.5 to 105.8) Secondary outcomes Significant increase in percent reduction in low-density lipoprotein cholesterol concentration at week 36 (16.8% vs. -6.3%; AD 23.1%, 95% CI 11.4 to 34.8) Significant increase in percent reduction in ApoB concentration at week 36 (10.2% vs. -7.4%; AD 17.6%, 95% CI 10.1 to 25.1) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In patients with established ASCVD and a lipoprotein(a) concentration > 150 nmol/L, olpasiran was superior to placebo with respect to percent reduction in lipoprotein(a) concentration at week 36. Reference Michelle L O'Donoghue, Robert S Rosenson, Baris Gencer et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Engl J Med. 2022 Nov 17;387(20):1855-1864. Open reference URL https://web.pathway.md/studies/recpnfHi4ptuw8wQz 2/2

6/28/23, 11:44 PM OCEAN(a)-DOSE (olpasiran 225 mg every 24 weeks) Pathway Feedback Search Clinical Topics Home Studies OCEAN(a)-DOSE (olpasiran 225 mg every 24 weeks) OCEAN(a)-DOSE (olpasiran 225 mg every 24 weeks) Disease Disease Disease Acute ischemic stroke Coronary artery disease Dyslipidem Trial question What is the role of olpasiran in patients with established ASCVD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 109 63.0% male 109 patients (40 female, 69 male) Inclusion criteria: patients with established ASCVD and a lipoprotein(a) concentration > 150 nmol/L Key exclusion criteria: severe renal dysfunction or active liver disease Interventions N=55 olpasiran (at a dose of 225 mg every 24 week) N=54 placebo (matching placebo every 12 week) Primary outcome https://web.pathway.md/studies/recBLvbMi0q2D58wS 1/2 6/28/23, 11:44 PM OCEAN(a)-DOSE (olpasiran 225 mg every 24 weeks) Pathway Significant increase in percent reduction in lipoprotein(a) concentration at week 36 (96.9% vs. -3.6%; AD 100.5%, 95% CI 95.8 to 105.2) Secondary outcomes Significant increase in percent reduction in low-density lipoprotein cholesterol concentration at week 36 (18.5% vs. -6.3%; AD 24.8%, 95% CI 13 to 36.5) Significant increase in percent reduction in ApoB concentration at week 36 (11.4% vs. -7.4%; AD 18.8%, 95% CI 11.2 to 26.3) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In patients with established ASCVD and a lipoprotein(a) concentration > 150 nmol/L, olpasiran was superior to placebo with respect to percent reduction in lipoprotein(a) concentration at week 36. Reference Michelle L O'Donoghue, Robert S Rosenson, Baris Gencer et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Engl J Med. 2022 Nov 17;387(20):1855-1864. Open reference URL https://web.pathway.md/studies/recBLvbMi0q2D58wS 2/2

6/28/23, 11:44 PM OCEAN(a)-DOSE (olpasiran 75 mg) Pathway Feedback Search Clinical Topics Home Studies OCEAN(a)-DOSE (olpasiran 75 mg) OCEAN(a)-DOSE (olpasiran 75 mg) Disease Disease Disease Acute ischemic stroke Coronary artery disease Dyslipidem Trial question What is the role of olpasiran in patients with established ASCVD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 112 63.0% male 112 patients (41 female, 71 male) Inclusion criteria: patients with established ASCVD and a lipoprotein(a) concentration > 150 nmol/L Key exclusion criteria: severe renal dysfunction or active liver disease Interventions N=58 olpasiran (at a dose of 75 mg every 12 week) N=54 placebo (matching placebo every 12 week) Primary outcome https://web.pathway.md/studies/recyrSaylmuV2Nd3s 1/2 6/28/23, 11:44 PM OCEAN(a)-DOSE (olpasiran 75 mg) Pathway Significant increase in percent reduction in lipoprotein(a) concentration at week 36 (93.8% vs. -3.6%; AD 97.4%, 95% CI 92.8 to 102) Secondary outcomes Significant increase in percent reduction in low-density lipoprotein cholesterol at week 36 (16.3% vs. -6.3%; AD 22.6%, 95% CI 11 to 34.1) Significant increase in percent reduction in ApoB concentration at week 36 (9.3% vs. -7.4%; AD 16.7%, 95% CI 9.3 to 24.1) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In patients with established ASCVD and a lipoprotein(a) concentration > 150 nmol/L, olpasiran was superior to placebo with respect to percent reduction in lipoprotein(a) concentration at week 36. Reference Michelle L O'Donoghue, Robert S Rosenson, Baris Gencer et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Engl J Med. 2022 Nov 17;387(20):1855-1864. Open reference URL https://web.pathway.md/studies/recyrSaylmuV2Nd3s 2/2

6/28/23, 11:44 PM ODYSSEY OUTCOMES Pathway Feedback Search Clinical Topics Home Studies ODYSSEY OUTCOMES ODYSSEY OUTCOMES Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the role of alirocumab in patients following acute coronary syndrome who are receiving high-intensity statin therapy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 25.0% female N = 18924 75.0% male 18924 patients (4762 female, 14162 male) Inclusion criteria: patients with acute coronary syndrome 1-12 months earlier who have qualifying lipid levels and are receiving high-intensity statin therapy Key exclusion criteria: age < 40 years; low-density lipoprotein cholesterol < 70 mg/dL; ApoB < 80 mg/dL; non-high-density lipoprotein cholesterol < 100 mg/dL; acute coronary syndrome event occurring > 52 weeks prior to randomization Interventions N=9462 alirocumab (subcutaneous dose of 75 mg every 2 weeks) N=9462 placebo (matching placebo every 2 weeks) https://web.pathway.md/studies/recxu6DHS3fD573vn 1/2 6/28/23, 11:44 PM ODYSSEY OUTCOMES Pathway Primary outcome Death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization 11.1 % 11.1 9.5 8.3 % 5.5 % Significant decrease 2.8 % NNT = 63 0.0 % Alirocumab Placebo Significant decrease in death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization (9.5% vs. 11.1%; HR 0.85, 95% CI 0.78 to 0.93) Secondary outcomes Significant decrease in composite of death, nonfatal myocardial infarction, or nonfatal ischemic stroke (10.3% vs. 11.9%; HR 0.86, 95% CI 0.79 to 0.93) Significant decrease in coronary heart disease event (12.7% vs. 14.3%; HR 0.88, 95% CI 0.81 to 0.95) Significant decrease in cardiovascular event (13.7% vs. 15.6%; HR 0.87, 95% CI 0.81 to 0.94) Safety outcomes No significant difference in adverse events. Significant difference in local injection site reaction (3.8% vs. 2.1%). Conclusion In patients with acute coronary syndrome 1-12 months earlier who have qualifying lipid levels and are receiving high-intensity statin therapy, alirocumab was superior to placebo with respect to death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. Reference Gregory G Schwartz, P Gabriel Steg, Michael Szarek et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov 29;379(22):2097-2107. Open reference URL https://web.pathway.md/studies/recxu6DHS3fD573vn 2/2

6/28/23, 11:44 PM ODYSSEY Pathway Feedback Search Clinical Topics Home Studies ODYSSEY ODYSSEY Disease Dyslipidemia Trial question What is the role of alirocumab in patients at high risk for cardiovascular events? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.0% female N = 2341 62.0% male 2341 patients (884 female, 1457 male) Inclusion criteria: patients at high risk for cardiovascular events who had LDL cholesterol levels 70 mg/dL and were receiving treatment with statins at the maximum tolerated dose, with or without other lipid-lowering therapy Key exclusion criteria: age < 18 years, LDL cholesterol < 70 mg/dL, fasting serum triglycerides > 400 mg/dL Interventions N=1553 alirocumab (150 mg as a single 1 ml subcutaneous injection every 2 weeks for 78 weeks) N=788 placebo (matching placebo as a single 1 ml subcutaneous injection every 2 weeks for 78 weeks) https://web.pathway.md/studies/recsHcBKqpIETbcSY 1/2 6/28/23, 11:44 PM ODYSSEY Pathway Primary outcome Significant decrease in the percentage change in calculated LDL cholesterol level at 24 weeks (-61% vs. 0.8%; ARD -61.9, 95% CI -64.3 to -59.4) Secondary outcomes Significant decrease in the percentage change in calculated LDL cholesterol at 78 weeks (-52.4% vs. 3.6%; ARD -56, 95% CI -59.1 to -52.8) Significant decrease in change in total cholesterol (-37.8% vs. -0.3%; ARD -37.5, 95% CI -39.1 to -35.9) Significant increase in change in HDL cholesterol (4% vs. -0.6%; AD 4.6%, 95% CI 3.3 to 5.9) Safety outcomes No significant difference in any adverse event and adverse event leading to study-drug discontinuation. Significant difference in myalgia (5.4% vs. 2.9%). Conclusion In patients at high risk for cardiovascular events who had LDL cholesterol levels 70 mg/dL and were receiving treatment with statins at the maximum tolerated dose, with or without other lipid- lowering therapy, alirocumab was superior to placebo with respect to the percentage change in calculated LDL cholesterol level at 24 weeks. Reference Robinson JG, Farnier M, Krempf M et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1489-99. Open reference URL https://web.pathway.md/studies/recsHcBKqpIETbcSY 2/2

6/28/23, 11:44 PM Omeprazole for peptic ulcer bleeding Pathway Feedback Search Clinical Topics Home Studies Omeprazole for peptic ulcer bleeding Omeprazole for peptic ulcer bleeding Disease Non-variceal upper gastrointesti Trial question What is the role of intravenous omeprazole in patients having undergone endoscopic treatment for bleeding peptic ulcers? Study design Single center Double blinded RCT Population Characteristics of study participants 33.0% female N = 240 67.0% male 240 patients (80 female, 160 male) Inclusion criteria: patients having undergone endoscopic treatment for bleeding peptic ulcers Key exclusion criteria: unsuccessful endoscopic treatment, terminal cancer, moribund state, or unwilling to provide consent Interventions N=120 omeprazole (as a bolus intravenous injection of 80 mg followed by an infusion of 8 mg per hour for 72 hours) N=120 placebo (matching placebo IV for 72 hours) Primary outcome https://web.pathway.md/studies/reczNULibBvVNbbXA 1/2 6/28/23, 11:44 PM Omeprazole for peptic ulcer bleeding Pathway Rate of bleeding recurrence within 30 days 22.5 % 22.5 16.9 % 11.3 % Significant decrease 6.7 5.6 % NNT = 6 0.0 % Omeprazole Placebo Significant decrease in the rate of bleeding recurrence within 30 days (6.7% vs. 22.5%; HR 0.25, 95% CI 0.11 to 0.58) Secondary outcomes Borderline significant decrease in death at 30 days (4.2% vs. 10%; RR 0.42, 95% CI -0.12 to 0.96) Conclusion In patients having undergone endoscopic treatment for bleeding peptic ulcers, omeprazole was superior to placebo with respect to the rate of bleeding recurrence within 30 days. Reference Lau JY, Sung JJ, Lee KK et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med. 2000 Aug 3;343(5):310-6. Open reference URL https://web.pathway.md/studies/reczNULibBvVNbbXA 2/2

6/28/23, 11:44 PM ONTARGET (telmisartan with ramipril) Pathway Feedback Search Clinical Topics Home Studies ONTARGET (telmisartan with ramipril) ONTARGET (telmisartan with ramipril) Disease Disease Disease Acute ischemic stroke Coronary artery disease Diabetes m Trial question Is a combination of telmisartan and ramipril superior to ramipril in patients with vascular disease or high-risk diabetes? Study design Multi-center Double blinded RCT Population Characteristics of study participants 27.0% female N = 17078 73.0% male 17078 patients (4581 female, 12497 male) Inclusion criteria: patients with vascular disease or high-risk diabetes without HF Key exclusion criteria: known hypersensitivity or intolerance to angiotensin 2 receptor antagonist or angiotensin-converting enzyme; symptomatic congestive HF; renal artery stenosis; hepatic dysfunction Interventions N=8502 combination therapy (80 mg telmisartan and 10 mg ramipril per day) N=8576 ramipril (at a dose of 10 mg per day) Primary outcome https://web.pathway.md/studies/recc9MykBIaoyWr1q 1/2 6/28/23, 11:44 PM ONTARGET (telmisartan with ramipril) Pathway Composite of death from cardiovascular causes, myocardial infarction, stroke or hospitalization for heart failure 16.5 % 16.5 16.3 12.4 % 8.3 % 4.1 % No significant difference 0.0 % Combination therapy Ramipril No significant difference in composite of death from cardiovascular causes, myocardial infarction, stroke or hospitalization for HF (16.3% vs. 16.5%; RR 0.99, 99% CI 0.92 to 1.07) Secondary outcomes No significant difference in revascularization (15.3% vs. 14.8%; RR 1.04, 95% CI 0.97 to 1.13) No significant difference in hospitalization for angina (11.2% vs. 10.8%; RR 1.04, 95% CI 0.95 to 1.14) Significant increase in renal impairment (13.5% vs. 10.2%; RR 1.33, 95% CI 1.22 to 1.44) Safety outcomes No significant difference in angioedema and cough. Significant differences in hypotensive symptoms (4.8% vs. 1.7%), syncope (0.3% vs. 0.2%). Conclusion In patients with vascular disease or high-risk diabetes without HF, combination therapy was not superior to ramipril with respect to the composite of death from cardiovascular causes, myocardial infarction, stroke or hospitalization for HF. Reference ONTARGET Investigators, Yusuf S, Teo KK et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008 Apr 10;358(15):1547-59. Open reference URL https://web.pathway.md/studies/recc9MykBIaoyWr1q 2/2

6/28/23, 11:44 PM ONTARGET (telmisartan) Pathway Feedback Search Clinical Topics Home Studies ONTARGET (telmisartan) ONTARGET (telmisartan) Disease Disease Disease Acute ischemic stroke Coronary artery disease Diabetes m Trial question Is telmisartan superior to ramipril in patients with vascular disease or high-risk diabetes? Study design Multi-center Double blinded RCT Population Characteristics of study participants 27.0% female N = 17118 73.0% male 17118 patients (4581 female, 12537 male) Inclusion criteria: patients with vascular disease or high-risk diabetes without HF Key exclusion criteria: known hypersensitivity or intolerance to angiotensin 2 receptor antagonist or angiotensin-converting enzyme; symptomatic congestive HF; renal artery stenosis; hepatic dysfunction Interventions N=8542 telmisartan (at a dose of 80 mg per day) N=8576 ramipril (at a dose of 10 mg per day) Primary outcome https://web.pathway.md/studies/rec1dvAspdW1Um9KB 1/2 6/28/23, 11:45 PM ONTARGET (telmisartan) Pathway Composite of death from cardiovascular causes, myocardial infarction, stroke or hospitalization for heart failure 16.7 % 16.7 16.5 12.5 % 8.3 % 4.2 % No significant difference 0.0 % Telmisartan Ramipril No significant difference in composite of death from cardiovascular causes, myocardial infarction, stroke or hospitalization for HF (16.7% vs. 16.5%; RR 1.01, 95% CI 0.94 to 1.09) Secondary outcomes No significant difference in revascularization (15.1% vs. 14.8%; RR 1.03, 95% CI 0.95 to 1.11) No significant difference in hospitalization for angina (11.2% vs. 10.8%; RR 1.04, 95% CI 0.95 to 1.14) No significant difference in renal impairment (10.6% vs. 10.2%; RR 1.04, 95% CI 0.96 to 1.14) Safety outcomes No significant differences in syncope, diarrhea, HF and AF. Significant differences in cough (1.1% vs. 4.2%), angioedema (0.1% vs. 0.3%), hypotensive symptoms (2.6% vs. 1.7%). Conclusion In patients with vascular disease or high-risk diabetes without HF, telmisartan was not superior to ramipril with respect to the composite of death from cardiovascular causes, myocardial infarction, stroke or hospitalization for HF. Reference ONTARGET Investigators, Yusuf S, Teo KK et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008 Apr 10;358(15):1547-59. Open reference URL https://web.pathway.md/studies/rec1dvAspdW1Um9KB 2/2

6/28/23, 11:44 PM OPTIMAL Pathway Feedback Search Clinical Topics Home Studies OPTIMAL OPTIMAL Trial question Is high-dose infusion of tranexamic acid superior to low-dose infusion in patients undergoing cardiac surgery with cardiopulmonary bypass? Study design Multi-center Double blinded RCT Population Characteristics of study participants 38.0% female N = 3031 62.0% male 3031 patients (1155 female, 1876 male) Inclusion criteria: adult patients undergoing cardiac surgery with cardiopulmonary bypass Key exclusion criteria: acquired defective chromatic vision; active intravascular coagulation; history of thrombophilia; previous convulsion or seizure Interventions N=1525 high-dose tranexamic acid regimen (30 mg/kg bolus, 16 mg/kg/hour maintenance dose, and 2 mg/kg prime) N=1506 low-dose tranexamic acid regimen (10 mg/kg bolus, 2 mg/kg/hour maintenance dose, and 1 mg/kg prime) Primary outcome Allogeneic red blood cell transfusion 26.0 % 26 21.8 19.5 % 13.0 % Significant decrease https://web.pathway.md/studies/recLQsOmcXXYAaIAD 1/2 6/28/23, 11:44 PM OPTIMAL Pathway 6.5 % NNT = 24 0.0 % High-dose tranexamic acid regimen Low-dose tranexamic acid regimen Significant decrease in allogeneic RBC transfusion (21.8% vs. 26%; RR 0.84, 95% CI 0.27 to 1.41) Secondary outcomes Borderline significant decrease in postoperative chest tube output (490 mL vs. 530 mL; AD -25 mL, 95% CI -50 to 0) No significant difference in reoperation for bleeding (1% vs. 1.4%; RR 0.75, 95% CI 0.39 to 1.43) Safety outcomes Significant differences in postoperative seizure, thrombotic events, kidney dysfunction, or death at day 30 (17.6% vs. 16.8%). Conclusion In adult patients undergoing cardiac surgery with cardiopulmonary bypass, high-dose tranexamic acid regimen was superior to low-dose tranexamic acid regimen with respect to allogeneic RBC transfusion. Reference Jia Shi, Chenghui Zhou, Wei Pan et al. Effect of High- vs Low-Dose Tranexamic Acid Infusion on Need for Red Blood Cell Transfusion and Adverse Events in Patients Undergoing Cardiac Surgery: The OPTIMAL Randomized Clinical Trial. JAMA. 2022 Jul 26;328(4):336-347. Open reference URL https://web.pathway.md/studies/recLQsOmcXXYAaIAD 2/2

6/28/23, 11:44 PM OptiTHO Pathway Feedback Search Clinical Topics Home Studies OptiTHO OptiTHO Disease Blunt chest trauma Trial question What is the role of prophylactic noninvasive ventilation and high-flow nasal oxygen therapy in hypoxemic blunt chest trauma patients? Study design Multi-center Open label RCT Population Characteristics of study participants 15.0% female N = 141 85.0% male 141 patients (21 female, 120 male) Inclusion criteria: adult patients admitted to the ICU within 48 hours after high-risk blunt chest trauma, non-severe hypoxemia, and no evidence of acute respiratory failure Key exclusion criteria: need for emergency intubation; hypercapnia; previous surgical intervention by thoracotomy or laparotomy; contraindications for noninvasive ventilation; a do-not-intubate order Interventions N=71 early noninvasive ventilation and high-flow nasal oxygen therapy (a prompt association of high-flow nasal oxygen therapy and early non-invasive ventilation in every patient for at least 48 hours) https://web.pathway.md/studies/recmPAKJxAgPlMjNM 1/2 6/28/23, 11:44 PM OptiTHO Pathway N=70 late noninvasive ventilation and conventional oxygen therapy (conventional oxygen therapy and late noninvasive ventilation, indicated in patients with respiratory deterioration and/or ratio of arterial oxygen partial pressure to fractional inspired oxygen 200 mmHg) Primary outcome Endotracheal intubation for delayed respiratory failure 8.6 % 8.6 7 6.4 % 4.3 % 2.1 % No significant difference 0.0 % Early noninvasive ventilation and high-flow nasal oxygen therapy Late noninvasive ventilation and conventional oxygen therapy No significant difference in endotracheal intubation for delayed respiratory failure (7% vs. 8.6%; OR 0.72, 95% CI 0.2 to 2.43) Safety outcomes No significant difference in secondary pneumothorax or vomiting/aspiration. Significant difference in excessive agitation with need for sedatives or noninvasive ventilation removal (21% vs. 3%). Conclusion In adult patients admitted to the ICU within 48 hours after high-risk blunt chest trauma, non-severe hypoxemia, and no evidence of acute respiratory failure, early noninvasive ventilation and high-flow nasal oxygen therapy were not superior to late noninvasive ventilation and conventional oxygen therapy with respect to endotracheal intubation for delayed respiratory failure. Reference C dric Carri , Benjamin Rieu, Antoine Benard et al. Early non-invasive ventilation and high-flow nasal oxygen therapy for preventing endotracheal intubation in hypoxemic blunt chest trauma patients: the OptiTHO randomized trial. Crit Care. 2023 Apr 26;27(1):163. Open reference URL https://web.pathway.md/studies/recmPAKJxAgPlMjNM 2/2

6/28/23, 11:45 PM Oral GLP-1 (danuglipron 120 mg) Pathway Feedback Search Clinical Topics Home Studies Oral GLP 1 (danuglipron 120 mg) Oral GLP 1 (danuglipron 120 mg) Disease Diabetes mellitus type 2 Trial question What is the effect of danuglipron in patients with T2DM? Study design Multi-center Double blinded RCT Population Characteristics of study participants 51.0% female N = 137 49.0% male 137 patients (70 female, 67 male) Inclusion criteria: adults with T2DM inadequately controlled by diet and exercise, with or without metformin treatment Key exclusion criteria: T1DM; secondary form of diabetes; recent history of cardiovascular events; gastrointestinal conditions possibly affecting drug absorption; medullary thyroid carcinoma Interventions N=71 danuglipron (at an oral dose of 120 mg BID with food for 16 weeks) N=66 placebo (matching placebo BID) Primary outcome Reduction in glycated hemoglobin at week 16 https://web.pathway.md/studies/recH8dX6e1Ne0gUK8 1/2 6/28/23, 11:45 PM Oral GLP-1 (danuglipron 120 mg) Pathway 1.2 % 1.18 0.9 % 0.6 % Significant increase 0.3 % NNT = 86 0.02 0.0 % Danuglipron Placebo Significant increase in reduction in glycated Hgb at week 16 (1.18% vs. 0.02%; MD 1.16, 90% CI 0.86 to 1.47) Secondary outcomes Significant increase in reduction in fasting plasma glucose at week 16 (31.93 mg/dL vs. -1.31 mg/dL; MD 33.24, 90% CI 20.84 to 45.63) Significant increase in reduction in body weight at week 16 (4.6 kg vs. 0.43 kg; MD 4.17, 90% CI 3.18 to 5.15) Conclusion In adults with T2DM inadequately controlled by diet and exercise, with or without metformin treatment, danuglipron was superior to placebo with respect to reduction in glycated Hgb at week 16. Reference Aditi R Saxena, Juan P Frias, Lisa S Brown et al. Efficacy and Safety of Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron for Glycemic Control Among Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA Netw Open. 2023 May 1;6(5):e2314493. Open reference URL https://web.pathway.md/studies/recH8dX6e1Ne0gUK8 2/2

6/28/23, 11:44 PM Oral GLP-1 (danuglipron 40 mg) Pathway Feedback Search Clinical Topics Home Studies Oral GLP 1 (danuglipron 40 mg) Oral GLP 1 (danuglipron 40 mg) Disease Diabetes mellitus type 2 Trial question What is the effect of danuglipron in patients with T2DM? Study design Multi-center Double blinded RCT Population Characteristics of study participants 51.0% female N = 137 49.0% male 137 patients (70 female, 67 male) Inclusion criteria: adults with T2DM inadequately controlled by diet and exercise, with or without metformin treatment Key exclusion criteria: T1DM; secondary form of diabetes; recent history of cardiovascular events; gastrointestinal conditions possibly affecting drug absorption; medullary thyroid carcinoma Interventions N=71 danuglipron (at an oral dose of 40 mg BID with food for 16 weeks) N=66 placebo (matching placebo BID) Primary outcome Reduction in glycated hemoglobin at week 16 https://web.pathway.md/studies/rec4hXMJR2vQEytZk 1/2 6/28/23, 11:45 PM Oral GLP-1 (danuglipron 40 mg) Pathway 1.0 % 1.03 0.8 % 0.5 % Significant increase 0.3 % NNT = 99 0.02 0.0 % Danuglipron Placebo Significant increase in reduction in glycated Hgb at week 16 (1.03% vs. 0.02%; MD 1.01, 90% CI 0.73 to 1.3) Secondary outcomes Significant increase in reduction in fasting plasma glucose at week 16 (30.47 mg/dL vs. -1.31 mg/dL; MD 31.78, 90% CI 20.35 to 43.2) Significant increase in reduction in body weight at week 16 (1.16 kg vs. 0.43 kg; MD 0.73, 90% CI 0.2 to 1.66) Conclusion In adults with T2DM inadequately controlled by diet and exercise, with or without metformin treatment, danuglipron was superior to placebo with respect to reduction in glycated Hgb at week 16. Reference Aditi R Saxena, Juan P Frias, Lisa S Brown et al. Efficacy and Safety of Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron for Glycemic Control Among Patients With Type 2 Diabetes: A Randomized Clinical Trial. JAMA Netw Open. 2023 May 1;6(5):e2314493. Open reference URL https://web.pathway.md/studies/rec4hXMJR2vQEytZk 2/2

6/28/23, 11:44 PM ORBIT-AF Pathway Feedback Search Clinical Topics Home Studies ORBIT AF ORBIT AF Disease Disease Disease Acute ischemic stroke Atrial fibrillation Transient Trial question What is the role of concomitant aspirin therapy in patients with AF receiving oral anticoagulation? Study design Multi-center Open label Observational study Population Characteristics of study participants 43.0% female N = 7347 57.0% male 7347 patients (3159 female, 4188 male) Inclusion criteria: patients with AF receiving oral anticoagulation Key exclusion criteria: anticipated life expectancy < 6 months, transient AF secondary to a reversible condition, such as, hyperthyroidism, PE, or postcardiothoracic surgery Interventions N=2543 dual therapy (aspirin plus oral anticoagulation therapy) N=4804 single therapy (oral anticoagulation alone) Primary outcome All-cause hospitalization 23.0 % 23 https://web.pathway.md/studies/recQR5QeanONeTRHr 1/2 6/28/23, 11:44 PM ORBIT-AF Pathway 3 19 17.3 % 11.5 % 5.8 % Borderline significant increase 0.0 % Dual therapy Single therapy Borderline significant increase in all-cause hospitalization (23% vs. 19%; aHR 1.08, 95% CI 1.08 to 1.17) Secondary outcomes No significant difference in nuisance bleeding (11% vs. 10%; aOR 1.09, 95% CI 0.96 to 1.25) Safety outcomes No significant differences in rates of ischemic events including myocardial infarction, coronary revascularization, stroke or non-CNS embolism, and TIA. Significant difference in intracranial hemorrhage (0.43% vs. 0.14%). Conclusion In patients with AF receiving oral anticoagulation, dual therapy was superior to single therapy with respect to a all-cause hospitalization. Reference Steinberg BA, Kim S, Piccini JP et al. Use and associated risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation: insights from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation. 2013 Aug 13;128(7):721- 8. Open reference URL https://web.pathway.md/studies/recQR5QeanONeTRHr 2/2

6/28/23, 11:44 PM ORBITA Pathway Feedback Search Clinical Topics Home Studies ORBITA ORBITA Disease Coronary artery disease Trial question What is the role of PCI in stable angina in patients with severe ( 70%) single-vessel stenoses? Study design Multi-center Double blinded RCT Population Characteristics of study participants 26.7% female N = 230 73.3% male 230 patients (54 female, 146 male) Inclusion criteria: patients with severe ( 70%) single-vessel stenoses who received medication optimization for 6 weeks after enrolment Key exclusion criteria: angiographic stenosis 50% in a non-target vessel, acute coronary syndrome, previous CABG surgery, left main stem coronary disease, contraindications to drug- eluting stents, chronic total coronary occlusion, severe valvular disease, moderate-to-severe pulmonary hypertension Interventions N=105 PCI (drug-eluting stents to achieve angiographic complete revascularization) N=95 placebo (coronary catheterization and sedation for 15 minutes without any intervention) https://web.pathway.md/studies/recWhpd4ILrhnjo3k 1/2 6/28/23, 11:45 PM ORBITA Pathway Primary outcome Exercise time increment 28.4 28.4 21.3 14.2 11.8 7.1 No significant difference 0.0 Percutaneous coronary intervention Placebo No significant difference in exercise time increment (28.4 vs. 11.8; difference 16.6, 95% CI -8.9 to 42) Secondary outcomes No significant difference in increment in peak oxygen uptake (-2 vs. 10.9; difference -12.9, 95% CI -90.2 to 64.3) Safety outcomes No significant difference in major bleeding events (2 vs. 3). Conclusion In patients with severe ( 70%) single-vessel stenoses who received medication optimization for 6 weeks after enrolment, PCI was not superior to placebo with respect to exercise time increment. Reference Al-Lamee R, Thompson D, Dehbi HM et al. Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet. 2018 Jan 6;391(10115):31-40. Open reference URL https://web.pathway.md/studies/recWhpd4ILrhnjo3k 2/2

6/28/23, 11:45 PM ORIGIN n-3 Fatty Acids Pathway Feedback Search Clinical Topics Home Studies ORIGIN n-3 Fatty Acids ORIGIN n-3 Fatty Acids Disease Diabetes mellitus type 2 Trial question What is the role of n-3 fatty acids in patients with or at risk for T2DM mellitus? Study design Multi-center Double blinded RCT Population Characteristics of study participants 35.0% female N = 12536 65.0% male 12536 patients (4386 female, 8150 male) Inclusion criteria: patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes Key exclusion criteria: unwilling to discontinue use of a nonstudy preparation of n-3 fatty acids, glycated Hgb level 9%, CABG within the previous 4 years with no intervening cardiovascular event, severe HF, or cancer that might affect survival Interventions N=6281 n-3 fatty acid supplementation (1 g capsule containing at least 900 mg of ethyl esters) N=6255 placebo (capsule containing 1 g of olive oil) Primary outcome https://web.pathway.md/studies/reczH9enCwL3F4epv 1/2 6/28/23, 11:45 PM ORIGIN n-3 Fatty Acids Pathway Cardiovascular death 9.3 % 9.3 9.1 7.0 % 4.7 % 2.3 % No significant difference 0.0 % N-3 fatty acid supplementation Placebo No significant difference in cardiovascular death (9.1% vs. 9.3%; HR 0.98, 95% CI 0.87 to 1.1) Secondary outcomes No significant difference in major vascular events (16.5% vs. 16.3%; HR 1.01, 95% CI 0.93 to 1.1) No significant difference in death from any cause (15.1% vs. 15.4%; HR 0.98, 95% CI 0.89 to 1.07) No significant difference in arrhythmic death (4.6% vs. 4.1%; HR 1.1, 95% CI 0.93 to 1.3) Safety outcomes No significant difference in adverse effects. Significant differences in triglycerides (-23.5 vs. -9.0 mg/dL, p < 0.001). Conclusion In patients who were at high risk for cardiovascular events and had impaired fasting glucose, impaired glucose tolerance, or diabetes, n-3 fatty acid supplementation was not superior to placebo with respect to cardiovascular death. Reference ORIGIN Trial Investigators, Bosch J, Gerstein HC et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012 Jul 26;367(4):309-18. Open reference URL https://web.pathway.md/studies/reczH9enCwL3F4epv 2/2

6/28/23, 11:45 PM ORION-10 Pathway Feedback Search Clinical Topics Home Studies ORION 10 ORION 10 Disease Disease Coronary artery disease Dyslipidemia Trial question What is the role of inclisiran in patients with increased low-density lipoprotein cholesterol despite statin therapy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 31.0% female N = 1561 69.0% male 1561 patients (478 female, 1083 male) Inclusion criteria: patients with ASCVD who had increased LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose Key exclusion criteria: any uncontrolled or serious disease; NYHA class IV HF; uncontrolled cardiac arrhythmia; uncontrolled severe hypertension; active liver disease; treatment with monoclonal antibodies directed toward PCSK9 within 90 days before screening Interventions N=781 inclisiran (284 mg administered SC on day 1, day 90, day 270, and day 450) N=780 placebo (matching placebo administered SC) https://web.pathway.md/studies/recvbU2kFsXvESkim 1/2 6/28/23, 11:45 PM ORION-10 Pathway Primary outcome Significant increase in LDL cholesterol reduction at day 510 (51.3% vs. -1%; AD 52.3%, 95% CI 48.8 to 55.7) Secondary outcomes Significant increase in time-adjusted LDL cholesterol reduction from day 90 to 540 (51.3% vs. -2.5%; AD 53.8%, 95% CI 51.3 to 56.2) Significant increase in absolute LDL cholesterol level reduction at day 510 (56.2 mg/dL vs. 2.1 mg/dL; AD 54.1 mg/dL, 95% CI 50.9 to 57.4) Significant increase in absolute LDL cholesterol level reduction from day 90 to 540 (53.7 mg/dL vs. 0.4 mg/dL; AD 53.3 mg/dL, 95% CI 50.8 to 55.8) Safety outcomes No significant difference in adverse events. Significant difference in injection-site adverse events (2.6% vs. 0.9%). Conclusion In patients with ASCVD who had increased LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose, inclisiran was superior to placebo with respect to LDL cholesterol reduction at day 510. Reference Kausik K Ray, R Scott Wright, David Kallend et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-1519. Open reference URL https://web.pathway.md/studies/recvbU2kFsXvESkim 2/2

6/28/23, 11:44 PM ORION-11 Pathway Feedback Search Clinical Topics Home Studies ORION 11 ORION 11 Disease Disease Coronary artery disease Dyslipidemia Trial question What is the role of inclisiran in patients with increased LDL cholesterol despite statin therapy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 28.0% female N = 1617 72.0% male 1617 patients (457 female, 1160 male) Inclusion criteria: patients with ASCVD or an ASCVD risk equivalent who had increased LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose Key exclusion criteria: any uncontrolled or serious disease; NYHA class IV HF; uncontrolled cardiac arrhythmia; uncontrolled severe hypertension; active liver disease; treatment with monoclonal antibodies directed toward PCSK9 within 90 days before screening Interventions N=810 inclisiran (284 mg administered SC on day 1, day 90, day 270, and day 450) N=807 placebo (matching placebo administered SC) Primary outcome https://web.pathway.md/studies/rec9xaFk3N8ceYmPz 1/2 6/28/23, 11:44 PM ORION-11 Pathway Significant increase in LDL cholesterol reduction at day 510 (45.8% vs. -4%; AD 49.9%, 95% CI 46.6 to 53.1) Secondary outcomes Significant increase in time-adjusted LDL cholesterol reduction from day 90 to 540 (45.8% vs. -3.4%; AD 49.2%, 95% CI 46.8 to 51.6) Significant increase in absolute LDL cholesterol level reduction at day 510 (50.9 mg/dL vs. -1 mg/dL; AD 51.9 mg/dL, 95% CI 48.7 to 55) Significant increase in absolute LDL cholesterol level reduction from day 90 to 540 (48.6 mg/dL vs. 0.3 mg/dL; AD 48.9 mg/dL, 95% CI 46.5 to 51.4) Safety outcomes No significant differences in adverse events, serious adverse events. Significant difference in injection-site adverse events (4.7% vs. 0.5%). Conclusion In patients with ASCVD or an ASCVD risk equivalent who had increased LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose, inclisiran was superior to placebo with respect to LDL cholesterol reduction at day 510. Reference Kausik K Ray, R Scott Wright, David Kallend et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020 Apr 16;382(16):1507-1519. Open reference URL https://web.pathway.md/studies/rec9xaFk3N8ceYmPz 2/2

6/28/23, 11:44 PM OSCILLATE Pathway Feedback Search Clinical Topics Home Studies OSCILLATE OSCILLATE Disease Acute respiratory distress syndr Trial question What is the role of high-frequency oscillatory ventilation in patients with early ARDS? Study design Multi-center Open label RCT Population Characteristics of study participants 41.3% female N = 1200 58.7% male 1200 patients (228 female, 320 male) Inclusion criteria: adults with new-onset, moderate-to-severe ARDS Key exclusion criteria: hypoxemia primarily related to LA hypertension, suspected vasculitic pulmonary hemorrhage, neuromuscular disorders, severe chronic respiratory disease, or preexisting conditions with an expected 6-month mortality > 50%, at risk for intracranial hypertension Interventions N=275 high-frequency oscillatory ventilation (targeting improved lung recruitment) N=273 low tidal volume ventilation (low tidal volumes and high PEEP) Primary outcome https://web.pathway.md/studies/recDgxiKlrJzu1htG 1/2 6/28/23, 11:44 PM OSCILLATE Pathway In-hospital death 47.0 % 47 35.3 % 35 23.5 % Significant increase 11.8 % NNH = 8 0.0 % High-frequency oscillatory ventilation Low tidal volume ventilation Significant increase in in-hospital death (47% vs. 35%; RR 1.33, 95% CI 1.09 to 1.64) Secondary outcomes No significant difference in new barotrauma (18% vs. 13%; RR 1.37, 95% CI 0.91 to 2.06) Significant decrease in refractory hypoxemia (7% vs. 14%; RR 0.5, 95% CI 0.29 to 0.84) No significant difference in refractory acidosis (3% vs. 3%; RR 1.12, 95% CI 0.44 to 2.85) Conclusion In adults with new-onset, moderate-to-severe ARDS, high-frequency oscillatory ventilation was inferior to low tidal volume ventilation with respect to a in-hospital death. Reference Ferguson ND, Cook DJ, Guyatt GH et al. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013 Feb 28;368(9):795-805. Open reference URL https://web.pathway.md/studies/recDgxiKlrJzu1htG 2/2

6/28/23, 11:44 PM Ototopical ABX and CS in AOE (ciprofloxacin plus fluocinolone vs. ciprofloxacin) Pathway Feedback Search Clinical Topics Home Studies Ototopical ABX and CS in AOE (ciprofloxacin plus fluocinolone vs. ciprofloxacin) Ototopical ABX and CS in AOE (ciprofloxacin plus fluocinolone vs. ciprofloxacin) Disease Acute otitis externa Trial question Is the combination of ciprofloxacin and fluocinolone acetonide superior to ciprofloxacin in patients with acute otitis externa? Study design Multi-center Double blinded RCT Population Characteristics of study participants 50.0% female N = 393 50.0% male 393 patients (198 female, 195 male) Inclusion criteria: adults and children aged > 6 months with acute otitis externa Key exclusion criteria: previous episode of acute otitis externa within 4 weeks or > 1 episode of acute otitis externa within 6 months; tympanic membrane perforation; otitis media; malignant otitis externa Interventions N=197 ciprofloxacin plus fluocinolone acetonide (ciprofloxacin 0.3% plus fluocinolone acetonide 0.025% otic solution BID for 7 days) N=196 ciprofloxacin alone (ciprofloxacin 0.3% otic solution BID for 7 days) https://web.pathway.md/studies/reccragARbEsf2SBn 1/2 6/28/23, 11:44 PM Ototopical ABX and CS in AOE (ciprofloxacin plus fluocinolone vs. ciprofloxacin) Pathway Primary outcome Clinical and microbiological cure at day 8-10 61.2 % 61.2 53.8 45.9 % 30.6 % 15.3 % No significant difference 0.0 % Ciprofloxacin plus fluocinolone acetonide Ciprofloxacin alone No significant difference in clinical and microbiological cure at day 8-10 (61.2% vs. 53.8%; AD 7.3%, 95% CI -6.6 to 21.2) Secondary outcomes No significant difference in median number of days until cessation of ear pain (5 days vs. 5.9 days; MD -0.9, 95% CI -4.3 to 7.3) Significant increase in sustained microbiological response (91.3% vs. 81.3%; AD 9.9%, 95% CI 0.3 to 19.6) Significant increase in clinical and microbiological cure at day 15-17 (87.4% vs. 75.8%; AD 11.6%, 95% CI 0.7 to 22.4) Safety outcomes No significant difference in adverse events. Conclusion In adults and children aged > 6 months with acute otitis externa, ciprofloxacin plus fluocinolone acetonide was not superior to ciprofloxacin alone with respect to clinical and microbiological cure at day 8-10. Reference Laurence Chu, Ana M Acosta, Hessam Aazami et al. Efficacy and Safety of Ciprofloxacin Plus Fluocinolone Acetonide Among Patients With Acute Otitis Externa: A Randomized Clinical Trial. JAMA Netw Open. 2022 Jul 1;5(7):e2221699. Open reference URL https://web.pathway.md/studies/reccragARbEsf2SBn 2/2

6/28/23, 11:44 PM Ototopical ABX and CS in AOE (ciprofloxacin plus fluocinolone vs. fluocinolone) Pathway Feedback Search Clinical Topics Home Studies Ototopical ABX and CS in AOE (ciprofloxacin plus fluocinolone vs. fluocinolone) Ototopical ABX and CS in AOE (ciprofloxacin plus fluocinolone vs. fluocinolone) Disease Acute otitis externa Trial question Is the combination of ciprofloxacin and fluocinolone acetonide superior to fluocinolone acetonide in patients with acute otitis externa? Study design Multi-center Double blinded RCT Population Characteristics of study participants 52.0% female N = 297 48.0% male 297 patients (153 female, 144 male) Inclusion criteria: adults and children aged > 6 months with acute otitis externa Key exclusion criteria: previous episode of acute otitis externa within 4 weeks or > 1 episode of acute otitis externa within 6 months; tympanic membrane perforation; otitis media; malignant otitis externa Interventions N=197 ciprofloxacin plus fluocinolone acetonide (ciprofloxacin 0.3% plus fluocinolone acetonide 0.025% otic solution BID for 7 days) N=100 fluocinolone acetonide alone (fluocinolone acetonide 0.025% otic solution BID for 7 days) https://web.pathway.md/studies/recEweNI4mdviJ4HX 1/2 6/28/23, 11:44 PM Ototopical ABX and CS in AOE (ciprofloxacin plus fluocinolone vs. fluocinolone) Pathway Primary outcome Clinical and microbiological cure at day 8-10 61.2 % 61.2 45.9 % 44.4 30.6 % 15.3 % No significant difference 0.0 % Ciprofloxacin plus fluocinolone acetonide Fluocinolone acetonide alone No significant difference in clinical and microbiological cure at day 8-10 (61.2% vs. 44.4%; AD 16.7%, 95% CI -0.6 to 34) Secondary outcomes No significant difference in median number of days until cessation of ear pain (5 days vs. 7.7 days; AD -2.7 days, 95% CI -6.7 to 9) Significant increase in sustained microbiological response (91.3% vs. 75.6%; AD 15.7%, 95% CI 2 to 29.4) No significant difference in clinical and microbiological cure at day 15-17 (87.4% vs. 80%; AD 7.4%, 95% CI -6 to 20.7) Safety outcomes No significant difference in adverse events. Conclusion In adults and children aged > 6 months with acute otitis externa, ciprofloxacin plus fluocinolone acetonide was not superior to fluocinolone acetonide alone with respect to clinical and microbiological cure at day 8-10. Reference Laurence Chu, Ana M Acosta, Hessam Aazami et al. Efficacy and Safety of Ciprofloxacin Plus Fluocinolone Acetonide Among Patients With Acute Otitis Externa: A Randomized Clinical Trial. JAMA Netw Open. 2022 Jul 1;5(7):e2221699. Open reference URL https://web.pathway.md/studies/recEweNI4mdviJ4HX 2/2

6/28/23, 11:44 PM OVIVA Pathway Feedback Search Clinical Topics Home Studies OVIVA OVIVA Disease Disease Septic arthritis Vertebral osteomyelitis Trial question Are oral antibiotics noninferior to IV antibiotics for bone and joint infection in adults? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 1054 64.0% male 1054 patients (376 female, 678 male) Inclusion criteria: patients being treated for bone or joint infection Key exclusion criteria: S. aureus bacteremia, bacterial endocarditis, or any other concomitant infection, mild osteomyelitis, septic shock Interventions N=527 oral antibiotic therapy (for the first 6 weeks of therapy) N=527 IV antibiotic therapy (for the first 6 weeks of therapy) Primary outcome Definitive treatment failure at 1 year 14.6 https://web.pathway.md/studies/recHhgA8hFAOWXmra 1/2 6/28/23, 11:45 PM OVIVA Pathway 6 14.6 % 13.2 10.9 % 7.3 % Difference not exceeding nonferiority margin 3.6 % 0.0 % Oral antibiotic therapy IV antibiotic therapy Difference not exceeding nonferiority margin in definitive treatment failure at 1 year (13.2% vs. 14.6%; ARD -1.4, 95% CI -5.6 to 2.9) Secondary outcomes No significant difference in probable or possible treatment failure (2% vs. 1.2%; ARD 0.7, 95% CI -5.1 to 3.8) Significant decrease in early discontinuation of therapy (12.8% vs. 18.9%; ARD -6.1, 95% CI -10.45 to -1.75) No significant difference in C. difficile infection (1% vs. 1.7%; ARD -0.7, 95% CI -2.2 to 0.6) Safety outcomes No significant differences in serious adverse events (26.2% vs. 27.7%, p=0.58). Conclusion In patients being treated for bone or joint infection, oral antibiotic therapy was noninferior to IV antibiotic therapy with respect to definitive treatment failure at 1 year. Reference Li HK, Rombach I, Zambellas R et al. Oral versus Intravenous Antibiotics for Bone and Joint Infection. N Engl J Med. 2019 Jan 31;380(5):425-436. Open reference URL https://web.pathway.md/studies/recHhgA8hFAOWXmra 2/2

6/29/23, 1:34 AM PAC in high-risk surgery Pathway Feedback Search Clinical Topics Home Studies PAC in high-risk surgery PAC in high-risk surgery Trial question What is the role of goal-directed therapy guided by a pulmonary artery catheter in high-risk surgical patients? Study design Multi-center Open label RCT Population Characteristics of study participants 29.0% female N = 1994 71.0% male 1994 patients (576 female, 1418 male) Inclusion criteria: high-risk adult patients aged 60 years who were scheduled for urgent or elective major surgery, followed by a stay in the ICU Key exclusion criteria: lack of available beds in the ICU; no informed consent; no referral by the treating physician Interventions N=997 pulmonary artery catheter (goal-directed therapy guided by a pulmonary artery catheter) N=997 no pulmonary artery catheter (standard of care without the use of a pulmonary artery catheter) Primary outcome Death in hospital 7.8 % 7.8 7.7 5.8 % 3.9 % https://web.pathway.md/studies/recFHopvaDc2zJMZb 1/2 6/29/23, 1:34 AM PAC in high-risk surgery Pathway 1.9 % No significant difference 0.0 % Pulmonary artery catheter No pulmonary artery catheter No significant difference in death in the hospital (7.8% vs. 7.7%; AD 0.1%, 95% CI -2.3 to 2.5) Secondary outcomes Significant increase in PE (AD 0.9%, 95% CI 0.29 to 1.51) No significant difference in survival at 12 months (83% vs. 83.9%; ARD -0.9, 95% CI -4.3 to 2.4) Safety outcomes No significant difference in adverse events due to pulmonary artery catheters or central venous catheters. Conclusion In high-risk adult patients aged 60 years who were scheduled for urgent or elective major surgery, followed by a stay in the ICU, pulmonary artery catheter was not superior to no pulmonary artery catheter with respect to death in the hospital. Reference James Dean Sandham, Russell Douglas Hull, Rollin Frederick Brant et al. A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med. 2003 Jan 2;348(1):5-14. Open reference URL https://web.pathway.md/studies/recFHopvaDc2zJMZb 2/2

6/29/23, 1:34 AM PAC-Man Pathway Feedback Search Clinical Topics Home Studies PAC Man PAC Man Trial question What is the role of pulmonary artery catheters in the management of critically ill patients? Study design Multi-center Open label RCT Population Characteristics of study participants 42.0% female N = 1014 58.0% male 1014 patients (423 female, 591 male) Inclusion criteria: adult patients admitted to an ICU Key exclusion criteria: age < 16 years; elective admission for preoperative optimization; presence of a pulmonary artery catheter on admission to intensive care; previous enrolment to the study; or hemodynamic optimization before organ donation Interventions N=519 pulmonary artery catheter (catheter placed as soon as possible after randomization, according to local practice) N=522 control (management without pulmonary artery catheter) Primary outcome Death in hospital 68.0 % 68 66 51.0 % 34.0 % 17.0 % https://web.pathway.md/studies/rechfIzKcL7f1Ewqr 1/2 6/29/23, 1:34 AM PAC-Man Pathway No significant difference 0.0 % Pulmonary artery catheter Control No significant difference in death in the hospital (68% vs. 66%; HR 1.07, 95% CI 0.92 to 1.24) Secondary outcomes No significant difference in median ICU length of stay among survivors (12.1 days vs. 11 days; AD 1.1 days, 95% CI -0.8 to 3) No significant difference in median hospital length of stay among survivors (34 days vs. 40 days; AD -6 days, 95% CI -20.65 to 8.65) Safety outcomes No significant differences in death at 28 days, death in the ICU. Conclusion In adult patients admitted to an ICU, pulmonary artery catheter was not superior to control with respect to death in the hospital. Reference Sheila Harvey, David A Harrison, Mervyn Singer et al. Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial. Lancet. 2005 Aug 6-12;366(9484):472-7. Open reference URL https://web.pathway.md/studies/rechfIzKcL7f1Ewqr 2/2

6/29/23, 1:34 AM PACMAN-AMI Pathway Feedback Search Clinical Topics Home Studies PACMAN AMI PACMAN AMI Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the effect of adding alirocumab to high-intensity statin therapy in patients with acute myocardial infarction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 19.0% female N = 300 81.0% male 300 patients (56 female, 243 male) Inclusion criteria: adult patients undergoing PCI for acute myocardial infarction Key exclusion criteria: left main or 3-vessel coronary artery disease; history of coronary artery bypass surgery; severe kidney dysfunction, liver disease, or known statin intolerance Interventions N=148 alirocumab (subcutaneous dose of 150 mg biweekly) N=152 placebo (subcutaneous administration of matching placebo biweekly) Primary outcome Reduction in atheroma volume at week 52 https://web.pathway.md/studies/recz0SeZ02JC3Jbz9 1/2 6/29/23, 1:34 AM PACMAN-AMI Pathway 2.1 % 2.13 1.6 % 1.1 % 0.92 Significant increase 0.5 % NNT = 83 0.0 % Alirocumab Placebo Significant increase in reduction in atheroma volume at week 52 (2.13% vs. 0.92%; AD 1.21%, 95% CI 0.65 to 1.78) Secondary outcomes Significant increase in reduction in maximum lipid core burden index within 4 mm (79.42 vs. 37.6; AD 41.24, 95% CI 11.77 to 70.71) Significant increase in improvement in minimal fibrous cap thickness (62.67 um vs. 33.19 um; AD 29.65 um, 95% CI 11.75 to 47.55) Safety outcomes No significant difference in adverse events. Conclusion In adult patients undergoing PCI for acute myocardial infarction, alirocumab was superior to placebo with respect to reduction in atheroma volume at week 52. Reference Lorenz R ber, MD, PhD et al. Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction The PACMAN-AMI Randomized Clinical Trial. JAMA. 2022 May 10;327(18):1771-1781. Open reference URL https://web.pathway.md/studies/recz0SeZ02JC3Jbz9 2/2

6/29/23, 1:34 AM PALOMA-3 Pathway Feedback Search Clinical Topics Home Studies PALOMA 3 PALOMA 3 Trial question What is the effect of palbociclib plus fulvestrant in premenopausal and postmenopausal Asian women who have endocrine therapy-resistant metastatic breast cancer? Study design Multi-center Double blinded RCT Population 105 female patients Inclusion criteria: premenopausal and postmenopausal Asian women with hormone receptor- positive/HER2-negative metastatic breast cancer with disease progression on endocrine therapy Interventions N=71 palbociclib plus fulvestrant (125 mg/d palbociclib PO for 3 weeks followed by 1 week off plus 500 mg fulvestrant administered IM on days 1 and 15 of cycle and then every 28 days thereafter starting from day 1 of cycle 1) N=31 fulvestrant alone (placebo plus fulvestrant 500 mg administered IM on days 1 and 15 of cycle 1 and then every 28 days thereafter starting from day 1 of cycle 1) Primary outcome Rate of complete response, partial response, or stable disease at 24 weeks 70.0 % 70 52.5 % 52 35.0 % 17.5 % No significant difference 0.0 % Palbociclib plus fulvestrant Fulvestrant alone No significant difference in the rate of complete response, partial response, or stable disease at 24 weeks (70% vs. 52%; OR 2.22, 95% CI 0.85 to 5.7) Safety outcomes https://web.pathway.md/studies/rec6tPf1ZuZy30iM3 1/2 6/29/23, 1:34 AM PALOMA-3 Pathway Significant difference in overall incidence of serious adverse events (14% vs. 23%). Conclusion In premenopausal and postmenopausal Asian women with hormone receptor-positive/HER2- negative metastatic breast cancer with disease progression on endocrine therapy, palbociclib plus fulvestrant was superior to fulvestrant alone with respect to the rate of complete response, partial response, or stable disease at 24 weeks. Reference Iwata H, Im SA, Masuda N et al. PALOMA-3: Phase III Trial of Fulvestrant With or Without Palbociclib in Premenopausal and Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That Progressed on Prior Endocrine Therapy-Safety and Efficacy in Asian Patients. J Glob Oncol. 2017 Apr 11;3(4):289-303. Open reference URL https://web.pathway.md/studies/rec6tPf1ZuZy30iM3 2/2

6/29/23, 1:34 AM PAMPer Pathway Feedback Search Clinical Topics Home Studies PAMPer PAMPer Disease Traumatic hemorrhage Trial question What is the role of prehospital administration of thawed plasma during air medical transport in trauma patients at risk for hemorrhagic shock? Study design Multi-center Open label RCT Population Characteristics of study participants 27.0% female N = 501 73.0% male 501 patients (137 female, 364 male) Inclusion criteria: injured patients who were at risk for hemorrhagic shock during air medical transport to a trauma center Key exclusion criteria: older than 90 years of age or younger than 18 years of age, non- establishment of intravenous or intraosseous access, cervical cord injury, penetrating brain injury, injury due to isolated drowning, or hanging Interventions N=230 plasma (administration of 2 units of thawed plasma initiated in the prehospital setting by the air transport team) https://web.pathway.md/studies/recDFloYgWGrKF2Ef 1/2 6/29/23, 1:34 AM PAMPer Pathway N=271 standard-care (resuscitation with the infusion of a crystalloid solution as the primary resuscitative fluid during the flight) Primary outcome Death at 30 days 33.0 % 33 24.8 % 23.2 16.5 % Significant decrease 8.3 % NNT = 10 0.0 % Plasma Standard-care Significant decrease in death at 30 days (23.2% vs. 33%; ARD -9.8, 95% CI -18.6 to -1) Secondary outcomes Significant decrease in death within 24 hours (13.9% vs. 22.1%; ARD -8.2, 95% CI -14.9 to -1.6) Significant decrease in death in the hospital (22.2% vs. 32.5%; ARD -10.3, 95% CI -18 to -2.6) No significant difference in multiorgan failure (63% vs. 57.6%; AD 5.4%, 95% CI -3.1 to 14.1) Safety outcomes No significant differences in acute lung injury-ARDS, nosocomial infection, allergic reaction or transfusion-related reaction. Significant difference in prothrombin-time ratio (1.2 vs. 1.3). Conclusion In injured patients who were at risk for hemorrhagic shock during air medical transport to a trauma center, plasma was superior to standard-care with respect to death at 30 days. Reference Jason L Sperry, Francis X Guyette, Joshua B Brown et al. Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock. N Engl J Med. 2018 Jul 26;379(4):315-326. Open reference URL https://web.pathway.md/studies/recDFloYgWGrKF2Ef 2/2

6/29/23, 1:34 AM PANORAMIC Pathway Feedback Search Clinical Topics Home Studies PANORAMIC PANORAMIC Disease COVID 19 infection Trial question What is the role of molnupiravir in high-risk vaccinated adults in the community with COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 59.0% female N = 25708 41.0% male 25708 patients (15053 female, 10648 male) Inclusion criteria: adult patients with relevant comorbidities with confirmed COVID-19 for 5 days in the community Key exclusion criteria: pregnancy; lactation; receipt of molnupiravir; allergy to molnupiravir Interventions N=12774 molnupiravir (molnupiravir at a dose of 800 mg BID for 5 days plus usual care) N=12934 standard care only (management of symptoms with antipyretics; monoclonal antibodies and antivirals for very high-risk patients) Primary outcome Hospitalizations or death from all causes at day 28 https://web.pathway.md/studies/recy6ziTTYryLDJNE 1/2 6/29/23, 1:34 AM PANORAMIC Pathway 1.0 % 1 1 0.8 % 0.5 % 0.3 % No significant difference 0.0 % Molnupiravir Standard care only No significant difference in hospitalizations or death from all causes at day 28 (1% vs. 1%; OR 1.06, 95% CI 0.81 to 1.41) Secondary outcomes Borderline significant increase in early sustained recovery (32% vs. 23%; OR 1.62, 95% CI 1.53 to 1.72) Borderline significant increase in days to alleviation of all symptoms (4 days vs. 4 days; HR 1.18, 95% CI 1.15 to 1.22) Safety outcomes No significant difference in serious adverse events. Conclusion In adult patients with relevant comorbidities with confirmed COVID-19 for 5 days in the community, molnupiravir was not superior to standard care only with respect to hospitalizations or death from all causes at day 28. Reference Christopher C Butler, F D Richard Hobbs, Oghenekome A Gbinigie et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet. 2022 Dec 22;S0140-6736(22)02597-1. Open reference URL https://web.pathway.md/studies/recy6ziTTYryLDJNE 2/2

6/29/23, 1:34 AM PANTER Pathway Feedback Search Clinical Topics Home Studies PANTER PANTER Disease Acute pancreatitis Trial question What is the role of minimally invasive step-up approach to treatment in patients with necrotizing pancreatitis and infected necrotic tissue? Study design Multi-center Open label RCT Population Characteristics of study participants 27.0% female N = 88 73.0% male 88 patients (24 female, 64 male) Inclusion criteria: patients with necrotizing pancreatitis and suspected or confirmed infected necrotic tissue Key exclusion criteria: flare-up of chronic pancreatitis, previous exploratory laparotomy during the current episode of pancreatitis, previous drainage or surgery for confirmed or suspected infected necrosis, pancreatitis caused by abdominal surgery, and an acute intraabdominal event Interventions N=43 a step-up approach to management of pancreatic necrosis (starting with drainage followed, if necessary, by videoscopic assisted retroperitoneal debridement) N=45 primary open necrosectomy (maximal necrosectomy by laparotomy) https://web.pathway.md/studies/recMl9ggOeii1lU1S 1/2 6/29/23, 1:34 AM PANTER Pathway Primary outcome Death or major complications 69.0 % 69 51.8 % 40 34.5 % Significant decrease 17.3 % NNT = 3 0.0 % A step-up approach to management of pancreatic necrosis Primary open necrosectomy Significant decrease in death or major complications (40% vs. 69%; RR 0.57, 95% CI 0.38 to 0.87) Secondary outcomes Significant increase in new-onset multiple-organ failure or systemic complications (12% vs. 42%; RR 28, 95% CI 0.11 to 0.67) No significant difference in death (19% vs. 16%; RR 1.2, 95% CI 0.48 to 3.01) Conclusion In patients with necrotizing pancreatitis and suspected or confirmed infected necrotic tissue, a step- up approach to management of pancreatic necrosis were superior to primary open necrosectomy with respect to death or major complications. Reference van Santvoort HC, Besselink MG, Bakker OJ et al. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med. 2010 Apr 22;362(16):1491-502. Open reference URL https://web.pathway.md/studies/recMl9ggOeii1lU1S 2/2

6/29/23, 1:34 AM PARADIGM-HF Pathway Feedback Search Clinical Topics Home Studies PARADIGM HF PARADIGM HF Disease Heart failure Trial question What is the role of angiotensin-neprilysin inhibition in patients with HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 22.0% female N = 8442 78.0% male 8442 patients (1832 female, 6567 male) Inclusion criteria: patients with class II, III, or IV HF and a reduced ejection fraction of 40% Key exclusion criteria: symptomatic hypotension, a systolic BP of < 95 mmHg at randomization, a serum potassium level > 5.4 mmol/L at randomization, or a history of angioedema or unacceptable side effects during receipt of ACE inhibitors or ARBs Interventions N=4187 sacubitril/valsartan (at a dose of 200 mg BID plus recommended therapy) N=4212 enalapril (at a dose of 10 mg BID plus recommended therapy) Primary outcome Death from cardiovascular causes or hospitalization for heart failure https://web.pathway.md/studies/recTMrSbLsQB8uM3l 1/2 6/29/23, 1:34 AM PARADIGM-HF Pathway 26.5 % 26.5 21.8 19.9 % 13.3 % Significant decrease 6.6 % NNT = 21 0.0 % Sacubitril/valsartan Enalapril Significant decrease in death from cardiovascular causes or hospitalization for HF (21.8% vs. 26.5%; HR 0.8, 95% CI 0.73 to 0.87) Secondary outcomes Significant decrease in death from any cause (17% vs. 19.8%; HR 0.84, 95% CI 0.76 to 0.93) Significant decrease in cardiovascular death (13.3% vs. 16.5%; HR 0.8, 95% CI 0.71 to 0.89) Significant decrease in hospitalization for HF (12.8% vs. 15.6%; HR 0.79, 95% CI 0.71 to 0.89) Safety outcomes No significant difference in nonserious angioedema (0.2% vs. 0.1%). Significant differences in hypotension (14.0% vs. 9.2%), cough (11.3% vs. 14.3%), hyperkalemia (4.3% vs. 5.6%) and renal impairment (0.7% vs. 1.4%). Conclusion In patients with class II, III, or IV HF and a reduced ejection fraction of 40%, sacubitril/valsartan was superior to enalapril with respect to death from cardiovascular causes or hospitalization for HF. Reference McMurray JJ, Packer M, Desai AS et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. Open reference URL https://web.pathway.md/studies/recTMrSbLsQB8uM3l 2/2

6/29/23, 1:34 AM PARAMEDIC2 Pathway Feedback Search Clinical Topics Home Studies PARAMEDIC2 PARAMEDIC2 Disease Cardiac arrest Trial question What is the effect of epinephrine in adult patients with out-of-hospital cardiac arrest? Study design Multi-center Double blinded RCT Population Characteristics of study participants 35.0% female N = 8014 65.0% male 8014 patients (2821 female, 5193 male) Inclusion criteria: patients with out-of-hospital cardiac arrest Key exclusion criteria: known or apparent pregnancy, an age < 16 years, cardiac arrest from anaphylaxis or asthma, or the administration of epinephrine before the arrival of the trial-trained paramedic Interventions N=4015 epinephrine (a single dose of 1 mg of epinephrine administered by an intravenous or intraosseous route every 3 to 5 minutes) N=3999 placebo (a single dose of 0.9% saline administered by an intravenous or intraosseous route every 3 to 5 minutes) https://web.pathway.md/studies/recRdqbhubTxK7qnh 1/2 6/29/23, 1:34 AM PARAMEDIC2 Pathway Primary outcome Rate of survival at 30 days 3.2 % 3.2 2.4 % 2.4 1.6 % Significant increase 0.8 % NNT = 125 0.0 % Epinephrine Placebo Significant increase in rate of survival at 30 days (3.2% vs. 2.4%; OR 1.39, 95% CI 1.06 to 1.82) Secondary outcomes No significant difference in rate of survival until hospital discharge with a favorable neurologic outcome, as indicated by a score 3 on the mRS (2.2% vs. 1.9%; OR 1.18, 95% CI 0.86 to 1.61) Borderline significant increase in survival until hospital admission (23.8% vs. 8%; OR 3.59, 95% CI 3.14 to 4.12) Borderline significant increase in survival at 3 months (3% vs. 2.2%; OR 1.41, 95% CI 1.07 to 1.87) Safety outcomes No significant difference in favorable neurologic outcome at 3 months. Significant difference in severe neurologic impairment at hospital discharge (31.0% vs. 17.8%). Conclusion In patients with out-of-hospital cardiac arrest, epinephrine was superior to placebo with respect to the rate of survival at 30 days. Reference Gavin D Perkins, Chen Ji, Charles D Deakin et al. A Randomized Trial of Epinephrine in Out-of- Hospital Cardiac Arrest. N Engl J Med. 2018 Aug 23;379(8):711-721. Open reference URL https://web.pathway.md/studies/recRdqbhubTxK7qnh 2/2

6/29/23, 1:34 AM PARAMOUNT Pathway Feedback Search Clinical Topics Home Studies PARAMOUNT PARAMOUNT Disease Non-small cell lung cancer Trial question What is the role of pemetrexed continuation maintenance therapy in patients with advanced nonsquamous non-small cell lung cancer? Study design Multi-center Double blinded RCT Population Characteristics of study participants 42.1% female N = 939 57.9% male 939 patients (226 female, 313 male) Inclusion criteria: patients with advanced nonsquamous non-small cell lung cancer who received four cycles of pemetrexed-cisplatin induction therapy Key exclusion criteria: concurrent administration of other antitumour therapy and tumour histology that was predominantly squamous cell, mixed small cell, or a combination of both histologies Interventions N=359 pemetrexed (continuation pemetrexed 500 mg/m IV plus best supportive care, on day 1 of 21-day cycles) N=180 placebo (0.9% sodium chloride IV plus best supportive care, on day 1 of 21-day cycles) https://web.pathway.md/studies/recjo23JKqsHIwxKp 1/2 6/29/23, 1:34 AM PARAMOUNT Pathway Primary outcome Overall survival 13.9 months 13.9 11 10.4 months 7.0 months 3.5 months Significant increase 0.0 months Pemetrexed Placebo Significant increase in overall survival (13.9 months vs. 11 months; HR 1.28, 95% CI 1.04 to 1.56) Secondary outcomes No significant difference in survival for complete/partial responders induction response (15.5 vs. 11.2; HR 1.23, 95% CI 0.9 to 1.69) No significant difference in survival for patients with stable disease (13.7 vs. 11.1; HR 1.32, 95% CI 0.99 to 1.75) Safety outcomes Significant differences in durg-related grade 3-4 anemia (6.4% vs. 0.6%), neutropenia (5.8% vs. 0%), and fatigue (4.7% vs. 1.1%). Conclusion In patients with advanced nonsquamous non-small cell lung cancer who received four cycles of pemetrexed-cisplatin induction therapy, pemetrexed was superior to placebo with respect to overall survival. Reference Paz-Ares LG, de Marinis F, Dediu M et al. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. Open reference URL https://web.pathway.md/studies/recjo23JKqsHIwxKp 2/2

6/29/23, 1:34 AM PARIS-2 Pathway Feedback Search Clinical Topics Home Studies PARIS 2 PARIS 2 Disease Disease Bronchiolitis Community-acquired pneumonia Trial question What is the effect of early high-flow nasal oxygen therapy in hospitalized children with acute hypoxemic respiratory failure? Study design Multi-center Open label RCT Population Characteristics of study participants 48.0% female N = 1517 52.0% male 1517 patients (732 female, 785 male) Inclusion criteria: children aged 1-4 years requiring hospital admission for acute hypoxemic respiratory failure Key exclusion criteria: craniofacial abnormalities; upper airway obstruction; cyanotic heart disease; and requirement of immediate higher-level care in the ICU or noninvasive or invasive mechanical ventilation Interventions N=753 high-flow oxygen therapy (high-flow therapy with nasal cannula at weight-specific flows) N=764 standard oxygen therapy (oxygen using subnasal cannula with flows up to 2 L/min or using a Hudson face mask) https://web.pathway.md/studies/reczz5onufgiBpTuo 1/2 6/29/23, 1:34 AM PARIS-2 Pathway Primary outcome Median length of hospital stay 1.8 days 1.77 1.5 1.3 days 0.9 days 0.4 days Significant decrease 0.0 days High-flow oxygen therapy Standard oxygen therapy Significant decrease in median length of hospital stay (1.77 days vs. 1.5 days; HR 0.83, 95% CI 0.75 to 0.92) Secondary outcomes Borderline significant increase in median length of oxygen therapy (1.07 days vs. 0.75 days; HR 1.28, 95% CI 1.16 to 1.42) Borderline significant increase in escalation of care to ICU (12.5% vs. 6.9%; OR 1.93, 95% CI 1.35 to 2.75) Borderline significant increase in change in oxygen therapy in general ward or emergency department (42.9% vs. 18.5%; OR 3.42, 95% CI 2.7 to 4.34) Safety outcomes No significant difference in adverse events including death. Conclusion In children aged 1-4 years requiring hospital admission for acute hypoxemic respiratory failure, high- flow oxygen therapy was inferior to standard oxygen therapy with respect to median length of hospital stay. Reference Donna Franklin, Franz E Babl, Shane George et al. Effect of Early High-Flow Nasal Oxygen vs Standard Oxygen Therapy on Length of Hospital Stay in Hospitalized Children With Acute Hypoxemic Respiratory Failure The PARIS-2 Randomized Clinical Trial. JAMA. 2023 Jan 17;329(3):224-234. Open reference URL https://web.pathway.md/studies/reczz5onufgiBpTuo 2/2

6/29/23, 1:34 AM PART Pathway Feedback Search Clinical Topics Home Studies PART PART Disease Cardiac arrest Trial question What is the effect of a strategy of initial laryngeal tube insertion among adults with out-of-hospital cardiac arrest? Study design Multi-center Open label RCT Population Characteristics of study participants 39.0% female N = 3004 61.0% male 3004 patients (1175 female, 1829 male) Inclusion criteria: adults with out-of-hospital cardiac arrest and an anticipated need for advanced airway management Key exclusion criteria: advanced airway device inserted prior to participation, pre-existing tracheostomy, asphyxial cardiac arrest, LV assist device, or total artificial heart Interventions N=1505 laryngeal tube (insertion of a supraglottic airway as an initial airway management strategy) N=1499 endotracheal intubation (insertion of a plastic breathing tube through the mouth and into the trachea as initial airway management strategy) https://web.pathway.md/studies/recE01UbX5vsR1ofi 1/2 6/29/23, 1:34 AM PART Pathway Primary outcome Survival to 72 hour 18.3 % 18.3 15.4 13.7 % 9.2 % Significant increase 4.6 % NNT = 34 0.0 % Laryngeal tube Endotracheal intubation Significant increase in survival to 72 hour (18.3% vs. 15.4%; AD 2.9%, 95% CI 0.2 to 5.6) Secondary outcomes Significant increase in ROSC on emergency department arrival (27.9% vs. 24.3%; AD 3.6%, 95% CI 0.3 to 6.8) Significant increase in survival to hospital discharge (10.8% vs. 8.1%; AD 2.7%, 95% CI 0.6 to 4.8) Significant increase in favorable neurologic status at discharge, mRS score 3 (7.1% vs. 5%; AD 2.1%, 95% CI 0.3 to 3.8) Safety outcomes No significant differences in oropharyngeal or hypopharyngeal injury, airway swelling, pneumonia, aspiration pneumonitis. Significant differences in airway insertion attempts (4.5% vs. 18.9%), unsuccessful initial airway insertion (11.8% vs. 44.1%), pneumothoraces (3.5% vs. 7.0%), rib fractures (3.3% vs. 7.0%). Conclusion In adults with out-of-hospital cardiac arrest and an anticipated need for advanced airway management, laryngeal tube was superior to endotracheal intubation with respect to survival to 72 hour. Reference Henry E Wang, Robert H Schmicker, Mohamud R Daya et al. Effect of a Strategy of Initial Laryngeal Tube Insertion vs Endotracheal Intubation on 72-Hour Survival in Adults With Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2018 Aug 28;320(8):769-778. Open reference URL https://web.pathway.md/studies/recE01UbX5vsR1ofi 2/2

6/29/23, 1:34 AM PARTITA Pathway Feedback Search Clinical Topics Home Studies PARTITA PARTITA Disease Disease Dilated cardiomyopathy Ventricular arrhythmias Trial question What is the role of VT ablation in patients with an implantable cardioverter defibrillator? Study design Multi-center Open label RCT Population Characteristics of study participants 15.0% female N = 47 85.0% male 47 patients (7 female, 40 male) Inclusion criteria: patients with dilated cardiomyopathy who received implantable cardioverter defibrillator shock for VT Key exclusion criteria: contraindication to transcatheter ablation or antithrombotic therapy; chronic treatment with class I or class III antiarrhythmic drug Interventions N=23 ablation (VT ablation within 2 months of the implantable cardioverter defibrillator shock) N=24 standard therapy (continuation of standard therapy) Primary outcome Composite outcome of death from any cause or hospitalization for worsening heart failure https://web.pathway.md/studies/recUxIaM4ZCCvGJVr 1/2 6/29/23, 1:34 AM PARTITA Pathway 42.0 % 42 31.5 % 21.0 % Significant decrease 10.5 % NNT = 3 4 0.0 % Ablation Standard therapy Significant decrease in composite outcome of death from any cause or hospitalization for worsening HF (4% vs. 42%; HR 0.11, 95% CI 0.01 to 0.85) Secondary outcomes Significant decrease in death from all causes (ARD -33, 95% CI -55.44 to -10.56) Significant decrease in recurrent VT with shocks (9% vs. 42%; ARD -33, 95% CI -64.39 to -1.61) No significant difference in worsening HF hospitalization (4% vs. 17%; ARD -13, 95% CI -31.07 to 5.07) Conclusion In patients with dilated cardiomyopathy who received implantable cardioverter defibrillator shock for VT, ablation was superior to standard therapy with respect to the composite outcome of death from any cause or hospitalization for worsening HF. Reference Paolo Della Bella, Francesca Baratto, Pasquale Vergara et al. Does Timing of Ventricular Tachycardia Ablation Affect Prognosis in Patients With an Implantable Cardioverter Defibrillator? Results From the Multicenter Randomized PARTITA Trial. Circulation. 2022 Jun 21;145(25):1829- 1838. Open reference URL https://web.pathway.md/studies/recUxIaM4ZCCvGJVr 2/2

6/29/23, 1:34 AM PARTNER 2 Pathway Feedback Search Clinical Topics Home Studies PARTNER 2 PARTNER 2 Disease Aortic stenosis Trial question Is TAVR noninferior to SAVR in intermediate-risk patients with severe aortic stenosis? Study design Multi-center Open label RCT Population Characteristics of study participants 45.0% female N = 2032 55.0% male 2032 patients (924 female, 1108 male) Inclusion criteria: intermediate risk patients with severe aortic stenosis Key exclusion criteria: heart team assessment of inoperability, evidence of acute myocardial infarction 1 month, congenital unicuspid or bicuspid aortic valve, mixed aortic valve disease, preexisting mechanical or bioprosthetic valve, complex coronary artery disease, hypertrophic cardiomyopathy with or without obstruction, leukopenia, acute anemia, severe ventricular dysfunction Interventions N=1011 TAVR (transfemoral or transthoracic placement of SAPIEN XT valve system) N=1021 surgery (surgical aortic-valve replacement) https://web.pathway.md/studies/rec8kM8aIqu3xXcoU 1/2 6/29/23, 1:34 AM PARTNER 2 Pathway Primary outcome Death from all causes or disabling stroke at 2 years 21.1 % 21.1 19.3 15.8 % 10.6 % Difference not exceeding nonferiority margin 5.3 % 0.0 % Transcatheter aortic valve replacement Surgery Difference not exceeding nonferiority margin in death from all causes or disabling stroke at 2 years (19.3% vs. 21.1%; HR 0.89, 95% CI 0.73 to 1.09) Secondary outcomes No significant difference in death from any cause at 2 years (16.7% vs. 18%; RR 0.93, 95% CI -1.44 to 3.3) No significant difference in disabling stroke at 2 years (6.2% vs. 6.4%; RR 0.97, 95% CI -7.32 to 9.26) No significant difference in rehospitalization at 2 years (19.6% vs. 17.3%; RR 1.13, 95% CI -0.67 to 2.93) Safety outcomes Significant differences in major vascular complications (7.9% vs. 5.0%), life-threatening bleeding (10.4% vs. 43.4%), AKI (1.3% vs. 3.1%), and new-onset AF (9.1% vs. 26.4%) at 30 days. Conclusion In intermediate risk patients with severe aortic stenosis, TAVR was noninferior to surgery with respect to death from all causes or disabling stroke at 2 years. Reference Leon MB, Smith CR, Mack MJ et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med. 2016 Apr 28;374(17):1609-20. Open reference URL https://web.pathway.md/studies/rec8kM8aIqu3xXcoU 2/2

6/29/23, 1:34 AM PARTNER 3 Pathway Feedback Search Clinical Topics Home Studies PARTNER 3 PARTNER 3 Disease Aortic stenosis Trial question Is TAVR superior to SAVR in patients with severe aortic stenosis and low surgical risk? Study design Multi-center Open label RCT Population Characteristics of study participants 31.0% female N = 950 69.0% male 950 patients (292 female, 658 male) Inclusion criteria: patients with severe aortic stenosis who were at low risk of death with surgery Key exclusion criteria: clinical frailty, bicuspid aortic valves, or other anatomical features increasing the risk of complications Interventions N=496 TAVR (with a third-generation balloon-expandable valve) N=454 surgical AVR (with a bioprosthetic valve) Primary outcome Death, stroke or rehospitalization at 1 year 15.1 % 15.1 https://web.pathway.md/studies/rec0smfwYooXbcrmV 1/2 6/29/23, 1:34 AM PARTNER 3 Pathway 5 11.3 % 8.5 7.5 % Significant decrease 3.8 % NNT = 15 0.0 % Transcatheter aortic valve replacement Surgical AVR Significant decrease in death, stroke or rehospitalization at 1 year (8.5% vs. 15.1%; HR 0.54, 95% CI 0.37 to 0.79) Secondary outcomes Significant decrease in stroke (0.6% vs. 2.4%; HR 0.25, 95% CI 0.07 to 0.88) Significant decrease in death or stroke (1% vs. 3.3%; HR 0.3, 95% CI 0.11 to 0.83) Significant decrease in new-onset AF (5% vs. 39.5%; HR 0.1, 95% CI 0.06 to 0.16) Safety outcomes No significant differences in safety end points at 30 days, including major vascular complications and new permanent pacemaker insertions. Conclusion In patients with severe aortic stenosis who were at low risk of death with surgery, TAVR was superior to surgical AVR with respect to death, stroke or rehospitalization at 1 year. Reference Mack MJ, Leon MB, Thourani VH et al. Transcatheter Aortic-Valve Replacement with a Balloon- Expandable Valve in Low-Risk Patients. N Engl J Med. 2019 May 2;380(18):1695-1705. Open reference URL https://web.pathway.md/studies/rec0smfwYooXbcrmV 2/2

6/29/23, 1:34 AM PARTNER A Pathway Feedback Search Clinical Topics Home Studies PARTNER A PARTNER A Disease Aortic stenosis Trial question Is TAVR noninferior to SAVR in high-risk patients with severe aortic stenosis? Study design Multi-center Open label RCT Population Characteristics of study participants 43.0% female N = 699 57.0% male 699 patients (298 female, 399 male) Inclusion criteria: high-risk patients with severe aortic stenosis Key exclusion criteria: bicuspid or noncalcified valve, coronary artery disease requiring revascularization, LVEF < 20%, an aortic annulus diameter < 18 mm or > 25 mm, severe mitral or AR, recent neurologic event, and severe renal insufficiency Interventions N=348 TAVR (with a balloon-expandable bovine pericardial valve, either a transfemoral or a transapical approach) N=351 surgical AVR (surgical aortic-valve replacement) Primary outcome https://web.pathway.md/studies/rectjsOuwhfWTUJaZ 1/2 6/29/23, 1:34 AM PARTNER A Pathway Death at 1 year 26.8 % 26.8 24.2 20.1 % 13.4 % Difference not exceeding nonferiority margin 6.7 % 0.0 % Transcatheter aortic valve replacement Surgical AVR Difference not exceeding nonferiority margin in death at 1 year (24.2% vs. 26.8%; MD -2.6, 95% CI -9.3 to 4.1) Secondary outcomes Significant increase in major vascular complications, at 30 days (11% vs. 3.2%; ARD 7.8, 95% CI 3.17 to 12.43) Safety outcomes Significant differences in at 30 days, major bleeding (9.3% vs. 19.5%, p < 0.001) and new-onset AF (8.6% vs. 16.0%, p = 0.006). Conclusion In high-risk patients with severe aortic stenosis, TAVR was noninferior to surgical AVR with respect to death at 1 year. Reference Smith CR, Leon MB, Mack MJ et al. Transcatheter versus surgical aortic-valve replacement in high- risk patients. N Engl J Med. 2011 Jun 9;364(23):2187-98. Open reference URL https://web.pathway.md/studies/rectjsOuwhfWTUJaZ 2/2

6/29/23, 1:37 AM PARTNER B Pathway Feedback Search Clinical Topics Home Studies PARTNER B PARTNER B Disease Aortic stenosis Trial question What is the role of TAVI in patients with severe aortic stenosis who are not suitable candidates for surgical replacement of aortic valve? Study design Multi-center Open label RCT Population Characteristics of study participants 54.0% female N = 358 46.0% male 358 patients (192 female, 166 male) Inclusion criteria: patients with severe aortic stenosis, whom surgeons considered not to be suitable candidates for surgery Key exclusion criteria: bicuspid or noncalcified aortic valve, acute myocardial infarction, substantial coronary artery disease requiring revascularization, a LVEF < 20%, severe mitral or AR, TIA or stroke within the previous 6 months, and severe renal insufficiency Interventions N=179 TAVR (transfemoral transcatheter implantation of a balloon-expandable bovine pericardial valve) N=179 standard therapy (balloon aortic valvuloplasty plus adjunctive pharmacologic therapy) https://web.pathway.md/studies/recp7BCgy3t27jU5u 1/2 6/29/23, 1:37 AM PARTNER B Pathway Primary outcome Death at 1 year 50.7 % 50.7 38.0 % 30.7 25.4 % Significant decrease 12.7 % NNT = 5 0.0 % Transcatheter aortic valve replacement Standard therapy Significant decrease in death at 1 year (30.7% vs. 50.7%; HR 0.55, 95% CI 0.4 to 0.74) Secondary outcomes Significant decrease in death from any cause or repeat hospitalization (42.5% vs. 71.6%; HR 0.46, 95% CI 0.35 to 0.59) Significant decrease in death from cardiovascular causes at 1 year (20.5% vs. 44.6%; HR 0.39, 95% CI 0.27 to 0.56) Significant decrease in death from any cause or major stroke at 1 year (33% vs. 51.3%; HR 0.58, 95% CI 0.43 to 0.78) Safety outcomes Significant differences in major vascular complications (16.2% vs. 1.1%, p < 0.001). Conclusion In patients with severe aortic stenosis, whom surgeons considered not to be suitable candidates for surgery, TAVR was superior to standard therapy with respect to death at 1 year. Reference Leon MB, Smith CR, Mack M et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010 Oct 21;363(17):1597-607. Open reference URL https://web.pathway.md/studies/recp7BCgy3t27jU5u 2/2

6/29/23, 1:34 AM PARTNER Pathway Feedback Search Clinical Topics Home Studies PARTNER PARTNER Trial question What is the role of a family-support intervention delivered by the interprofessional ICU team among critically ill patients and their surrogates? Study design Multi-center Open label RCT Population Characteristics of study participants 49.0% female N = 1420 51.0% male 1420 patients (695 female, 725 male) Inclusion criteria: ICU patients with a high risk of death and their surrogates Key exclusion criteria: no surrogate decision-maker or receipt of only comfort-focused treatment, surrogates < 18 years of age, or unable to read or understand English Interventions N=547 family-support intervention (a multicomponent family-support intervention delivered by the interprofessional ICU team with 429 surrogates) N=873 control (usual care, with 677 surrogates) Primary outcome Surrogates' mean score on Hospital Anxiety and Depression Scale at 6 months 12.0 12 11.7 9.0 6.0 3.0 https://web.pathway.md/studies/recmC5YnAS1Todo8t 1/2 6/29/23, 1:34 AM PARTNER Pathway No significant difference 0.0 Family-support intervention Control No significant difference in surrogates' mean score on the Hospital Anxiety and Depression Scale at 6 months (11.7 vs. 12; AD -0.34, 95% CI -1.67 to 0.99) Secondary outcomes No significant difference in surrogates' mean scores on the Impact of Event Scale (21.2 vs. 20.3; AD 0.9, 95% CI -1.66 to 3.47) Significant increase in surrogates' mean Quality of Communication score (69.1 vs. 62.7; AD 6.39, 95% CI 2.57 to 10.2) Significant decrease in length of ICU stay (6.7 days vs. 7.4 days; IRR 0.9, 95% CI 0.81 to 1) Safety outcomes No significant differences in death at 6 months, living independently at home at 6 months. Significant differences in modified Patient Perception of Patient Centeredness score (1.7 vs. 1.8), death in the hospital (36.0% vs. 28.5%). Conclusion In ICU patients with a high risk of death and their surrogates, family-support intervention was not superior to control with respect to surrogates' mean score on the Hospital Anxiety and Depression Scale at 6 months. Reference Douglas B White, Derek C Angus, Anne-Marie Shields et al. A Randomized Trial of a Family- Support Intervention in Intensive Care Units. N Engl J Med. 2018 Jun 21;378(25):2365-2375. Open reference URL https://web.pathway.md/studies/recmC5YnAS1Todo8t 2/2

6/29/23, 1:37 AM PATCH Pathway Feedback Search Clinical Topics Home Studies PATCH PATCH DiseaseIntracerebral hemorrhage Trial question What is the role of platelet transfusion after acute spontaneous primary intracerebral hemorrhage in people taking antiplatelet therapy? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 190 59.0% male 190 patients (78 female, 112 male) Inclusion criteria: adult patients with supratentorial intracerebral hemorrhage who had used antiplatelet therapy for the last 7 days and had a Glasgow Coma Scale score 8 Key exclusion criteria: blood on brain imaging suggestive of epidural or subdural hematoma, or an underlying aneurysm or AVM; planned surgical evacuation of intracerebral hemorrhage within 24 h of admission; previous adverse reaction to platelet transfusion; history of coagulopathy; known thrombocytopenia; lacking mental capacity by national legal standards before intracerebral hemorrhage; or if death appeared imminent; infratentorial or large intraventricular hematomas Interventions https://web.pathway.md/studies/recYoUUTvSKo7hwfz 1/2 6/29/23, 1:37 AM PATCH Pathway N=97 platelet transfusion (1-2 platelet concentrates depending on the type of antiplatelet therapy; COX inhibitor or ADP receptor inhibitor plus standard care) N=93 standard care (standard care alone) Primary outcome Death or functional dependence at 3 months 72.0 % 72 56 54.0 % 36.0 % Significant increase 18.0 % NNH = 6 0.0 % Platelet transfusion Standard care Significant increase in death or functional dependence at 3 months (72% vs. 56%; aOR 2.05, 95% CI 1.18 to 3.56) Secondary outcomes No significant difference in survival at 3 months (68% vs. 77%; OR 0.62, 95% CI 0.33 to 1.19) No significant difference in poor outcome with mRS score 3-6 at 3 months (89% vs. 82%; OR 1.75, 95% CI 0.77 to 3.97) No significant difference in intracerebral hemorrhage growth at 24 hours (2.01 mL vs. 1.16 mL; AD 0.85 mL, 95% CI -5.66 to 7.36) Safety outcomes Significant difference in serious adverse events (42% vs. 29%) and death during hospital stay (24% vs. 17%). Conclusion In adult patients with supratentorial intracerebral hemorrhage who had used antiplatelet therapy for the last 7 days and had a Glasgow Coma Scale score 8, platelet transfusion was inferior to standard care with respect to death or functional dependence at 3 months. Reference Baharoglu MI, Cordonnier C, Salman RA et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016 Jun 25;387(10038):2605-2613. Open reference URL https://web.pathway.md/studies/recYoUUTvSKo7hwfz 2/2

6/29/23, 1:37 AM PATCH-I Pathway Feedback Search Clinical Topics Home Studies PATCH I PATCH I DiseaseCellulitis Trial question What is the role of low-dose penicillin in patients with recurrent cellulitis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 60.0% female N = 274 40.0% male 274 patients (165 female, 109 male) Inclusion criteria: patients with 2 episodes of cellulitis of the leg Key exclusion criteria: use of antibiotics for the prevention of cellulitis in the preceding 6 months; allergy to penicillin; previous leg ulceration, surgery, or penetrating trauma; an age of < 16 years Interventions N=136 penicillin (250 mg BID for 12 months) N=138 placebo (matching placebo BID for 12 months) Primary outcome First cellulitis recurrence, during prophylaxis phase 37.0 % 37 https://web.pathway.md/studies/recnIeCoObEtQdJcP 1/2 6/29/23, 1:37 AM PATCH-I Pathway 3 27.8 % 22 18.5 % Significant decrease 9.3 % NNT = 7 0.0 % Penicillin Placebo Significant decrease in first cellulitis recurrence, during the prophylaxis phase (22% vs. 37%; HR 0.55, 95% CI 0.35 to 0.86) Secondary outcomes No significant difference in first cellulitis recurrence, during the no-intervention follow-up period (27% vs. 27%; HR 1.08, 95% CI 0.61 to 1.93) Safety outcomes No significant differences in adverse events (37 vs. 48, p=0.50). Conclusion In patients with 2 episodes of cellulitis of the leg, penicillin was superior to placebo with respect to first cellulitis recurrence, during the prophylaxis phase. Reference Thomas KS, Crook AM, Nunn AJ et al. Penicillin to prevent recurrent leg cellulitis. N Engl J Med. 2013 May 2;368(18):1695-703. Open reference URL https://web.pathway.md/studies/recnIeCoObEtQdJcP 2/2

6/29/23, 1:37 AM PATHWAY-2 (spironolactone vs. bisoprolol) Pathway Feedback Search Clinical Topics Home Studies PATHWAY 2 (spironolactone vs. bisoprolol) PATHWAY 2 (spironolactone vs. bisoprolol) DiseaseHypertension Trial question Is spironolactone superior to add-on bisoprolol in patients with drug-resistant hypertension? Study design Multi-center Double blinded RCT Population Characteristics of study participants 31.0% female N = 335 69.0% male 335 patients (105 female, 230 male) Inclusion criteria: patients aged 18-79 years with seated clinic systolic BP 140 mmHg and home systolic BP 130 mmHg, despite treatment with maximally tolerated doses of 3 antihypertensive drugs for at least 3 months Key exclusion criteria: secondary/accelerated hypertension; T1DM; eGFR < 45 mL/min; sustained AF; non-adherence to antihypertensive treatment Interventions N=285 spironolactone (at a dose of 25 mg/day through week 6, forced uptitration to 50 mg/day through week 12) N=285 bisoprolol (at a dose of 5 mg/day through week 6, forced uptitration to 10 mg/day through week 12) https://web.pathway.md/studies/recUVUYxpWoOc5dBb 1/2 6/29/23, 1:37 AM PATHWAY-2 (spironolactone vs. bisoprolol) Pathway Primary outcome Reduction in home systolic blood pressure through week 6 to week 12 12.8 mmHg 12.8 9.6 mmHg 8.3 6.4 mmHg 3.2 mmHg Significant increase 0.0 mmHg Spironolactone Bisoprolol Significant increase in reduction in home systolic BP through week 6 to week 12 (12.8 mmHg vs. 8.3 mmHg; AD 4.48 mmHg, 95% CI 3.46 to 5.5) Secondary outcomes Significant increase in reduction in home systolic BP at week 12 (14.4 mmHg vs. 8.4 mmHg; AD 5.98 mmHg, 95% CI 4.51 to 7.45) Significant increase in reduction in seated clinic systolic BP through week 6 to week 12 (20.7 mmHg vs. 16.3 mmHg; AD 4.45 mmHg, 95% CI 3.11 to 5.8) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In patients aged 18-79 years with seated clinic systolic BP 140 mmHg and home systolic BP 130 mmHg, despite treatment with maximally tolerated doses of 3 antihypertensive drugs for at least 3 months, spironolactone was superior to bisoprolol with respect to reduction in home systolic BP through week 6 to week 12. Reference Bryan Williams, Thomas M MacDonald, Steve Morant et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015 Nov 21;386(10008):2059- 2068. Open reference URL https://web.pathway.md/studies/recUVUYxpWoOc5dBb 2/2

6/29/23, 1:37 AM PATHWAY-2 (spironolactone vs. doxazosin) Pathway Feedback Search Clinical Topics Home Studies PATHWAY 2 (spironolactone vs. doxazosin) PATHWAY 2 (spironolactone vs. doxazosin) DiseaseHypertension Trial question Is spironolactone superior to add-on doxazosin in patients with drug-resistant hypertension? Study design Multi-center Double blinded RCT Population Characteristics of study participants 31.0% female N = 335 69.0% male 335 patients (105 female, 230 male) Inclusion criteria: patients aged 18-79 years with seated clinic systolic BP 140 mmHg and home systolic BP 130 mmHg, despite treatment with maximally tolerated doses of 3 antihypertensive drugs for at least 3 months Key exclusion criteria: secondary/accelerated hypertension; T1DM; eGFR < 45 mL/min; sustained AF; non-adherence to antihypertensive treatment Interventions N=285 spironolactone (at a dose of 25 mg/day through week 6, forced uptitration to 50 mg/day through week 12) N=282 doxazosin (at a dose of 4 mg/day through week 6, forced uptitration to 8 mg/day through week 12) https://web.pathway.md/studies/recfEl7A9aHjWykQD 1/2 6/29/23, 1:37 AM PATHWAY-2 (spironolactone vs. doxazosin) Pathway Primary outcome Reduction in home systolic blood pressure through week 6 to week 12 12.8 mmHg 12.8 9.6 mmHg 8.7 6.4 mmHg 3.2 mmHg Significant increase 0.0 mmHg Spironolactone Doxazosin Significant increase in reduction in home systolic BP through week 6 to week 12 (12.8 mmHg vs. 8.7 mmHg; AD 4.03 mmHg, 95% CI 3.02 to 5.04) Secondary outcomes Significant increase in reduction in home systolic BP at week 12 (14.4 mmHg vs. 9.1 mmHg; AD 5.3 mmHg, 95% CI 3.83 to 6.77) Significant increase in reduction in seated clinic systolic BP through week 6 to week 12 (20.7 mmHg vs. 16.3 mmHg; AD 4.42 mmHg, 95% CI 3.09 to 5.75) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In patients aged 18-79 years with seated clinic systolic BP 140 mmHg and home systolic BP 130 mmHg, despite treatment with maximally tolerated doses of 3 antihypertensive drugs for at least 3 months, spironolactone was superior to doxazosin with respect to reduction in home systolic BP through week 6 to week 12. Reference Bryan Williams, Thomas M MacDonald, Steve Morant et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015 Nov 21;386(10008):2059- 2068. Open reference URL https://web.pathway.md/studies/recfEl7A9aHjWykQD 2/2

6/29/23, 1:37 AM PATHWAY-2 (spironolactone vs. placebo) Pathway Feedback Search Clinical Topics Home Studies PATHWAY 2 (spironolactone vs. placebo) PATHWAY 2 (spironolactone vs. placebo) DiseaseHypertension Trial question What is the role of add-on spironolactone in patients with drug-resistant hypertension? Study design Multi-center Double blinded RCT Population Characteristics of study participants 31.0% female N = 335 69.0% male 335 patients (105 female, 230 male) Inclusion criteria: patients aged 18-79 years with seated clinic systolic BP 140 mmHg and home systolic BP 130 mmHg, despite treatment with maximally tolerated doses of 3 antihypertensive drugs for at least 3 months Key exclusion criteria: secondary/accelerated hypertension; T1DM; eGFR < 45 mL/min; sustained AF; non-adherence to antihypertensive treatment Interventions N=285 spironolactone (at a dose of 25 mg/day through week 6, forced uptitration to 50 mg/day through week 12) N=274 placebo (matching placebo daily for 12 weeks) https://web.pathway.md/studies/recmySHyWd5uHSjys 1/2 6/29/23, 1:37 AM PATHWAY-2 (spironolactone vs. placebo) Pathway Primary outcome Reduction in home systolic blood pressure through week 6 to week 12 12.8 mmHg 12.8 9.6 mmHg 6.4 mmHg 4.1 3.2 mmHg Significant increase 0.0 mmHg Spironolactone Placebo Significant increase in reduction in home systolic BP through week 6 to week 12 (12.8 mmHg vs. 4.1 mmHg; AD 8.7 mmHg, 95% CI 7.69 to 9.72) Secondary outcomes Significant increase in reduction in home systolic BP at week 12 (14.4 mmHg vs. 4.2 mmHg; AD 10.2 mmHg, 95% CI 8.74 to 11.7) Significant increase in reduction in seated clinic systolic BP through week 6 to week 12 (20.7 mmHg vs. 10.8 mmHg; AD 9.92 mmHg, 95% CI 8.59 to 11.3) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In patients aged 18-79 years with seated clinic systolic BP 140 mmHg and home systolic BP 130 mmHg, despite treatment with maximally tolerated doses of 3 antihypertensive drugs for at least 3 months, spironolactone was superior to placebo with respect to reduction in home systolic BP through week 6 to week 12. Reference Bryan Williams, Thomas M MacDonald, Steve Morant et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015 Nov 21;386(10008):2059- 2068. Open reference URL https://web.pathway.md/studies/recmySHyWd5uHSjys 2/2

6/29/23, 1:37 AM PAUSE-SCD Pathway Feedback Search Clinical Topics Home Studies PAUSE SCD PAUSE SCD DiseaseDilated cardiomyopathy DiseaseHypertrophic cardiomyopathy DiseaseVentricula Trial question Is first-line catheter ablation therapy superior to conventional medical therapy in patients with cardiomyopathy of varied etiologies? Study design Multi-center Open label RCT Population Characteristics of study participants 19.0% female N = 121 81.0% male 121 patients (23 female, 98 male) Inclusion criteria: patients with cardiomyopathy and monomorphic VT with an indication for ICD implantation Key exclusion criteria: acute STEMI within 60 days; revascularization within 45 days; reversible causes of VT or cardiomyopathy; LVEF < 15%; HF; life expectancy < 1 year Interventions N=60 ablation therapy (early ablation therapy plus ICD implantation) N=61 conventional therapy (medical therapy plus ICD implantation) Primary outcome https://web.pathway.md/studies/rectLsXUcySv8vvSz 1/2 6/29/23, 1:37 AM PAUSE-SCD Pathway Composite outcome of ventricular tachycardia recurrence, cardiovascular hospitalization or death 65.5 % 65.5 49.1 % 49.3 32.8 % Significant decrease 16.4 % NNT = 6 0.0 % Ablation therapy Conventional therapy Significant decrease in composite outcome of VT recurrence, cardiovascular hospitalization or death (49.3% vs. 65.5%; HR 0.58, 95% CI 0.35 to 0.96) Secondary outcomes Significant decrease in VT recurrence (31.7% vs. 50.8%; HR 0.51, 95% CI 0.29 to 0.9) No significant difference in cardiovascular hospitalization (28.3% vs. 32.8%; HR 0.82, 95% CI 0.43 to 1.56) No significant difference in death from any cause (8.3% vs. 6.6%; HR 1.4, 95% CI 0.38 to 5.22) Safety outcomes Significant difference in ablation-related complications (8.3% vs. 0%). Conclusion In patients with cardiomyopathy and monomorphic VT with an indication for ICD implantation, ablation therapy was superior to conventional therapy with respect to the composite outcome of VT recurrence, cardiovascular hospitalization or death. Reference Roderick Tung, Yumei Xue, Minglong Chen et al. First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent with Defibrillator Implantation: The PAUSE- SCD Randomized Trial. Circulation. 2022 Jun 21;145(25):1839-1849. Open reference URL https://web.pathway.md/studies/rectLsXUcySv8vvSz 2/2

6/29/23, 1:37 AM PCPT Pathway Feedback Search Clinical Topics Home Studies PCPT PCPT DiseaseProstate cancer Trial question What is the role of finasteride on the development of prostate cancer? Study design Multi-center Double blinded RCT Population 18882 male patients Inclusion criteria: men 55 years with a normal DRE and PSA level 3.0 ng/mL Key exclusion criteria: PSA level > 3.0 ng/mL, previous prostate cancer, early termination of the study, or declined biopsy Interventions N=9423 finasteride (5 mg/day for 7 years) N=9459 placebo (matching placebo for 7 years) Primary outcome Prevalence of prostate cancer over the 7-year period 24.4 % 24.4 18.3 % 18.4 12.2 % Significant decrease 6.1 % NNT = 17 0.0 % Finasteride Placebo https://web.pathway.md/studies/recS6onWOWpiawLJf 1/2 6/29/23, 1:37 AM PCPT Pathway Significant decrease in the prevalence of prostate cancer over the 7-year period (18.4% vs. 24.4%; RR 0.75, 95% CI 0.69 to 0.81) Secondary outcomes Significant increase in tumors of Gleason grade 7, 8, 9, or 10 (6.4% vs. 5.1%; RR 1.27, 95% CI 1.07 to 1.5) Safety outcomes No significant difference in number of deaths (5 vs. 5). Significant difference in sexual side-effects more common in finasteride group (p < 0.001 for all comparisons) and urinary symptoms more common in placebo group (p < 0.001 for all comparisons). Conclusion In men 55 years with a normal DRE and PSA level 3.0 ng/mL, finasteride was superior to placebo with respect to the prevalence of prostate cancer over the 7-year period. Reference Thompson IM, Goodman PJ, Tangen CM et al. The influence of finasteride on the development of prostate cancer. N Engl J Med. 2003 Jul 17;349(3):215-24. Open reference URL https://web.pathway.md/studies/recS6onWOWpiawLJf 2/2

6/29/23, 1:37 AM PEITHO Pathway Feedback Search Clinical Topics Home Studies PEITHO PEITHO DiseaseDeep vein thrombosis DiseasePulmonary embolism Trial question What is the role of tenecteplase in normotensive patients with intermediate-risk PE? Study design Multi-center Double blinded RCT Population Characteristics of study participants 53.0% female N = 1006 47.0% male 1006 patients (532 female, 473 male) Inclusion criteria: normotensive patients with intermediate-risk PE Key exclusion criteria: significant bleeding risk, coagulation disorder, administration of thrombolytic agents within the previous 4 days, uncontrolled hypertension, hypersensitivity to tenecteplase, alteplase, UFH, or pregnancy, lactation or parturition within the previous 30 days Interventions N=506 tenecteplase (fibrinolysis received as a single weight-based intravenous bolus of 30-50 mg tenecteplase given over a period of 5-10 seconds) N=500 placebo (a single intravenous bolus of the same volume and appearance as the bolus of tenecteplase) https://web.pathway.md/studies/rec7JTIz3bAhJ6odR 1/2 6/29/23, 1:37 AM PEITHO Pathway Primary outcome Death or hemodynamic decompensation at 7 days 5.6 % 5.6 4.2 % 2.8 % 2.6 Significant decrease 1.4 % NNT = 33 0.0 % Tenecteplase Placebo Significant decrease in death or hemodynamic decompensation at 7 days (2.6% vs. 5.6%; OR 0.44, 95% CI 0.23 to 0.87) Secondary outcomes No significant difference in death at 7 days (1.2% vs. 1.8%; OR 0.65, 95% CI 0.23 to 1.85) Significant decrease in the rate of hemodynamic compensation within 7 days (1.6% vs. 5%; OR 0.3, 95% CI 0.14 to 0.68) No significant difference in death at 30 days (2.4% vs. 3.2%; OR 0.73, 95% CI 0.34 to 1.57) Safety outcomes Significant differences in extracranial bleeding (6.3% vs. 1.2%, p < 0.001) and stroke (2.4% vs. 0.2%, p = 0.003). Conclusion In normotensive patients with intermediate-risk PE, tenecteplase was superior to placebo with respect to death or hemodynamic decompensation at 7 days. Reference Meyer G, Vicaut E, Danays T et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. Open reference URL https://web.pathway.md/studies/rec7JTIz3bAhJ6odR 2/2

6/29/23, 1:37 AM PEPTIC Pathway Feedback Search Clinical Topics Home Studies PEPTIC PEPTIC DiseasePeptic ulcer disease Trial question What is the effect of proton pump inhibitors for stress ulcer prophylaxis among ICU patients receiving invasive mechanical ventilation? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 26982 64.0% male 26982 patients (9691 female, 17137 male) Inclusion criteria: patients requiring invasive mechanical ventilation within 24 hours of ICU admission Key exclusion criteria: ICU admission diagnosis of upper gastrointestinal bleeding, previous ICU admission Interventions N=13436 proton pump inhibitors (esomeprazole, pantoprazole, lansoprazole, omeprazole, rabeprazole, through all routes) N=13392 histamine-2 receptor blockers (ranitidine intravenous or enteral) https://web.pathway.md/studies/recgbW9JiBMhoko8d 1/2 6/29/23, 1:38 AM PEPTIC Pathway Primary outcome Rate of death in the hospital by day 90 18.3 % 18.3 17.5 13.7 % 9.2 % 4.6 % Borderline significant increase 0.0 % Proton pump inhibitors Histamine-2 receptor blockers Borderline significant increase in the rate of death in the hospital by day 90 (18.3% vs. 17.5%; RR 1.05, 95% CI 1 to 1.1) Secondary outcomes Significant decrease in clinically important upper gastrointestinal bleeding (1.3% vs. 1.8%; RR 0.73, 95% CI 0.57 to 0.92) No significant difference in C. difficile infection (0.3% vs. 0.43%; RR 0.74, 95% CI 0.51 to 1.09) No significant difference in hospital length of stay (12.2 days vs. 12 days; ROM 1.01, 95% CI 0.98 to 1.03) Safety outcomes No significant difference in allergic reactions or clinically important upper gastrointestinal bleeding. Conclusion In patients requiring invasive mechanical ventilation within 24 hours of ICU admission, proton pump inhibitors were inferior to histamine-2 receptor blockers with respect to the rate of death in the hospital by day 90. Reference PEPTIC Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group, Alberta Health Services Critical Care Strategic Clinical Network, and the Irish Critical Care Trials Group et al. Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial. JAMA. 2020 Feb 18;323(7):616-626. Open reference URL https://web.pathway.md/studies/recgbW9JiBMhoko8d 2/2

6/29/23, 1:37 AM PEXIVAS (corticosteroids) Pathway Feedback Search Clinical Topics Home Studies PEXIVAS (corticosteroids) PEXIVAS (corticosteroids) DiseaseEosinophilic granulomatosis wit DiseaseGranulomatosis with polyangiitis DiseaseMicroscop Trial question Is a reduced-dose regimen noninferior to a standard-dose regimen of oral corticosteroids in patients with severe ANCA-associated vasculitis? Study design Multi-center Open label RCT Population Characteristics of study participants 44.0% female 56.0% male 704 patients (307 female, 397 male) Inclusion criteria: patients with severe ANCA-associated vasculitis Key exclusion criteria: age < 15 years; treatment with > 30 mg/day of prednisone/prednisolone for > 14 days; diagnosis of vasculitis other than granulomatosis with polyangiitis or microscopic polyangiitis; pregnancy Interventions N=353 a reduced-dose corticosteroid regimen (dose reduction by approximately 50% of the standard regimen) N=351 a standard-dose corticosteroid regimen (no dose reduction) https://web.pathway.md/studies/recv6w0U8UAHRCD85 1/2 6/29/23, 1:37 AM PEXIVAS (corticosteroids) Pathway Primary outcome Composite outcome of death from any cause or end-stage kidney disease 27.9 % 27.9 25.5 20.9 % 13.9 % 7.0 % 0.0 % A reduced-dose corticosteroid regimen A standard-dose corticosteroid regimen Difference not exceeding nonferiority margin in composite outcome of death from any cause or end- stage kidney disease (27.9% vs. 25.5%; AD 2.3%, 95% CI -4.5 to 9.1) Safety outcomes No significant difference in serious adverse events. Significant difference in serious infections at 1 year (27.2% vs. 33.0%). Conclusion In patients with severe ANCA-associated vasculitis, a reduced-dose corticosteroid regimen was noninferior to a standard-dose corticosteroid regimen with respect to the composite outcome of death from any cause or end-stage kidney disease. Reference Michael Walsh, Peter A Merkel, Chen-Au Peh et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med. 2020 Feb 13;382(7):622-631. Open reference URL https://web.pathway.md/studies/recv6w0U8UAHRCD85 2/2

6/29/23, 1:37 AM PEXIVAS (plasmapheresis) Pathway Feedback Search Clinical Topics Home Studies PEXIVAS (plasmapheresis) PEXIVAS (plasmapheresis) DiseaseEosinophilic granulomatosis wit DiseaseGranulomatosis with polyangiitis DiseaseMicroscop Trial question What is the role of plasma exchange in patients with severe ANCA-associated vasculitis? Study design Multi-center Open label RCT Population Characteristics of study participants 44.0% female 56.0% male 704 patients (307 female, 397 male) Inclusion criteria: patients with severe ANCA-associated vasculitis Key exclusion criteria: age < 15 years; plasma exchange within 3 months' diagnosis of vasculitis; pregnancy Interventions N=352 plasma exchange (seven plasma exchanges within 14 days after randomization) N=352 no plasma exchange (no exchange of plasma) Primary outcome Composite outcome of death from any cause or end-stage kidney disease 31 https://web.pathway.md/studies/recImZqBZg1Kb2Iw4 1/2 6/29/23, 1:37 AM PEXIVAS (plasmapheresis) Pathway 3 31.0 % 28.4 23.3 % 15.5 % 7.8 % 0.0 % Plasma exchange No plasma exchange No significant difference in composite outcome of death from any cause or end-stage kidney disease (28.4% vs. 31%; HR 0.86, 95% CI 0.65 to 1.13) Safety outcomes No significant differences in serious adverse events, serious infections at 1 year. Conclusion In patients with severe ANCA-associated vasculitis, plasma exchange was not superior to no plasma exchange with respect to the composite outcome of death from any cause or end-stage kidney disease. Reference Michael Walsh, Peter A Merkel, Chen-Au Peh et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med. 2020 Feb 13;382(7):622-631. Open reference URL https://web.pathway.md/studies/recImZqBZg1Kb2Iw4 2/2

6/29/23, 1:37 AM PHARLAP Pathway Feedback Search Clinical Topics Home Studies PHARLAP PHARLAP DiseaseAcute respiratory distress syndr Trial question What is the role of maximal recruitment open lung ventilation in patients with ARDS? Study design Multi-center Open label RCT Population Characteristics of study participants 42.4% female N = 115 57.6% male 115 patients (48 female, 66 male) Inclusion criteria: adults patients with moderate to severe ARDS who were mechanically ventilated for < 72 hours Key exclusion criteria: ventilation for > 10 days; evidence of barotrauma; active bronchospasm or significant obstructive or restrictive pulmonary disease; any suspicion of raised ICP; unstable cardiovascular status Interventions N=58 PHARLAP intervention (maximal lung recruitment, titrated positive end expiratory pressure and further tidal volume limitation for up to the first 5 days) N=57 control (protective ventilation based on ARDS Network protocol) https://web.pathway.md/studies/rec1aKN7SfqJZ1uFr 1/2 6/29/23, 1:37 AM PHARLAP Pathway Primary outcome Ventilator-free days at day 28 16.0 days 16 14.5 12.0 days 8.0 days 4.0 days No significant difference 0.0 days PHARLAP intervention Control No significant difference in ventilator-free days at day 28 (16 days vs. 14.5 days; AD 1.5 days, 95% CI -41.26 to 44.26) Secondary outcomes No significant difference in death at day 28 (24.6% vs. 26.8%; ARD -2.2, 95% CI -17.47 to 13.07) No significant difference in length of stay in the ICU (11.1 days vs. 13.8 days; AD -2.7 days, 95% CI -15.4 to 10) No significant difference in length of hospital stay (20.1 days vs. 17.9 days; AD 2.2 days, 95% CI -13.82 to 18.22) Safety outcomes No significant differences in serious adverse events, barotrauma, pneumothorax requiring chest drain, bradycardia, severe hypotension. Significant differences in new cardiac arrhythmia (29% vs. 13%), new inhaled nitric oxide cases (10.3% vs. 28.6%), new ECMO (1.7% vs. 12.5%), new prone positioning cases (6.9% vs. 12.5%). Conclusion In adults patients with moderate to severe ARDS who were mechanically ventilated for < 72 hours, PHARLAP intervention was not superior to control with respect to a ventilator-free days at day 28. Reference Carol L Hodgson, D James Cooper, Yaseen Arabi et al. Maximal Recruitment Open Lung Ventilation in Acute Respiratory Distress Syndrome (PHARLAP). A Phase II, Multicenter Randomized Controlled Clinical Trial. Am J Respir Crit Care Med. 2019 Dec 1;200(11):1363-1372. Open reference URL https://web.pathway.md/studies/rec1aKN7SfqJZ1uFr 2/2

6/29/23, 1:37 AM PHOENIX Pathway Feedback Search Clinical Topics Home Studies PHOENIX PHOENIX Disease Preeclampsia Trial question Is planned early delivery superior to expectant management in women with late preterm preeclampsia? Study design Multi-center Open label RCT Population 901 female patients Inclusion criteria: women with late preterm preeclampsia from 34 to 37 weeks' gestation Key exclusion criteria: decision to deliver within the next 48 hours Interventions N=450 planned delivery (induction of labor, unless there was an additional specific indication for pre-labor C-section) N=451 expectant management (delivery at 37 weeks' gestation or sooner as clinical needs dictated) Primary outcome Composite outcome of maternal death and systolic blood pressure 160 mmHg 75.0 % 75 65 56.3 % 37.5 % Significant decrease 18.8 % NNT = 10 0 0 % https://web.pathway.md/studies/recSDzyqVyxGEXPJq 1/2 6/29/23, 1:37 AM 0.0 % PHOENIX Pathway Planned delivery Expectant management Significant decrease in composite outcome of maternal death and systolic BP 160 mmHg (65% vs. 75%; RR 0.86, 95% CI 0.79 to 0.94) Secondary outcomes Significant increase in composite outcome of neonatal deaths and perinatal deaths or neonatal unit admissions at 7 days (42% vs. 34%; RR 1.26, 95% CI 1.08 to 1.47) Borderline significant decrease in the percentage of patients who progressed to severe pre- eclampsia (64% vs. 74%; RR 0.86, 95% CI 0.79 to 0.94) Borderline significant decrease in maternal morbidity (15% vs. 20%; RR 0.76, 95% CI 0.59 to 0.98) Safety outcomes No significant difference in serious adverse events. Conclusion In women with late preterm preeclampsia from 34 to 37 weeks' gestation, planned delivery was superior to expectant management with respect to the composite outcome of maternal death and systolic BP 160 mmHg. Reference Lucy C Chappell, Peter Brocklehurst, Marcus E Green et al. Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial. Lancet. 2019 Sep 28;394(10204):1181-1190. Open reference URL https://web.pathway.md/studies/recSDzyqVyxGEXPJq 2/2

6/29/23, 1:37 AM PINETREE Pathway Feedback Search Clinical Topics Home Studies PINETREE PINETREE Disease COVID 19 infection Trial question What is the effect of remdesivir in nonhospitalized patients who are at high risk for COVID-19 progression? Study design Multi-center Double blinded RCT Population Characteristics of study participants 48.0% female N = 562 52.0% male 562 patients (269 female, 293 male) Inclusion criteria: nonhospitalized patients with COVID-19 who had at least one risk factor for disease progression Key exclusion criteria: receipt of supplemental oxygen or hospital care; previous hospitalization for COVID-19; previous treatment for COVID-19; receipt of SARS-CoV-2 vaccine Interventions N=279 remdesivir (intravenous dose of 200 mg on day 1 and 100 mg on day 2 and 3) N=283 placebo (matching placebo on day 1 to 3) Primary outcome https://web.pathway.md/studies/recDcKtjWoKdN8pR9 1/2 6/29/23, 1:37 AM PINETREE Pathway Hospitalization related to COVID-19 or death from any cause at day 28 5.3 % 5.3 4.0 % 2.6 % Significant decrease 1.3 % NNT = 22 0.7 0.0 % Remdesivir Placebo Significant decrease in hospitalization related to COVID-19 or death from any cause at day 28 (0.7% vs. 5.3%; HR 0.13, 95% CI 0.03 to 0.59) Secondary outcomes Borderline significant decrease in medically attended visit related to COVID-19 or death from any cause at day 28 (1.6% vs. 8.3%; HR 0.19, 95% CI 0.07 to 0.56) Borderline significant decrease in hospitalization for any cause at day 28 (1.8% vs. 6.4%; HR 0.28, 95% CI 0.1 to 0.75) No significant difference in alleviation of symptoms at day 14 (34.8% vs. 25%; RR 1.41, 95% CI 0.73 to 2.69) Safety outcomes No significant differences in adverse events, nasopharyngeal viral load at day 7. Conclusion In nonhospitalized patients with COVID-19 who had at least one risk factor for disease progression, remdesivir was superior to placebo with respect to hospitalization related to COVID-19 or death from any cause at day 28. Reference Robert L Gottlieb, Carlos E Vaca, Roger Paredes et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022 Jan 27;386(4):305-315. Open reference URL https://web.pathway.md/studies/recDcKtjWoKdN8pR9 2/2

6/29/23, 1:37 AM PIONEER AF-PCI (low-dose rivaroxaban) Pathway Feedback Search Clinical Topics Home Studies PIONEER AF PCI (low-dose rivaroxaban) PIONEER AF PCI (low-dose rivaroxaban) Disease Atrial fibrillation Trial question What is the role of low-dose rivaroxaban in patients with AF undergoing PCI? Study design Multi-center Open label RCT Population Characteristics of study participants 26.0% female N = 1415 74.0% male 1415 patients (369 female, 1046 male) Inclusion criteria: patients with nonvalvular AF who had undergone PCI with stenting Key exclusion criteria: history of stroke or TIA; clinically significant gastrointestinal bleeding within 12 months; calculated CrCl < 30 mL/min; increased risk of bleeding Interventions N=709 low-dose rivaroxaban (rivaroxaban 15 mg/day plus P2Y12 inhibitor for 12 months) N=706 standard therapy (standard therapy with a dose-adjusted vitamin K antagonist once daily plus dual antiplatelet therapy for 1, 6, or 12 months) Primary outcome Clinically significant bleeding https://web.pathway.md/studies/receAFVlfs8QcR8Hz 1/2 6/29/23, 1:37 AM PIONEER AF-PCI (low-dose rivaroxaban) Pathway 26.7 % 26.7 20.0 % 16.8 13.3 % Significant decrease 6.7 % NNT = 10 0.0 % Low-dose rivaroxaban Standard therapy Significant decrease in clinically significant bleeding (16.8% vs. 26.7%; HR 0.59, 95% CI 0.47 to 0.76) Secondary outcomes No significant difference in major adverse cardiovascular event (6.5% vs. 6%; HR 1.08, 95% CI 0.69 to 1.68) No significant difference in death from cardiovascular causes (2.4% vs. 1.9%; HR 1.29, 95% CI 0.59 to 2.8) No significant difference in stent thrombosis (0.8% vs. 0.7%; HR 1.2, 95% CI 0.32 to 4.45) Conclusion In patients with nonvalvular AF who had undergone PCI with stenting, low-dose rivaroxaban was superior to standard therapy with respect to clinically significant bleeding. Reference C Michael Gibson, Roxana Mehran, Christoph Bode et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016 Dec 22;375(25):2423-2434. Open reference URL https://web.pathway.md/studies/receAFVlfs8QcR8Hz 2/2

6/29/23, 1:37 AM PIONEER AF-PCI (very-low-dose rivaroxaban) Pathway Feedback Search Clinical Topics Home Studies PIONEER AF PCI (very-low-dose rivaroxaban) PIONEER AF PCI (very-low-dose rivaroxaban) Disease Atrial fibrillation Trial question What is the role of low-dose rivaroxaban in patients with AF undergoing PCI? Study design Multi-center Open label RCT Population Characteristics of study participants 26.0% female N = 1415 74.0% male 1415 patients (362 female, 1053 male) Inclusion criteria: patients with nonvalvular AF who had undergone PCI with stenting Key exclusion criteria: history of stroke or TIA; clinically significant gastrointestinal bleeding within 12 months; calculated CrCl < 30 mL/min; increased risk of bleeding Interventions N=709 very-low-dose rivaroxaban (rivaroxaban 2.5 mg BID plus dual antiplatelet therapy for 1, 6, or 12 months) N=706 standard therapy (standard therapy with a dose-adjusted vitamin K antagonist once daily plus dual antiplatelet therapy for 1, 6, or 12 months) Primary outcome https://web.pathway.md/studies/recB5ym1RfwexzGAE 1/2 6/29/23, 1:37 AM PIONEER AF-PCI (very-low-dose rivaroxaban) Pathway Clinically significant bleeding 26.7 % 26.7 20.0 % 18 13.3 % Significant decrease 6.7 % NNT = 11 0.0 % Very-low-dose rivaroxaban Standard therapy Significant decrease in clinically significant bleeding (18% vs. 26.7%; HR 0.63, 95% CI 0.5 to 0.8) Secondary outcomes No significant difference in major adverse cardiovascular event (5.6% vs. 6%; HR 0.93, 95% CI 0.59 to 1.48) No significant difference in death from cardiovascular causes (2.2% vs. 1.9%; HR 1.19, 95% CI 0.54 to 2.62) No significant difference in stent thrombosis (0.9% vs. 0.7%; HR 1.44, 95% CI 0.4 to 5.09) Conclusion In patients with nonvalvular AF who had undergone PCI with stenting, very-low-dose rivaroxaban was superior to standard therapy with respect to clinically significant bleeding. Reference C Michael Gibson, Roxana Mehran, Christoph Bode et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016 Dec 22;375(25):2423-2434. Open reference URL https://web.pathway.md/studies/recB5ym1RfwexzGAE 2/2

6/29/23, 1:39 AM PIOPED II Pathway Feedback Search Clinical Topics Home Studies PIOPED II PIOPED II Disease Disease Deep vein thrombosis Pulmonary embolism Reference Stein PD, Fowler SE, Goodman LR et al. Multidetector computed tomography for acute pulmonary embolism. N Engl J Med. 2006 Jun 1;354(22):2317-27. Open reference URL https://web.pathway.md/studies/recVdhQ7J0BmgG0tJ 1/1

6/29/23, 1:44 AM Pivetta Pathway Feedback Search Clinical Topics Home Studies Pivetta Pivetta Disease Heart failure Trial question What is the role of lung ultrasound integrated with clinical assessment in patients with acute decompensated HF in the emergency department? Study design Multi-center Open label RCT Population Characteristics of study participants 47.0% female N = 518 53.0% male 518 patients (241 female, 277 male) Inclusion criteria: adult patients who presented to the emergency department with acute dyspnea Key exclusion criteria: mechanical ventilation with positive pressure, either invasively or non invasively, at the time of first evaluation, or presentation with acute dyspnea in the context of trauma Interventions N=258 LUS (lung ultrasound with clinical assessment) N=260 CXR/NT-proBNP (chest radiography and level of N-terminal pro-B-type natriuretic peptide with clinical evaluation) https://web.pathway.md/studies/recDjgxNZEyHuHKGz 1/2 6/29/23, 1:45 AM Pivetta Pathway Primary outcome Diagnostic accuracy, area under receiver operating characteristic curve 94.5 % 94.5 87.2 70.9 % 47.3 % Significant increase 23.6 % NNH = 14 0.0 % LUS CXR/NT-proBNP Significant increase in diagnostic accuracy, area under the receiver operating characteristic curve (94.5% vs. 87.2%; AD 7.3%, 95% CI 1.74 to 12.86) Secondary outcomes Significant decrease in median time needed to formulate the diagnostic hypothesis (5 min vs. 104.5 min; AD -99.5 min, 95% CI -175.23 to -23.77) Safety outcomes No significant difference in death in the hospital. Conclusion In adult patients who presented to the emergency department with acute dyspnea, LUS was superior to CXR/NT-proBNP with respect to diagnostic accuracy, area under the receiver operating characteristic curve. Reference Emanuele Pivetta, Alberto Goffi, Peiman Nazerian et al. Lung ultrasound integrated with clinical assessment for the diagnosis of acute decompensated heart failure in the emergency department: a randomized controlled trial. Eur J Heart Fail. 2019 Jun;21(6):754-766. Open reference URL https://web.pathway.md/studies/recDjgxNZEyHuHKGz 2/2

6/29/23, 1:37 AM PLACIDE Pathway Feedback Search Clinical Topics Home Studies PLACIDE PLACIDE Disease Clostridioides difficile infection Trial question What is the role of multistrain preparation of lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhea and C. difficile diarrhea in older patients? Study design Multi-center Double blinded RCT Population Characteristics of study participants 52.9% female N = 17420 47.1% male 17420 patients (1485 female, 1456 male) Inclusion criteria: inpatients 65 years of age and exposed to 1 oral or parenteral antibiotics Key exclusion criteria: existing diarrhea, immunocompromised, active IBD, suspected acute pancreatitis, illness needing high dependency or intensive care, prosthetic heart valve, CDD in the previous 3 months Interventions N=1493 microbial preparation (multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 10(10) organisms, one capsule per day for 21 days) N=1488 placebo (identical placebo, one capsule per day for 21 days) https://web.pathway.md/studies/recVxW6rNqtnnW56P 1/2 6/29/23, 1:37 AM PLACIDE Pathway Primary outcome Antibiotic-associated diarrhea 10.8 % 10.8 10.4 8.1 % 5.4 % 2.7 % No significant difference 0.0 % Microbial preparation Placebo No significant difference in antibiotic-associated diarrhea (10.8% vs. 10.4%; RR 1.04, 95% CI 0.84 to 1.28) Secondary outcomes No significant difference in C. difficile diarrhea (0.8% vs. 1.2%; RR 0.71, 95% CI 0.34 to 1.47) Safety outcomes No significant difference in serious adverse events. Conclusion In inpatients 65 years of age and exposed to 1 oral or parenteral antibiotics, microbial preparation was not superior to placebo with respect to a antibiotic-associated diarrhea. Reference Allen SJ, Wareham K, Wang D et al. Lactobacilli and bifidobacteria in the prevention of antibiotic- associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2013 Oct 12;382(9900):1249-57. Open reference URL https://web.pathway.md/studies/recVxW6rNqtnnW56P 2/2

6/29/23, 1:45 AM PlasmAr Study Pathway Feedback Search Clinical Topics Home Studies PlasmAr Study PlasmAr Study Disease COVID 19 infection Trial question What is the role of convalescent plasma in severe COVID-19 pneumonia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 32.0% female N = 333 68.0% male 333 patients (108 female, 225 male) Inclusion criteria: hospitalized adult patients with severe COVID-19 pneumonia Key exclusion criteria: pregnancy or lactation, a history of blood component allergies, an infectious cause of pneumonia other than Coronavirus 2019, a requirement for mechanical ventilation, multiorgan failure Interventions N=228 convalescent plasma (a single administration of a median titer of 1:3200 of total Coronavirus 2019 antibodies plus standard treatment) N=105 placebo (normal saline solution plus standard treatment) Primary outcome https://web.pathway.md/studies/recTRahzRHsoBxA1o 1/2 6/29/23, 1:45 AM PlasmAr Study Pathway Death at 30 days 11.4 % 11.43 10.96 8.6 % 5.7 % 2.9 % No significant difference 0.0 % Convalescent plasma Placebo No significant difference in death at 30 days (10.96% vs. 11.43%; ARD -0.46, 95% CI -7.8 to 6.8) Secondary outcomes No significant difference in median time from intervention to hospital discharge (13 days vs. 12 days; subHR 0.99, 99% CI 0.75 to 1.32) Safety outcomes No significant difference in overall adverse events and serious adverse events. Significant difference in infusion-related adverse events (4.8% vs. 1.9%) and nonhemolytic febrile reactions (2.2% vs. 0%). Conclusion In hospitalized adult patients with severe COVID-19 pneumonia, convalescent plasma was not superior to placebo with respect to death at 30 days. Reference Ventura A Simonovich, Leandro D Burgos Pratx, Paula Scibona et al. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med. 2021 Feb 18;384(7):619-629. Open reference URL https://web.pathway.md/studies/recTRahzRHsoBxA1o 2/2

6/29/23, 1:44 AM PlasmAr Pathway Feedback Search Clinical Topics Home Studies PlasmAr PlasmAr Disease COVID 19 infection Trial question What is the role of convalescent plasma in severe coronavirus 2019 pneumonia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 32.3% female N = 334 67.7% male 334 patients (108 female, 225 male) Inclusion criteria: hospitalized adult patients with SARS-CoV-2 pneumonia Key exclusion criteria: pregnancy or lactation, a history of blood component allergies, an infectious cause of pneumonia other than SARS-CoV-2, requirement for mechanical ventilation, multiorgan failure Interventions N=228 convalescent plasma (a single administration of COVID-19 convalescent plasma in addition to standard treatment) N=105 placebo (normal saline solution plus standard treatment) Primary outcome https://web.pathway.md/studies/recnWm7mteXf0uurD 1/2 6/29/23, 1:44 AM PlasmAr Pathway Death at 30 days 11.4 % 11.43 10.96 8.6 % 5.7 % 2.9 % No significant difference 0.0 % Convalescent plasma Placebo No significant difference in death at 30 days (10.96% vs. 11.43%; ARD -0.46, 95% CI -7.8 to 6.8) Secondary outcomes No significant difference in median time from intervention to hospital discharge (13 days vs. 12 days; subHR 0.99, 99% CI 0.75 to 1.32) No significant difference in median time from intervention to complete restoration of physical functions (15 days vs. 15 days; subHR 0.89, 95% CI 0.66 to 1.18) Safety outcomes No significant difference in adverse and serious adverse events. Significant difference in infusion-related adverse events (4.8% vs. 1.9%). Conclusion In hospitalized adult patients with SARS-CoV-2 pneumonia, convalescent plasma was not superior to placebo with respect to death at 30 days. Reference Ventura A Simonovich, Leandro D Burgos Pratx, Paula Scibona et al. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med. 2021 Feb 18;384(7):619-629. Open reference URL https://web.pathway.md/studies/recnWm7mteXf0uurD 2/2

6/29/23, 1:37 AM PLATO Pathway Feedback Search Clinical Topics Home Studies PLATO PLATO Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the effect of ticagrelor in patients with acute coronary syndromes? Study design Multi-center Double blinded RCT Population Characteristics of study participants 28.0% female N = 18624 72.0% male 18624 patients (5288 female, 13336 male) Inclusion criteria: patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation Key exclusion criteria: any contraindication against the use of clopidogrel, fibrinolytic therapy within 24 hours before randomization, need for oral anticoagulation therapy, increased risk of bradycardia, and concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer Interventions N=9333 ticagrelor (180 mg loading dose, 90 mg BID thereafter) N=9291 clopidogrel (300-600 mg loading dose, 75 mg daily thereafter) Primary outcome https://web.pathway.md/studies/recW5ucFTXxg5RJCQ 1/2 6/29/23, 1:37 AM PLATO Pathway Death from vascular causes, myocardial infarction, or stroke 11.7 % 11.7 9.8 8.8 % 5.8 % Significant decrease 2.9 % NNT = 53 0.0 % Ticagrelor Clopidogrel Significant decrease in death from vascular causes, myocardial infarction, or stroke (9.8% vs. 11.7%; HR 0.84, 95% CI 0.77 to 0.92) Secondary outcomes Significant decrease in myocardial infarction (5.8% vs. 6.9%; HR 0.84, 95% CI 0.75 to 0.95) Significant decrease in death from vascular causes (4% vs. 5.1%; HR 0.79, 95% CI 0.69 to 0.91) Significant decrease in death from any cause (4.5% vs. 5.9%; HR 0.78, 95% CI 0.69 to 0.89) Safety outcomes No significant differences in rates of major bleeding (11.6% vs. 11.2%, p=0.43). Significant differences in rates of major bleeding not related to CABG (4.5% vs. 3.8%, p = 0.03). Conclusion In patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation, ticagrelor was superior to clopidogrel with respect to death from vascular causes, myocardial infarction, or stroke. Reference Wallentin L, Becker RC, Budaj A et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. Open reference URL https://web.pathway.md/studies/recW5ucFTXxg5RJCQ 2/2

6/29/23, 1:38 AM PLUS Pathway Feedback Search Clinical Topics Home Studies PLUS PLUS Trial question What is the role of balanced multielectrolyte solution in critically ill patients in the ICU? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.0% female N = 5037 61.0% male 5037 patients (1948 female, 3089 male) Inclusion criteria: critically ill patients Key exclusion criteria: specific fluid requirements; receipt of > 500 mL of fluid resuscitation; imminent risk of death or a preexisting life expectancy < 90 days; TBI or at risk for cerebral edema Interventions N=2515 balanced multielectrolyte solution (Plasma-Lyte 148 for up to 90 days) N=2522 saline solution (0.9% sodium chloride) Primary outcome Death from any cause at day 90 22.0 % 22 21.8 16.5 % 11.0 % 5.5 % No significant difference 0.0 % https://web.pathway.md/studies/recRNCoqU7hX8yEh1 1/2 6/29/23, 1:38 AM PLUS Pathway Balanced multielectrolyte solution Saline solution No significant difference in death from any cause at day 90 (21.8% vs. 22%; OR 0.99, 99% CI 0.86 to 1.14) Secondary outcomes No significant difference in the percentage of patients who received new renal-replacement therapy (12.7% vs. 12.9%; OR 0.98, 95% CI 0.83 to 1.16) No significant difference in maximum elevation in serum creatinine level (0.41 mg/dL vs. 0.41 mg/dL; AD 0.01 mg/dL, 95% CI -0.05 to 0.06) No significant difference in days alive without mechanical ventilation (68.3 days vs. 68.2 days; AD 0.06 days, 95% CI -1.79 to 1.91) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In critically ill patients, balanced multielectrolyte solution was not superior to saline solution with respect to death from any cause at day 90. Reference Simon Finfer, Sharon Micallef, Naomi Hammond et al. Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults. N Engl J Med. 2022 Mar 3;386(9):815-826. Open reference URL https://web.pathway.md/studies/recRNCoqU7hX8yEh1 2/2

6/29/23, 1:44 AM PneumA Pathway Feedback Search Clinical Topics Home Studies PneumA PneumA Disease Ventilator-associated pneumonia Trial question What is the role of 8 days of antibiotic therapy in adults with ventilator-associated pneumonia ? Study design Multi-center Double blinded RCT Population Characteristics of study participants 28.0% female N = 401 72.0% male 401 patients (112 female, 289 male) Inclusion criteria: patients with ventilator-associated pneumonia by quantitative culture results of bronchoscopic specimens and who had received initial appropriate empirical antimicrobial therapy Key exclusion criteria: pregnancy, little chance of survival, neutropenia, concomitant stage 3 AIDS, or immunosuppression or long-term corticosteroid therapy Interventions N=197 antibiotic treatment for 8 days (8 days of antibiotic therapy) N=204 antibiotic treatment for 15 days (15 days of antibiotic therapy) Primary outcome Death at 28 days https://web.pathway.md/studies/recfB5N16EQLCTW4T 1/2 6/29/23, 1:45 AM PneumA Pathway 18.8 % 18.8 17.2 14.1 % 9.4 % 4.7 % No significant difference 0.0 % Antibiotic treatment for 8 days Antibiotic treatment for 15 days No significant difference in death at 28 days (18.8% vs. 17.2%; ARD 1.6, 90% CI -3.7 to 6.9) Secondary outcomes No significant difference in recurrent infections (28.9% vs. 26%; difference 2.9, 90% CI -3.2 to 9.1) Significant increase in mean (SD) antibiotic-free days (13.1 days vs. 8.7 days; MD 4.4, 95% CI 3.1 to 5.6) Significant increase in recurrent pulmonary infection (40.6% vs. 25.4%; MD 15.2, 90% CI 0.04 to 0.27) Conclusion In patients with ventilator-associated pneumonia by quantitative culture results of bronchoscopic specimens and who had received initial appropriate empirical antimicrobial therapy, antibiotic treatment for 8 days were not superior to antibiotic treatment for 15 days with respect to death at 28 days. Reference Chastre J, Wolff M, Fagon JY et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator- associated pneumonia in adults: a randomized trial. JAMA. 2003 Nov 19;290(19):2588-98. Open reference URL https://web.pathway.md/studies/recfB5N16EQLCTW4T 2/2

6/29/23, 1:41 AM POEM for achalasia Pathway Feedback Search Clinical Topics Home Studies POEM for achalasia POEM for achalasia Disease Achalasia Trial question Is POEM noninferior to laparoscopic Heller's myotomy in patients with idiopathic achalasia? Study design Multi-center Open label RCT Population Characteristics of study participants 42.0% female N = 221 58.0% male 221 patients (93 female, 128 male) Inclusion criteria: patients with symptomatic achalasia Key exclusion criteria: previous surgery of the stomach or esophagus, including surgical therapy of achalasia, diagnosis of secondary achalasia or other organic causes of dysphagia Interventions N=112 POEM (POEM) N=109 laparoscopic Heller's myotomy (LHM) Primary outcome Clinical success at 2 years 83 83.0 % 81 7 https://web.pathway.md/studies/rec4tAU7mcoMDGzmc 1/2 6/29/23, 1:41 AM 83.0 % POEM for achalasia Pathway 83 81.7 62.3 % 41.5 % Difference not exceeding nonferiority margin 20.8 % 0.0 % Peroral endoscopic myotomy Laparoscopic Heller's myotomy Difference not exceeding nonferiority margin in clinical success at 2 years (83% vs. 81.7%; ARD 1.4, 95% CI -8.7 to 11.4) Secondary outcomes Borderline significant increase in reflux esophagitis at 3 months (57% vs. 20%; OR 5.74, 95% CI 2.99 to 11) Safety outcomes No significant differences in serious adverse events (2.7% vs. 7.3%, absolute between-group difference, 4.6 percentage points; 95% CI, 1.1 to 10.4). Conclusion In patients with symptomatic achalasia, POEM was noninferior to laparoscopic Heller's myotomy with respect to clinical success at 2 years. Reference Werner YB, Hakanson B, Martinek J et al. Endoscopic or Surgical Myotomy in Patients with Idiopathic Achalasia. N Engl J Med. 2019 Dec 5;381(23):2219-2229. Open reference URL https://web.pathway.md/studies/rec4tAU7mcoMDGzmc 2/2

6/29/23, 1:41 AM POINT Pathway Feedback Search Clinical Topics Home Studies POINT POINT Disease Disease Acute ischemic stroke Transient ischemic attack Trial question What is the effect of combination antiplatelet therapy with clopidogrel and aspirin in patients with minor ischemic stroke or high-risk TIA? Study design Multi-center Double blinded RCT Population Characteristics of study participants 45.0% female N = 4881 55.0% male 4881 patients (2195 female, 2686 male) Inclusion criteria: patients with minor ischemic stroke or high-risk TIA Key exclusion criteria: thrombolytic therapy within 1 week before the event, candidates for thrombolysis, endovascular therapy, or endoarterectomy, planned use of antiplatelet therapy or anticoagulation therapy, contraindication to aspirin or clopidogrel Interventions N=2432 dual antiplatelet therapy (clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day plus aspirin at a dose of 50-325 mg per day) N=2449 aspirin alone (at a dose of 50-325 mg per day plus matched placebo) https://web.pathway.md/studies/recjAkRav6pzZJBeA 1/2 6/29/23, 1:41 AM POINT Pathway Primary outcome Major ischemic events at 90 days 6.5 % 6.5 5 4.9 % 3.3 % Significant decrease 1.6 % NNT = 67 0.0 % Dual antiplatelet therapy Aspirin alone Significant decrease in major ischemic events at 90 days (5% vs. 6.5%; HR 0.75, 95% CI 0.59 to 0.95) Secondary outcomes Significant decrease in ischemic stroke (4.6% vs. 6.3%; HR 0.72, 95% CI 0.56 to 0.92) Significant decrease in total ischemic or hemorrhagic stroke (4.8% vs. 6.4%; HR 0.74, 95% CI 0.58 to 0.94) No significant difference in ischemic stroke, myocardial infarction, death from ischemic vascular causes, or major hemorrhage (5.8% vs. 6.8%; HR 0.84, 95% CI 0.67 to 1.05) Safety outcomes No significant differences in the rates of hemorrhagic stroke, symptomatic intracerebral hemorrhage, or other symptomatic intracranial hemorrhage and death from hemorrhagic vascular causes. Significant differences in major hemorrhage (0.9% vs. 0.4%, p = 0.02; HR 2.32, 95% CI 1.10-4.87) and minor hemorrhage (1.6% vs. 0.5%, p = 0.002; HR 3.12, 95% CI 1.67-5.83. Conclusion In patients with minor ischemic stroke or high-risk TIA, dual antiplatelet therapy was superior to aspirin alone with respect to major ischemic events at 90 days. Reference Johnston SC, Easton JD, Farrant M et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med. 2018 Jul 19;379(3):215-225. Open reference URL https://web.pathway.md/studies/recjAkRav6pzZJBeA 2/2

6/29/23, 1:41 AM POISE Pathway Feedback Search Clinical Topics Home Studies POISE POISE Trial question What is the effect of ER metoprolol succinate in patients undergoing noncardiac surgery? Study design Multi-center Quadruple blinded RCT Population Characteristics of study participants 37.0% female N = 8351 63.0% male 8351 patients (3058 female, 5293 male) Inclusion criteria: patients with, or at risk of, atherosclerotic disease who were undergoing noncardiac surgery Key exclusion criteria: HR under 50 beats/min; second or third-degree heart block; asthma; receiving a -blocker; prior adverse reaction to a -blocker; CABG surgery in the preceding 5 years and no cardiac ischemia since Interventions N=4174 metoprolol succinate (oral ER 100 mg daily 2-4 hours before surgery) N=4177 placebo (matching placebo 2-4 hours before surgery) Primary outcome Cardiovascular death, nonfatal myocardial infarction, or nonfatal cardiac arrest, at 30 days 6.9 % 6.9 5.8 5.2 % 3.5 % Significant decrease 1.7 % https://web.pathway.md/studies/recoKxWyeRr3JstMn 1/2 6/29/23, 1:41 AM POISE Pathway NNT = 91 0.0 % Metoprolol succinate Placebo Significant decrease in cardiovascular death, nonfatal myocardial infarction, or nonfatal cardiac arrest, at 30 days (5.8% vs. 6.9%; HR 0.84, 95% CI 0.7 to 0.99) Secondary outcomes Significant decrease in myocardial infarction (4.2% vs. 5.7%; HR 0.73, 95% CI 0.6 to 0.89) Significant increase in death (3.1% vs. 2.3%; HR 1.33, 95% CI 1.03 to 1.74) Significant increase in stroke (1% vs. 0.5%; HR 2.17, 95% CI 1.26 to 3.74) Safety outcomes Significant differences in clinically significant hypotension (15.0% vs. 9.7%, p < 0.0001) and bradycardia (6.6% vs. 2.4%, p < 0.0001). Conclusion In patients with, or at risk of, atherosclerotic disease who were undergoing noncardiac surgery, metoprolol succinate was superior to placebo with respect to cardiovascular death, nonfatal myocardial infarction, or nonfatal cardiac arrest, at 30 days. Reference POISE Study Group, Devereaux PJ, Yang H et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008 May 31;371(9627):1839-47. Open reference URL https://web.pathway.md/studies/recoKxWyeRr3JstMn 2/2

6/29/23, 1:41 AM POISE-2 (aspirin) Pathway Feedback Search Clinical Topics Home Studies POISE 2 (aspirin) POISE 2 (aspirin) Disease Perioperative management of an Trial question What is the role of aspirin in patients undergoing noncardiac surgery? Study design Multi-center Double blinded RCT Population Characteristics of study participants 47.0% female N = 10010 53.0% male 10010 patients (4727 female, 5283 male) Inclusion criteria: patients undergoing noncardiac surgery who were at risk for vascular complications Key exclusion criteria: hypersensitivity or known allergy to aspirin, consumption of aspirin within 72 hours prior to surgery, systolic BP < 105 m Hg, active peptic ulcer disease or gastrointestinal bleeding within 6 weeks before surgery, undergoing intracranial surgery, carotid endarterectomy, or retinal surgery Interventions N=4998 aspirin (at a dose of 200 mg before surgery and continued daily at a dose of 100 mg for 30 days in the initiation stratum and for 7 days in the continuation stratum) N=5012 placebo (matching dose) https://web.pathway.md/studies/recr5nHBPuC6cDvAR 1/2 6/29/23, 1:41 AM POISE-2 (aspirin) Pathway Primary outcome Death or nonfatal myocardial infarction at 30 days 7.1 % 7.1 7 5.3 % 3.5 % 1.8 % No significant difference 0.0 % Aspirin Placebo No significant difference in death or nonfatal myocardial infarction at 30 days (7% vs. 7.1%; HR 0.99, 99% CI 0.86 to 1.15) Secondary outcomes No significant difference in myocardial infarction (6.2% vs. 6.3%; HR 0.98, 95% CI 0.84 to 1.15) Safety outcomes Significant differences in major bleeding (4.6% vs. 3.8%, p = 0.04; HR 1.23, 95% CI 1.01 - 1.49). Conclusion In patients undergoing noncardiac surgery who were at risk for vascular complications, aspirin was not superior to placebo with respect to death or nonfatal myocardial infarction at 30 days. Reference Devereaux PJ, Mrkobrada M, Sessler DI et al. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014 Apr 17;370(16):1494-503. Open reference URL https://web.pathway.md/studies/recr5nHBPuC6cDvAR 2/2

6/29/23, 1:41 AM POISE-2 (clonidine) Pathway Feedback Search Clinical Topics Home Studies POISE 2 (clonidine) POISE 2 (clonidine) Trial question What is the role of clonidine in patients undergoing noncardiac surgery? Study design Multi-center Double blinded RCT Population Characteristics of study participants 47.0% female N = 10010 53.0% male 10010 patients (4727 female, 5283 male) Inclusion criteria: patients with, or at risk for, atherosclerotic disease who were undergoing noncardiac surgery Key exclusion criteria: hypersensitivity or known allergy to clonidine, active peptic ulcer disease, intracranial hemorrhage in the 6 months before surgery, subarachnoid hemorrhage or epidural hematoma within 6 months, drug-eluting coronary stent < 1 year before surgery, or bare-metal coronary stent < 6 weeks before surgery Interventions N=5009 clonidine (0.2 mg/day just before surgery and continued until 72 hours after surgery) N=5001 placebo (matching placebo per day just before surgery and continued until 72 hours after surgery) Primary outcome Death or nonfatal myocardial infarction at 30 days 7.3 % 7.3 6.8 5.5 % 3 6 % https://web.pathway.md/studies/rec6i6FE7WW54rYT2 1/2 6/29/23, 1:41 AM 3.6 % POISE-2 (clonidine) Pathway 1.8 % No significant difference 0.0 % Clonidine Placebo No significant difference in death or nonfatal myocardial infarction at 30 days (7.3% vs. 6.8%; HR 1.08, 95% CI 0.93 to 1.26) Secondary outcomes No significant difference in death, nonfatal myocardial infarction, or nonfatal stroke (7.6% vs. 7%; HR 1.08, 95% CI 0.93 to 1.25) No significant difference in myocardial infarction (6.6% vs. 5.9%; HR 1.11, 95% CI 0.95 to 1.3) Significant increase in nonfatal cardiac arrest (0.3% vs. 0.1%; HR 3.2, 95% CI 1.17 to 8.73) Safety outcomes Significant differences in clinically important hypotension (47/6% vs. 37.1, p < 0.001) and clinically important bradycardia (12.0% vs. 8.1%, p < 0.001). Conclusion In patients with, or at risk for, atherosclerotic disease who were undergoing noncardiac surgery, clonidine was not superior to placebo with respect to death or nonfatal myocardial infarction at 30 days. Reference Devereaux PJ, Mrkobrada M, Sessler DI et al. Aspirin in patients undergoing noncardiac surgery. N Engl J Med. 2014 Apr 17;370(16):1494-503. Open reference URL https://web.pathway.md/studies/rec6i6FE7WW54rYT2 2/2

6/29/23, 1:41 AM POISE-3 Pathway Feedback Search Clinical Topics Home Studies POISE 3 POISE 3 Trial question What is the role of tranexamic acid in patients undergoing noncardiac surgery? Study design Multi-center Double blinded RCT Population Characteristics of study participants 44.0% female N = 9535 56.0% male 9535 patients (4183 female, 5350 male) Inclusion criteria: adult patients undergoing noncardiac surgery Key exclusion criteria: patients undergoing cardiac surgery or cranial neurosurgery; use of systemic tranexamic acid during surgery; CrCl < 30 ml/min; receipt of long-term dialysis Interventions N=4757 tranexamic acid (1 g intravenous bolus at the start and end of surgery) N=4778 placebo (1 g 0.9% normal saline at the start and end of the surgery) Primary outcome Composite outcome of life-threatening bleeding, major bleeding, or bleeding into a critical organ at 30 days 11.7 % 11.7 9.1 8.8 % 5.8 % Significant decrease 2.9 % NNT = 38 https://web.pathway.md/studies/rec3h33rCJR4eZQeu 1/2 6/29/23, 1:41 AM POISE-3 Pathway 0.0 % Tranexamic acid Placebo Significant decrease in composite outcome of life-threatening bleeding, major bleeding, or bleeding into a critical organ at 30 days (9.1% vs. 11.7%; HR 0.76, 95% CI 0.67 to 0.87) Secondary outcomes No significant difference in life-threatening bleeding (1.6% vs. 1.7%; HR 0.99, 99% CI 0.73 to 1.36) Borderline significant decrease in major bleeding (7.6% vs. 10.4%; HR 0.72, 95% CI 0.63 to 0.83) No significant difference in bleeding into a critical organ (0.3% vs. 0.4%; HR 0.57, 95% CI 0.28 to 1.16) Safety outcomes No significant difference in cardiovascular outcome event at 30 days. Conclusion In adult patients undergoing noncardiac surgery, tranexamic acid was superior to placebo with respect to the composite outcome of life-threatening bleeding, major bleeding, or bleeding into a critical organ at 30 days. Reference P J Devereaux, Maura Marcucci, Thomas W Painter et al. Tranexamic Acid in Patients Undergoing Noncardiac Surgery. N Engl J Med. 2022 May 26;386(21):1986-1997. Open reference URL https://web.pathway.md/studies/rec3h33rCJR4eZQeu 2/2

6/29/23, 1:41 AM POLAR Pathway Feedback Search Clinical Topics Home Studies POLAR POLAR Disease Traumatic brain injury Trial question What is the effect of early sustained prophylactic hypothermia among patients with severe TBI? Study design Multi-center Open label RCT Population Characteristics of study participants 19.6% female N = 511 80.4% male 511 patients (99 female, 401 male) Inclusion criteria: patients both out-of-hospital and in emergency departments after severe TBI Key exclusion criteria: significant bleeding suggested by systolic hypotension or sustained tachycardia, possible uncontrolled bleeding, Glasgow Coma Scale score of 3 and unreactive pupils Interventions N=266 hypothermia (targeting a core temperature of 33 C or 35 C if bleeding concerns persist) N=245 normothermia (the temperature target of 37 +- 0.5 degree Celsius) Primary outcome Favorable neurologic outcome, Glasgow Outcome Scale-Extended score of 5-8, at 6 months https://web.pathway.md/studies/rec0RdEBTgQLZH5Tc 1/2 6/29/23, 1:41 AM POLAR Pathway 49.1 % 49.1 48.8 36.8 % 24.6 % 12.3 % No significant difference 0.0 % Hypothermia Normothermia No significant difference in favorable neurologic outcome, Glasgow Outcome Scale-Extended score of 5-8, at 6 months (48.8% vs. 49.1%; RR 0.99, 99% CI 0.82 to 1.19) Secondary outcomes No significant difference in death in the hospital (20% vs. 18%; RR 1.11, 95% CI 0.77 to 1.6) No significant difference in death at 6 months (21.1% vs. 18.4%; RR 1.15, 95% CI 0.8 to 1.64) No significant difference in new or worsening intracranial bleeding (18.1% vs. 15.4%; RR 1.23, 95% CI 0.43 to 3.5) Safety outcomes No significant differences in bacteremia, pneumonia, new significant extracranial bleeding. Conclusion In patients both out-of-hospital and in emergency departments after severe TBI, hypothermia was not superior to normothermia with respect to favorable neurologic outcome, Glasgow Outcome Scale-Extended score of 5-8, at 6 months. Reference D James Cooper, Alistair D Nichol, Michael Bailey et al. Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial. JAMA. 2018 Dec 4;320(21):2211-2220. Open reference URL https://web.pathway.md/studies/rec0RdEBTgQLZH5Tc 2/2

6/29/23, 1:41 AM POP-UP Pathway Feedback Search Clinical Topics Home Studies POP UP POP UP Trial question What is the effect of pantoprazole for stress ulcer prophylaxis in critically ill patients? Study design Single center Double blinded RCT Population Characteristics of study participants 35.0% female N = 214 65.0% male 214 patients (74 female, 140 male) Inclusion criteria: mechanically ventilated critically ill patients suitable for enteral nutrition Key exclusion criteria: acid-suppressive therapy prior to admission, gastrointestinal bleeding, history of proven peptic ulcer disease, administration of > 100 mg daily of prednisolone (or equivalent of other corticosteroid), surgery on the upper gastrointestinal tract or cardiac surgery during the current hospital admission, or pregnancy Interventions N=106 pantoprazole (intravenous infusion of 40 mg in 10 mL of 0.9% saline) N=108 placebo (intravenous infusion of 10 mL of 0.9% saline) Primary outcome Death at 90 days 28.3 % 28.3 23.1 21.2 % 14.2 % 7.1 % https://web.pathway.md/studies/recB640GbRgzfl9QJ 1/2 6/29/23, 1:41 AM POP-UP Pathway No significant difference 0.0 % Pantoprazole Placebo No significant difference in death at 90 days (28.3% vs. 23.1%; aHR 1.68, 95% CI 0.97 to 2.9) Secondary outcomes No significant difference in length of hospital stay (16 days vs. 18 days; AD -2 days, 95% CI -26.07 to 22.07) Safety outcomes No significant differences in ventilator-associated pneumonia, overt bleeding. Conclusion In mechanically ventilated critically ill patients suitable for enteral nutrition, pantoprazole was not superior to placebo with respect to death at 90 days. Reference Selvanderan SP, Summers MJ, Finnis ME et al. Pantoprazole or Placebo for Stress Ulcer Prophylaxis (POP-UP): Randomized Double-Blind Exploratory Study. Crit Care Med. 2016 Oct;44(10):1842-50. Open reference URL https://web.pathway.md/studies/recB640GbRgzfl9QJ 2/2

6/29/23, 1:41 AM POPLAR Pathway Feedback Search Clinical Topics Home Studies POPLAR POPLAR Disease Non-small cell lung cancer Trial question What is the role of atezolizumab in patients with previously treated non-small cell lung cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 287 59.0% male 287 patients (118 female, 169 male) Inclusion criteria: patients with previously treated non-small cell lung cancer Key exclusion criteria: active or untreated CNS metastases, history of pneumonitis, autoimmune or chronic viral diseases, or previous treatment with docetaxel, CD137 agonists, anti-CTLA4, anti- PD-L1, or anti-PD-1 therapeutic antibodies, or PD-L1-PD-1 pathway-targeting agents Interventions N=144 atezolizumab (intravenous dosage of 1200 mg once every 3 weeks) N=143 atezolizumab (intravenous dosage of 75 mg/m once every 3 weeks) Primary outcome Overall survival https://web.pathway.md/studies/recbfmlgbL3W41z3j 1/2 6/29/23, 1:42 AM POPLAR Pathway 12.6 months 12.6 9.7 9.4 months 6.3 months 3.1 months Significant increase 0.0 months Atezolizumab Atezolizumab Significant increase in overall survival (12.6 months vs. 9.7 months; HR 1.37, 95% CI 1.01 to 1.89) Secondary outcomes No significant difference in progression-free survival (2.7 months vs. 3 months; HR 0.94, 95% CI 0.72 to 1.23) Safety outcomes Significant differences in treatment-related grade 3-4 adverse events (11% vs. 39%), discontinuation because of adverse events (8% vs. 22%), and death from treatment-related adverse event (< 1% vs. 2%). Conclusion In patients with previously treated non-small cell lung cancer, atezolizumab was superior to atezolizumab with respect to overall survival. Reference Fehrenbacher L, Spira A, Ballinger M et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016 Apr 30;387(10030):1837-46. Open reference URL https://web.pathway.md/studies/recbfmlgbL3W41z3j 2/2

6/29/23, 1:42 AM PORTEC-1 Pathway Feedback Search Clinical Topics Home Studies PORTEC 1 PORTEC 1 Disease Endometrial cancer Trial question What is the role of external beam pelvic radiotherapy in patients with endometrial carcinoma? Study design Multi-center Open label RCT Population 714 female patients Inclusion criteria: women with stage IC grade 1-2 or stage IB grade 2-3 endometrial carcinoma after surgery Key exclusion criteria: history of invasive cancer, except for basal cell carcinoma of the skin; receipt of chemotherapy; receipt of hormonal therapy; receipt of radiotherapy; interval of > 8 weeks between surgery and radiotherapy Interventions N=354 radiotherapy (external beam pelvic radiotherapy with a total dose of 46 Gy in 2 Gy daily fractions) N=360 no radiotherapy (no additional treatment after surgery) Primary outcome Locoregional recurrence at 15 years 15.5 15.5 % 11.6 % 7.8 % 5 8 https://web.pathway.md/studies/recifpQTOQacGu4Gl 1/2 6/29/23, 1:42 AM PORTEC-1 Pathway 5.8 Significant increase 3.9 % NNH = 10 0.0 % Radiotherapy No radiotherapy Significant increase in locoregional recurrence at 15 years (5.8% vs. 15.5%; HR 3.46, 95% CI 1.93 to 6.18) Secondary outcomes No significant difference in overall survival at 15 years (52% vs. 60%; ARD -8, 95% CI -18.62 to 2.62) No significant difference in failure-free survival at 15 years (50% vs. 54%; ARD -4, 95% CI -99.23 to 91.23) No significant difference in distant metastases at 15 years (9% vs. 7%; AD 2%, 95% CI -1.39 to 5.39) Safety outcomes No significant difference in second primary cancers. Conclusion In women with stage IC grade 1-2 or stage IB grade 2-3 endometrial carcinoma after surgery, radiotherapy was superior to no radiotherapy with respect to locoregional recurrence at 15 years. Reference Carien L Creutzberg, Remi A Nout, Marnix L M Lybeert et al. Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e631-8. Open reference URL https://web.pathway.md/studies/recifpQTOQacGu4Gl 2/2

6/29/23, 1:41 AM PORTEC-2 Pathway Feedback Search Clinical Topics Home Studies PORTEC 2 PORTEC 2 Disease Endometrial cancer Trial question Is vaginal brachytherapy superior to pelvic radiotherapy in women with high-intermediate risk endometrial carcinoma? Study design Multi-center Open label RCT Population 427 female patients Inclusion criteria: women with high-intermediate risk endometrial cancer Key exclusion criteria: serous or clear cell carcinoma; staging lymphadenectomy; > 8 weeks interval between surgery and radiotherapy; history of previous malignancy; previous radiotherapy, hormonal or chemotherapy; Crohn's disease or ulcerative colitis Interventions N=213 vaginal brachytherapy (total dose of 21 Gy in 3 fractions of 7 Gy, with an interval of 1 week) N=214 pelvic EBRT (total dose of 46 Gy in 2 Gy daily fractions, five times per week) Primary outcome Vaginal recurrence at 10 years 3.4 % 3.4 2.5 % 2.4 1.7 % 0 8 % https://web.pathway.md/studies/reczSweXimbJYpe8i 1/2 6/29/23, 1:41 AM 0.8 % PORTEC-2 Pathway No significant difference 0.0 % Vaginal brachytherapy Pelvic external beam radiotherapy No significant difference in vaginal recurrence at 10 years (3.4% vs. 2.4%; HR 1.42, 95% CI 0.45 to 4.46) Secondary outcomes Significant increase in pelvic recurrence at 10 years (6.3% vs. 0.9%; HR 6.65, 95% CI 1.5 to 29.48) No significant difference in distant metastases at 10 years (10.4% vs. 8.9%; HR 1.25, 95% CI 0.67 to 2.33) No significant difference in overall survival at 10 years (69.5% vs. 67.6%; HR 0.94, 95% CI 0.67 to 1.32) Conclusion In women with high-intermediate risk endometrial cancer, vaginal brachytherapy was not superior to pelvic EBRT with respect to vaginal recurrence at 10 years. Reference B G Wortman, C L Creutzberg, H Putter et al. Ten-year results of the PORTEC-2 trial for high- intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy. Br J Cancer. 2018 Oct;119(9):1067-1074. Open reference URL https://web.pathway.md/studies/reczSweXimbJYpe8i 2/2

6/29/23, 1:42 AM PORTEC-3 (post-hoc) Pathway Feedback Search Clinical Topics Home Studies PORTEC 3 (post-hoc) PORTEC 3 (post-hoc) Disease Endometrial cancer Trial question Is chemoradiotherapy superior to radiotherapy alone in women with high-risk endometrial cancer? Study design Multi-center Open label RCT Population 660 female patients Inclusion criteria: women with high-risk endometrial cancer Key exclusion criteria: uterine sarcoma or carcinosarcoma; previous malignancy, except for non- melanomatous skin cancer, within the past 10 years; previous pelvic radiotherapy; previous hormonal therapy or chemotherapy; bulky cervical involvement with radical hysterectomy Interventions N=330 chemoradiotherapy (two cycles of cisplatin 50 mg/m given IV during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m given IV) N=330 radiotherapy alone (48.6 Gy in 1.8 Gy fractions given on 5 days per week) Primary outcome Overall survival at 5 years 81.4 % 81.4 76.1 61.1 % 40.7 % Significant increase 20.4 % NNT = 19 0.0 % https://web.pathway.md/studies/recmhFJr2NOD81DfB 1/2 6/29/23, 1:42 AM PORTEC-3 (post-hoc) Pathway Chemoradiotherapy Radiotherapy alone Significant increase in overall survival at 5 years (81.4% vs. 76.1%; HR 1.43, 95% CI 1.03 to 1.96) Secondary outcomes Significant increase in failure-free survival at 5 years (76.5% vs. 69.1%; HR 1.43, 95% CI 1.06 to 1.92) Significant decrease in distant metastases as first site of recurrence (21.4% vs. 29.1%; HR 0.74, 95% CI 0.55 to 0.99) No significant difference in isolated pelvic recurrence as first site of recurrence (0.9% vs. 0.9%; HR 0.75, 95% CI 0.17 to 3.33) Safety outcomes No significant difference in grade 3 adverse events at 5 years. Significant differences in grade 2 or worse adverse events at 5 years (38% vs. 23%), persistence of sensory neuropathy (6% vs. 0%). Conclusion In women with high-risk endometrial cancer, chemoradiotherapy was superior to radiotherapy alone with respect to overall survival at 5 years. Reference Stephanie M de Boer, Melanie E Powell, Linda Mileshkin et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019 Sep;20(9):1273- 1285. Open reference URL https://web.pathway.md/studies/recmhFJr2NOD81DfB 2/2

6/29/23, 1:41 AM PORTEC-3 Pathway Feedback Search Clinical Topics Home Studies PORTEC 3 PORTEC 3 Disease Endometrial cancer Trial question Is adjuvant chemoradiotherapy superior to radiotherapy in women with high-risk endometrial cancer? Study design Multi-center Open label RCT Population 660 female patients Inclusion criteria: women with high-risk endometrial cancer Key exclusion criteria: uterine sarcoma; previous pelvic radiotherapy, hormonal therapy, or chemotherapy; bulky cervical involvement with radical hysterectomy; IBD; impaired renal or cardiac function Interventions N=330 chemoradiotherapy (radiotherapy plus chemotherapy consisting of two cycles of cisplatin 50 mg/m given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m ) N=330 radiotherapy (48.6 Gy in 1.8 Gy fractions given on 5 days per week) Primary outcome Overall survival at 5 years 81.8 % 81.8 76.7 61.3 % 40.9 % https://web.pathway.md/studies/recMdNYIB3HUpyuyA 1/2 6/29/23, 1:42 AM PORTEC-3 Pathway 20.4 % No significant difference 0.0 % Chemoradiotherapy Radiotherapy No significant difference in overall survival at 5 years (81.8% vs. 76.7%; HR 1.32, 95% CI 0.94 to 1.85) Secondary outcomes Significant increase in failure-free survival at 5 years (75.5% vs. 68.6%; HR 1.41, 95% CI 1.05 to 1.89) Significant decrease in pelvic recurrence (4.9% vs. 9.2%; HR 0.51, 95% CI 0.28 to 0.92) No significant difference in distant metastases (23.1% vs. 29.7%; HR 0.77, 95% CI 0.57 to 1.03) Safety outcomes No significant difference in hypertension. Significant differences in grade 3 or worse adverse events (60% vs. 12%), persistence of grade 2 neuropathy or worse at 3 years (8% vs. 1%). Conclusion In women with high-risk endometrial cancer, chemoradiotherapy was not superior to radiotherapy with respect to overall survival at 5 years. Reference Stephanie M de Boer, Melanie E Powell, Linda Mileshkin et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Mar;19(3):295- 309. Open reference URL https://web.pathway.md/studies/recMdNYIB3HUpyuyA 2/2

6/29/23, 1:42 AM POSEIDON (chemotherapy plus durvalumab and tremelimumab) Pathway Feedback Search Clinical Topics Home Studies POSEIDON (chemotherapy plus durvalumab and tremelimumab) POSEIDON (chemotherapy plus durvalumab and tremelimumab) Disease Non-small cell lung cancer Trial question What is the role of first-line tremelimumab plus durvalumab and chemotherapy in patients with metastatic non-small cell lung cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 23.0% female N = 675 77.0% male 675 patients (158 female, 517 male) Inclusion criteria: adult patients with epidermal growth factor receptor/ALK wild-type metastatic non-small cell lung cancer Key exclusion criteria: mixed small cell lung cancer and non-small cell lung cancer histology; autoimmune or inflammatory disorders; brain metastases or spinal cord compression; active infection Interventions N=338 tremelimumab plus durvalumab and chemotherapy (at a dose of 75 mg plus 1500 mg and platinum-based chemotherapy, respectively, for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose) https://web.pathway.md/studies/recTjXm9zwpK5xC8U 1/2 6/29/23, 1:42 AM POSEIDON (chemotherapy plus durvalumab and tremelimumab) Pathway N=337 chemotherapy (chemotherapy for up to six 21-day cycles with or without maintenance pemetrexed) Primary outcome Progression-free survival 6.2 months 6.2 4.8 4.7 months 3.1 months 1.6 months Significant increase 0.0 months Tremelimumab plus durvalumab and chemotherapy Chemotherapy Significant increase in progression-free survival (6.2 months vs. 4.8 months; HR 1.38, 95% CI 1.16 to 1.66) Secondary outcomes Significant increase in overall survival (14 months vs. 11.7 months; HR 1.29, 95% CI 1.08 to 1.53) Borderline significant increase in unconfirmed objective response rate (46.3% vs. 33.4%; OR 1.72, 95% CI 1.26 to 2.37) Safety outcomes No significant differences in adverse events, grade 3/4 treatment-related adverse events. Conclusion In adult patients with epidermal growth factor receptor/ALK wild-type metastatic non-small cell lung cancer, tremelimumab plus durvalumab and chemotherapy were superior to chemotherapy with respect to a progression-free survival. Reference Melissa L Johnson, Byoung Chul Cho, Alexander Luft et al. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small- Cell Lung Cancer: The Phase III POSEIDON Study. J Clin Oncol. 2022 Nov 3;JCO2200975. Open reference URL https://web.pathway.md/studies/recTjXm9zwpK5xC8U 2/2

6/29/23, 1:42 AM POSEIDON (chemotherapy plus durvalumab) Pathway Feedback Search Clinical Topics Home Studies POSEIDON (chemotherapy plus durvalumab) POSEIDON (chemotherapy plus durvalumab) Disease Non-small cell lung cancer Trial question What is the role of first-line durvalumab plus chemotherapy in patients with metastatic non-small cell lung cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 26.0% female N = 675 74.0% male 675 patients (174 female, 501 male) Inclusion criteria: adult patients with epidermal growth factor receptor/ALK wild-type metastatic non-small cell lung cancer Key exclusion criteria: mixed small cell lung cancer and non-small cell lung cancer histology; autoimmune or inflammatory disorders; brain metastases or spinal cord compression; active infection Interventions N=338 durvalumab plus chemotherapy (at a dose of 1500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression) https://web.pathway.md/studies/rec37I5uhTQ6CL2y7 1/2 6/29/23, 1:42 AM POSEIDON (chemotherapy plus durvalumab) Pathway N=337 chemotherapy (chemotherapy for up to six 21-day cycles with or without maintenance pemetrexed) Primary outcome Progression-free survival 5.5 months 5.5 4.8 4.1 months 2.8 months 1.4 months Significant increase 0.0 months Durvalumab plus chemotherapy Chemotherapy Significant increase in progression-free survival (5.5 months vs. 4.8 months; HR 1.35, 95% CI 1.12 to 1.61) Secondary outcomes No significant difference in overall survival (13.3 months vs. 11.7 months; HR 1.16, 95% CI 0.98 to 1.38) Borderline significant increase in unconfirmed objective response rate (48.5% vs. 33.4%; OR 1.9, 95% CI 1.38 to 2.62) Safety outcomes No significant difference in adverse events; grade 3/4 treatment-related adverse events. Conclusion In adult patients with epidermal growth factor receptor/ALK wild-type metastatic non-small cell lung cancer, durvalumab plus chemotherapy was superior to chemotherapy with respect to a progression-free survival. Reference Melissa L Johnson, Byoung Chul Cho, Alexander Luft et al. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small- Cell Lung Cancer: The Phase III POSEIDON Study. J Clin Oncol. 2022 Nov 3;JCO2200975. Open reference URL https://web.pathway.md/studies/rec37I5uhTQ6CL2y7 2/2

6/29/23, 1:41 AM PRAMI Pathway Feedback Search Clinical Topics Home Studies PRAMI PRAMI Disease Disease Coronary artery disease ST-elevation myocardial infarction Trial question What is the role of preventive PCI in patients with acute STEMI and multivessel coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 22.0% female N = 465 78.0% male 465 patients (102 female, 363 male) Inclusion criteria: acute STEMI (including 3 patients with left bundle-branch block) and multivessel coronary artery disease detected at the time of emergency infarct artery PCI Key exclusion criteria: cardiogenic shock, previous CABG, a noninfarct artery stenosis 50% in the left main stem or the ostia of both the left anterior descending and circumflex arteries, or if the only noninfarct stenosis was a chronic total occlusion Interventions N=234 preventive PCI (immediate preventive PCI in noninfarct arteries with > 50% stenoses) N=231 no preventive PCI (no further PCI procedures) https://web.pathway.md/studies/recv4HPpLFNU1bc2P 1/2 6/29/23, 1:41 AM PRAMI Pathway Primary outcome Death from cardiac causes, nonfatal myocardial infarction, or refractory angina 23.0 % 23 17.3 % 11.5 % 9 Significant decrease 5.8 % NNT = 7 0.0 % Preventive PCI No preventive percutaneous coronary intervention Significant decrease in death from cardiac causes, nonfatal myocardial infarction, or refractory angina (9% vs. 23%; HR 0.35, 95% CI 0.21 to 0.58) Secondary outcomes No significant difference in cardiovascular death (4 vs. 10; HR 0.34, 95% CI 0.11 to 1.08) Significant decrease in nonfatal myocardial infarction (7 vs. 20; HR 0.32, 95% CI 0.13 to 0.75) Significant decrease in refractory angina (12 vs. 30; HR 0.35, 95% CI 0.18 to 0.69) Conclusion In acute STEMI (including 3 patients with left bundle-branch block) and multivessel coronary artery disease detected at the time of emergency infarct artery PCI, preventive PCI was superior to no preventive PCI with respect to death from cardiac causes, nonfatal myocardial infarction, or refractory angina. Reference Wald DS, Morris JK, Wald NJ et al. Randomized trial of preventive angioplasty in myocardial infarction. N Engl J Med. 2013 Sep 19;369(12):1115-23. Open reference URL https://web.pathway.md/studies/recv4HPpLFNU1bc2P 2/2

6/29/23, 1:44 AM Prednisone in RIF Pathway Feedback Search Clinical Topics Home Studies Prednisone in RIF Prednisone in RIF Trial question What is the role of prednisone in patients with recurrent implantation failure undergoing IVF? Study design Multi-center Double blinded RCT Population 715 female patients Inclusion criteria: women who have undergone 2 embryo transfer cycles with good-quality embryos without achieving a clinical pregnancy Key exclusion criteria: autoimmune diseases; receipt of corticosteroids or immunosuppression medications; diagnosed diseases affecting the cavity; history of recurrent pregnancy loss Interventions N=357 prednisone (an oral dose of 10 mg/day) N=358 placebo (matching placebo once daily) Primary outcome Live birth 38.8 % 38.8 37.8 29.1 % 19.4 % 9.7 % No significant difference 0.0 % Prednisone Placebo No significant difference in live birth (37.8% vs. 38.8%; RR 0.97, 95% CI 0.81 to 1.17) Secondary outcomes Significant increase in biochemical pregnancy loss (17.3% vs. 9.9%; RR 1.75, 95% CI 1.03 to 2.99) https://web.pathway.md/studies/rec1cpyAkwZ5eZnjj 1/2 6/29/23, 1:44 AM Prednisone in RIF Pathway No significant difference in biochemical pregnancy (54.9% vs. 50.8%; RR 1.08, 95% CI 0.94 to 1.24) No significant difference in implantation (42.5% vs. 40.4%; RR 1.05, 95% CI 0.9 to 1.24) Safety outcomes No significant differences in neonatal complications, congenital anomalies, other adverse events. Significant difference in preterm delivery (11.8% vs. 5.5%). Conclusion In women who have undergone 2 embryo transfer cycles with good-quality embryos without achieving a clinical pregnancy, prednisone was not superior to placebo with respect to live birth. Reference Yun Sun, Linlin Cui, Yao Lu et al. Prednisone vs Placebo and Live Birth in Patients With Recurrent Implantation Failure Undergoing In Vitro Fertilization: A Randomized Clinical Trial. JAMA. 2023 May 2;329(17):1460-1468. Open reference URL https://web.pathway.md/studies/rec1cpyAkwZ5eZnjj 2/2

6/29/23, 1:44 AM PregnAnZI-2 Pathway Feedback Search Clinical Topics Home Studies PregnAnZI 2 PregnAnZI 2 Trial question What is the effect of intrapartum azithromycin on neonatal sepsis and death? Study design Multi-center Double blinded RCT Population 11625 female patients Inclusion criteria: birthing parents and their newborns Key exclusion criteria: human immunodeficiency virus infection, chronic or acute condition, planned cesarean delivery or known required referral, severe congenital malformation, allergy to macrolides, use in the last 2 weeks of drugs known to prolong the QT interval Interventions N=5802 azithromycin (an oral 2 g dose during labor) N=5823 placebo (matching placebo during labor) Primary outcome Neonatal sepsis or death 2.0 % 2 1.9 1.5 % 1.0 % 0.5 % No significant difference 0.0 % Azithromycin Placebo No significant difference in neonatal sepsis or death (2% vs. 1.9%; OR 1.06, 95% CI 0.8 to 1.38) Secondary outcomes No significant difference in neonatal death (0.8% vs. 0.8%; OR 1.05, 95% CI 0.7 to 1.6) Significant decrease in neonatal skin infections (0.8% vs. 1.7%; OR 0.48, 95% CI 0.34 to 0.67) https://web.pathway.md/studies/recILsV8NeS3IUYC0 1/2 6/29/23, 1:44 AM PregnAnZI-2 Pathway Significant decrease in mastitis among postpartum parents (0.3% vs. 0.5%; OR 0.53, 95% CI 0.29 to 0.98) Safety outcomes No significant difference in death and hospitalization for both parents and newborns. Significant differences in dizziness (4.4% vs. 5.3%), reported fever (0.8% vs. 1.3%), vomiting (10.1% vs. 6.1%), edema (4.2% vs. 3.2%) in birthing parents. Conclusion In birthing parents and their newborns, azithromycin was not superior to placebo with respect to neonatal sepsis or death. Reference Anna Roca, Bully Camara, Joel D Bognini et al. Effect of Intrapartum Azithromycin vs Placebo on Neonatal Sepsis and Death: A Randomized Clinical Trial. JAMA. 2023 Mar 7;329(9):716-724. Open reference URL https://web.pathway.md/studies/recILsV8NeS3IUYC0 2/2

6/29/23, 1:42 AM PREOXYFLOW Pathway Feedback Search Clinical Topics Home Studies PREOXYFLOW PREOXYFLOW Trial question What is the role of high-flow therapy by nasal cannula for preoxygenation in patients with acute hypoxemia? Study design Multi-center Open label RCT Population Characteristics of study participants 34.0% female N = 119 66.0% male 119 patients (41 female, 78 male) Inclusion criteria: adult patients with acute hypoxemia requiring intubation Key exclusion criteria: contraindication to orotracheal intubation; intubation without anesthetic rapid sequence induction; intubation for cardiac arrest; asphyxia requiring immediate intubation; nasopharyngeal obstacle; Grade 4 glottis exposure on the Cormack-Lehane scale Interventions N=62 high-flow nasal cannula (for preoxygenation before intubation) N=57 high fraction-inspired oxygen facial mask Primary outcome Oxygen saturation at its lowest during intubation procedure 91.5 % 91.5 89.5 68.6 % 45.8 % 22.9 % https://web.pathway.md/studies/rec73A27tcs9Vjako 1/2 6/29/23, 1:42 AM PREOXYFLOW Pathway No significant difference 0.0 % High-flow nasal cannula High fraction-inspired oxygen facial mask No significant difference in oxygen saturation at its lowest during the intubation procedure (91.5% vs. 89.5%; AD 2%, 95% CI -2.99 to 6.99) Secondary outcomes No significant difference in ventilator-free days (14 days vs. 5 days; AD 9 days, 95% CI -1.41 to 19.41) No significant difference in difficult intubation (1.6% vs. 7.1%; ARD -5.5, 95% CI -13.52 to 2.52) No significant difference in death at day 28 (35.4% vs. 42.1%; ARD -6.7, 95% CI -24.9 to 11.5) Safety outcomes No significant differences in ventilator-associated pneumonia, intubation-related adverse events including desaturation. Conclusion In adult patients with acute hypoxemia requiring intubation, high-flow nasal cannula was not superior to high fraction-inspired oxygen facial mask with respect to oxygen saturation at its lowest during the intubation procedure. Reference Micka l Vourc'h, Pierre Asfar, Christelle Volteau et al. High-flow nasal cannula oxygen during endotracheal intubation in hypoxemic patients: a randomized controlled clinical trial. Intensive Care Med. 2015 Sep;41(9):1538-48. Open reference URL https://web.pathway.md/studies/rec73A27tcs9Vjako 2/2

6/29/23, 1:42 AM PREPARE II Pathway Feedback Search Clinical Topics Home Studies PREPARE II PREPARE II Trial question What is the effect of fluid bolus administration in critically ill adults undergoing tracheal intubation? Study design Multi-center Open label RCT Population Characteristics of study participants 42.0% female N = 1065 58.0% male 1065 patients (448 female, 617 male) Inclusion criteria: critically ill adults undergoing tracheal intubation with sedation and positive pressure ventilation Key exclusion criteria: immediate need for tracheal intubation precluding randomization; indication or contraindication for fluid bolus administration Interventions N=538 fluid bolus (500 mL intravenous infusion of isotonic crystalloid solution of the clinician's choice) N=527 no fluid bolus (initiation of a new intravenous fluid bolus not permitted except as treatment for hypotension) Primary outcome Cardiovascular collapse 21.0 % 21 18.2 15.8 % 10.5 % https://web.pathway.md/studies/reconuVj1tPPmN6Jc 1/2 6/29/23, 1:42 AM PREPARE II Pathway No significant difference 5.3 % 0.0 % Fluid bolus No fluid bolus No significant difference in cardiovascular collapse (21% vs. 18.2%; AD 2.8%, 95% CI -2.2 to 7.7) Secondary outcomes No significant difference in the rate of death prior to day 28 (40.5% vs. 42.3%; ARD -1.8, 95% CI -7.9 to 4.3) No significant difference in severe hypoxemia (14.9% vs. 13.7%; AD 1.2%, 95% CI -3.3 to 5.6) No significant difference in median invasive mechanical ventilation-free days through day 28 (14 days vs. 12 days; MD 2, 95% CI -10 to 15) Conclusion In critically ill adults undergoing tracheal intubation with sedation and positive pressure ventilation, fluid bolus were not superior to no fluid bolus with respect to cardiovascular collapse. Reference Derek W Russell, Jonathan D Casey, Kevin W Gibbs et al. Effect of Fluid Bolus Administration on Cardiovascular Collapse Among Critically Ill Patients Undergoing Tracheal Intubation: A Randomized Clinical Trial. JAMA. 2022 Jul 19;328(3):270-279. Open reference URL https://web.pathway.md/studies/reconuVj1tPPmN6Jc 2/2

6/29/23, 1:42 AM PREPARE Pathway Feedback Search Clinical Topics Home Studies PREPARE PREPARE Disease Asthma Trial question What is the role of patient-activated reliever-triggered ICS therapy in Black and Latinx adults with asthma? Study design Multi-center Open label RCT Population Characteristics of study participants 84.0% female N = 1201 16.0% male 1201 patients (1005 female, 196 male) Inclusion criteria: Black and Latinx adults with moderate-to-severe asthma Key exclusion criteria: being prescribed daily inhaled glucocorticoids; uncontrolled asthma; previous asthma exacerbation leading to the use of systemic glucocorticoids or overnight hospitalization Interventions N=600 reliever-triggered ICS (80 g beclomethasone dipropionate plus usual care) N=601 usual care (provider-enhanced usual care) Primary outcome https://web.pathway.md/studies/rec8nz3LtLBaqnDQ1 1/2 6/29/23, 1:42 AM PREPARE Pathway Annualized rate of severe asthma exacerbations 0.8 0.82 0.69 0.6 0.4 0.2 Significant decrease 0.0 Reliever-triggered inhaled corticosteroid Usual care Significant decrease in annualized rate of severe asthma exacerbations (0.69 vs. 0.82; HR 0.85, 95% CI 0.72 to 0.99) Secondary outcomes Significant increase in mean improvement in asthma control test scores (3.4 points vs. 2.5 points; MD 0.9, 95% CI 0.5 to 1.2) Significant increase in mean improvement in asthma symptom utility index scores (0.12 points vs. 0.08 points; MD 0.04, 95% CI 0.02 to 0.05) Borderline significant decrease in annualized rate of missed days of work, school, or usual activities (13.4 days vs. 16.8 days; RR 0.8, 95% CI 0.67 to 0.95) Safety outcomes No significant differences in serious adverse events, asthma-related hospitalizations. Conclusion In Black and Latinx adults with moderate-to-severe asthma, reliever-triggered ICS was superior to usual care with respect to annualized rate of severe asthma exacerbations. Reference Elliot Israel, Juan-Carlos Cardet, Jennifer K Carroll et al. Reliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma. N Engl J Med. 2022 Apr 21;386(16):1505-1518. Open reference URL https://web.pathway.md/studies/rec8nz3LtLBaqnDQ1 2/2

6/29/23, 1:42 AM PREPIC 2 Pathway Feedback Search Clinical Topics Home Studies PREPIC 2 PREPIC 2 Disease Disease Deep vein thrombosis Pulmonary embolism Trial question What is the role of retrievable IVC filter plus anticoagulation in patients with acute VTE? Study design Multi-center Open label RCT Population Characteristics of study participants 52.0% female N = 399 48.0% male 399 patients (207 female, 192 male) Inclusion criteria: hospitalized patients with acute, symptomatic PE associated with lower-limb vein thrombosis and at least 1 criterion for severity Key exclusion criteria: insertion of a vena cava filter indicated because of a transient or permanent contraindication to anticoagulation therapy or because recurrent thromboembolism had occurred despite adequate anticoagulant therapy, vena cava filter already inserted, noncancer surgery within the past 3 months or cancer surgery within the past 10 days, life expectancy < 6 months, and pregnancy Interventions N=200 IVC filter implantation (filter implantation plus anticoagulation) N=199 no IVC filter implantation (anticoagulation alone with no filter implantation) https://web.pathway.md/studies/rec1fVmF0DbFdh06m 1/2 6/29/23, 1:42 AM PREPIC 2 Pathway Primary outcome Symptomatic recurrent pulmonary embolism at 3 months 3.0 % 3 2.3 % 1.5 % 1.5 0.8 % No significant difference 0.0 % Inferior vena cava filter implantation No inferior vena cava filter implantation No significant difference in symptomatic recurrent PE at 3 months (3% vs. 1.5%; RR 2, 95% CI 0.51 to 7.89) Secondary outcomes No significant difference in recurrent PE at 6 months, Kaplan-Meier estimates (3.5% vs. 2%; HR 1.78, 95% CI 0.52 to 6.09) Safety outcomes No significant difference in major bleeding at 3 months (4% vs. 5%) and major bleeding at 6 months (6.5% vs. 7.5%). Conclusion In hospitalized patients with acute, symptomatic PE associated with lower-limb vein thrombosis and at least 1 criterion for severity, IVC filter implantation was not superior to no IVC filter implantation with respect to symptomatic recurrent PE at 3 months. Reference Mismetti P, Laporte S, Pellerin O et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015 Apr 28;313(16):1627-35. Open reference URL https://web.pathway.md/studies/rec1fVmF0DbFdh06m 2/2