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6/28/23, 12:25 AM CandiSep Pathway Feedback Search Clinical Topics Home Studies CandiSep CandiSep Disease Disease Invasive candidiasis Sepsis and septic shock Trial question What is the role of (1,3)- -D-glucan-guided antifungal therapy in patients with sepsis at high risk for invasive candidiasis? Study design Multi-center Open label RCT Population Characteristics of study participants 35.0% female N = 339 65.0% male 339 patients (120 female, 222 male) Inclusion criteria: adult patients with sepsis at high risk for invasive Candida infection Key exclusion criteria: proven invasive Candida infection; systemic antifungal therapy prior to inclusion; liver cirrhosis of Child-Pugh class c; recent treatment with immunoglobulins; immunosuppression Interventions N=172 (1,3)- -D-glucan guidance (receipt of antifungals if at least one of two consecutive (1,3)- -D-glucan samples taken during the first two study days 80 pg/mL) N=167 standard care (receipt of targeted antifungal therapy driven by culture results) Primary outcome Death at day 28 33.7 33 7 % 30 5 https://web.pathway.md/studies/recyd4AWnZJ8GVlvA 1/2 6/28/23, 12:25 AM 33.7 % CandiSep Pathway 30.5 25.3 % 16.9 % 8.4 % No significant difference 0.0 % (1,3)-beta-D-glucan guidance Standard care No significant difference in death at day 28 (33.7% vs. 30.5%; RR 1.1, 95% CI 0.8 to 1.51) Secondary outcomes No significant difference in death in the hospital (34.5% vs. 35.9%; RR 0.96, 96% CI 0.71 to 1.29) Significant increase in antifungal-free survival at day 28 (30.2% vs. 52.1%; RR 2.97, 95% CI 2.1 to 4.2) Significant decrease in time to antifungal therapy (1.1 days vs. 4.4 days; AD -3.3 days, 95% CI -5.81 to -0.79) Conclusion In adult patients with sepsis at high risk for invasive Candida infection, (1,3)- -D-glucan guidance was not superior to standard care with respect to death at day 28. Reference Frank Bloos, J rgen Held, Stefan Kluge et al. (1 3)- -D-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial. Intensive Care Med. 2022 Jul;48(7):865-875. Open reference URL https://web.pathway.md/studies/recyd4AWnZJ8GVlvA 2/2

6/28/23, 12:02 AM CANVAS Pathway Feedback Search Clinical Topics Home Studies CANVAS CANVAS Disease Diabetes mellitus type 2 Trial question What is the effect of canagliflozin in patients with T2DM and high cardiovascular risk? Study design Multi-center Single blinded RCT Population Characteristics of study participants 36.0% female N = 10142 64.0% male 10142 patients (3633 female, 6509 male) Inclusion criteria: patients with T2DM and high cardiovascular risk Key exclusion criteria: history of diabetic ketoacidosis, TIDM, pancreas or -cell transplantation, renal disease requiring treatment with immunosuppressive therapy, history of chronic dialysis or renal transplant Interventions N=5795 canagliflozin (at a dose of 300 mg or 100 mg in CANVAS and initial dose of 100 mg daily with an optional increase to 300 mg starting from week 13 in CANVAS-R) N=4347 placebo (matching placebo) Primary outcome Death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke 31.5 31.5 26.9 23 6 https://web.pathway.md/studies/recW41JzdOCKZqNyb 1/2 6/28/23, 12:02 AM CANVAS Pathway 23.6 15.8 7.9 Significant decrease 0.0 Canagliflozin Placebo Significant decrease in death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (26.9 vs. 31.5; HR 0.86, 95% CI 0.75 to 0.97) Secondary outcomes Borderline significant decrease in progression of albuminuria (89.4 vs. 128.7; HR 0.73, 95% CI 0.67 to 0.79) Safety outcomes No significant differences in adverse events leading to discontinuation (35.5 vs. 32.8 participants per 1,000 patient-years; HR 1.13, 95% CI 0.99-1.28). Significant differences in risk of amputation of toes, feet, or legs (6.3 vs. 3.4 participants per 1,000 patient-years; HR 1.97, 95% CI 1.41-2.75) and serious adverse events (104.3 vs. 120.0 participants per 1,000 patient-years; HR 0.93, 95% CI 0.87-1.00). Conclusion In patients with T2DM and high cardiovascular risk, canagliflozin was superior to placebo with respect to death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Reference Neal B, Perkovic V, Mahaffey KW et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657. Open reference URL https://web.pathway.md/studies/recW41JzdOCKZqNyb 2/2

6/28/23, 12:02 AM CAPE COD Pathway Feedback Search Clinical Topics Home Studies CAPE COD CAPE COD Disease Community-acquired pneumonia Trial question What is the role of hydrocortisone in severe community-acquired pneumonia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 31.0% female N = 795 69.0% male 795 patients (243 female, 552 male) Inclusion criteria: adults who had been admitted to the ICU for severe community-acquired pneumonia Key exclusion criteria: do-not-intubate order; pneumonia caused by influenza; and septic shock Interventions N=400 hydrocortisone (200 mg daily for either 4 or 8 days as determined by clinical improvement, followed by tapering for a total of 8 or 14 days) N=395 placebo (matching placebo) Primary outcome Death at day 28 11.9 % 11.9 8.9 % https://web.pathway.md/studies/recsRlfT36t9jujAM 1/2 6/28/23, 12:02 AM CAPE COD Pathway 6.2 6.0 % Significant decrease 3.0 % NNT = 18 0.0 % Hydrocortisone Placebo Significant decrease in death at day 28 (6.2% vs. 11.9%; ARD -5.6, 95% CI -9.6 to -1.7) Secondary outcomes Borderline significant decrease in the rate of endotracheal intubation by day 28 in patients not undergoing mechanical ventilation at baseline (18% vs. 29.5%; HR 0.59, 95% CI 0.4 to 0.86) Borderline significant decrease in the rate of endotracheal intubation by day 28 in patients not receiving endotracheal intubation at baseline (19.5% vs. 27.7%; HR 0.69, 95% CI 0.5 to 0.94) Borderline significant decrease in the rate of vasopressors initiation by day 28 in patients not receiving vasopressor at baseline (15.3% vs. 25%; HR 0.59, 95% CI 0.43 to 0.82) Safety outcomes No significant differences in composite of hospital-acquired infection, gastrointestinal bleeding, weight change. Significant difference in median daily dose of insulin by day 7 in patients receiving insulin therapy (35.5 IU/day vs. 20.5 IU/day). Conclusion In adults who had been admitted to the ICU for severe community-acquired pneumonia, hydrocortisone was superior to placebo with respect to death at day 28. Reference Pierre-Fran ois Dequin, Ferhat Meziani, Jean-Pierre Quenot et al. Hydrocortisone in Severe Community-Acquired Pneumonia. N Engl J Med. 2023 May 25;388(21):1931-1941. Open reference URL https://web.pathway.md/studies/recsRlfT36t9jujAM 2/2

6/28/23, 12:02 AM CAPITAL CHILL Pathway Feedback Search Clinical Topics Home Studies CAPITAL CHILL CAPITAL CHILL Disease Cardiac arrest Trial question Is moderate therapeutic hypothermia superior to mild therapeutic hypothermia among comatose survivors of out-of-hospital cardiac arrest? Study design Single center Double blinded RCT Population Characteristics of study participants 19.0% female N = 367 81.0% male 367 patients (69 female, 298 male) Inclusion criteria: patients with out-of-hospital cardiac arrest surviving to hospital admission and referred for post-cardiac arrest care Key exclusion criteria: known inability to perform activities of daily living, cardiac arrest secondary to intracranial bleed, severe coagulopathy with clinical evidence of major bleeding, coma not attributable to the cardiac arrest Interventions N=193 moderate hypothermia (a target body temperature of 31 degree Celsius for a period of 24 hours) N=196 mild hypothermia (a target body temperature of 34 degree Celsius for a period of 24 hours) Primary outcome https://web.pathway.md/studies/reckiaCgHfor96wWu 1/2 6/28/23, 12:02 AM CAPITAL CHILL Pathway Death or poor neurologic outcome at day 180 48.4 % 48.4 45.4 36.3 % 24.2 % 12.1 % No significant difference 0.0 % Moderate hypothermia Mild hypothermia No significant difference in death or poor neurologic outcome at day 180 (48.4% vs. 45.4%; RR 1.07, 95% CI 0.86 to 1.33) Secondary outcomes No significant difference in death at day 180 (43.5% vs. 41%; RR 1.06, 95% CI 0.83 to 1.35) No significant difference in stroke at day 180 (4.4% vs. 1.6%; RR 2.65, 95% CI 0.71 to 9.84) No significant difference in length of stay in the ICU (10 days vs. 7 days; AD 1.4 days, 95% CI -1.2 to 4.1) Safety outcomes No significant differences in deep vein thrombosis, IVC thrombus. Conclusion In patients with out-of-hospital cardiac arrest surviving to hospital admission and referred for post-cardiac arrest care, moderate hypothermia was not superior to mild hypothermia with respect to death or poor neurologic outcome at day 180. Reference Michel Le May, Christina Osborne, Juan Russo et al. Effect of Moderate vs Mild Therapeutic Hypothermia on Mortality and Neurologic Outcomes in Comatose Survivors of Out-of-Hospital Cardiac Arrest: The CAPITAL CHILL Randomized Clinical Trial. JAMA. 2021 Oct 19;326(15):1494-1503. Open reference URL https://web.pathway.md/studies/reckiaCgHfor96wWu 2/2

6/28/23, 12:03 AM CAPRIE Pathway Feedback Search Clinical Topics Home Studies CAPRIE CAPRIE Disease Disease Coronary artery disease Transient ischemic attack Trial question Is clopidogrel superior to aspirin in patients with atherosclerotic vascular disease? Study design Multi-center Double blinded RCT Population Characteristics of study participants 28.0% female N = 19185 72.0% male 19185 patients (5372 female, 13813 male) Inclusion criteria: patients with atherosclerotic vascular disease Key exclusion criteria: age < 21 years, women of childbearing age not using reliable contraception, uncontrolled hypertension, scheduled for major surgery, or contraindications to study drugs Interventions N=9599 clopidogrel (75 mg daily) N=9586 aspirin (325 mg daily) Primary outcome Ischemic stroke, myocardial infarction, or vascular death 5.8 % 5.83 5.32 4.4 % https://web.pathway.md/studies/recCvxEEUZwV4H1KV 1/2 6/28/23, 12:03 AM CAPRIE Pathway 2.9 % Significant decrease 1.5 % NNT = 196 0.0 % Clopidogrel Aspirin Significant decrease in ischemic stroke, myocardial infarction, or vascular death (5.32% vs. 5.83%; RR 0.91, 95% CI 0.84 to 0.97) Secondary outcomes No significant difference in ischemic stroke, MI, amputation, or vascular death (5.56% vs. 6.01%; RR 0.92, 95% CI 0.85 to 1.08) Safety outcomes No significant difference in adverse events. Conclusion In patients with atherosclerotic vascular disease, clopidogrel was superior to aspirin with respect to ischemic stroke, myocardial infarction, or vascular death. Reference CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996 Nov 16;348(9038):1329-39. Open reference URL https://web.pathway.md/studies/recCvxEEUZwV4H1KV 2/2

6/28/23, 12:03 AM CARDEA Pathway Feedback Search Clinical Topics Home Studies CARDEA CARDEA Disease COVID 19 infection Trial question What is the role of auxora, a calcium release-activated calcium channel inhibitor, in patients with severe COVID-19 pneumonia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 33.0% female N = 261 67.0% male 261 patients (85 female, 176 male) Inclusion criteria: adult patients with 1 symptom consistent with COVID-19 infection and pneumonia Key exclusion criteria: receipt of either non-invasive or invasive mechanical ventilation; expected survival < 7 days; PaO /FiO 75 at the time of screening; multiple organ dysfunction or failure; shock Interventions N=130 auxora (4-hour intravenous infusion of 1.25 mL/kg on day 1, and 1.0 mL/kg on day 2 and 3) N=131 placebo (4-hour intravenous infusion of matching placebo) Primary outcome Time to recovery at day 60 https://web.pathway.md/studies/recq1ySVZ0aVuhcbf 1/2 6/28/23, 12:03 AM CARDEA Pathway 10.0 days 10 7.5 days 7 5.0 days 2.5 days No significant difference 0.0 days Auxora Placebo No significant difference in time to recovery at day 60 (7 days vs. 10 days; AD -3 days, 95% CI -6.56 to 0.56) Secondary outcomes No significant difference in death from all causes at day 60 (13.8% vs. 20.6%; ARD -6.75, 95% CI -15.75 to 2.24) Significant decrease in death from all causes at day 30 (7.7% vs. 17.6%; ARD -9.86, 95% CI -17.8 to -1.93) No significant difference in the percentage of patients who undergone invasive mechanical ventilation at day 60 (19% vs. 28%; ARD -9, 95% CI -22.37 to 4.37) Safety outcomes No significant difference in serious adverse events. Conclusion In adult patients with 1 symptom consistent with COVID-19 infection and pneumonia, auxora was not superior to placebo with respect to time to recovery at day 60. Reference Charles Bruen, Mukhtar Al-Saadi, Edward A Michelson et al. Auxora vs. placebo for the treatment of patients with severe COVID-19 pneumonia: a randomized-controlled clinical trial. Crit Care. 2022 Apr 8;26(1):101. Open reference URL https://web.pathway.md/studies/recq1ySVZ0aVuhcbf 2/2

6/28/23, 12:03 AM CARES Pathway Feedback Search Clinical Topics Home Studies CARES CARES Disease Gout Trial question Is febuxostat noninferior to allopurinol in patients with gout and major cardiovascular coexisting conditions? Study design Multi-center Double blinded RCT Population Characteristics of study participants 25.0% female N = 6190 75.0% male 6190 patients (1534 female, 4656 male) Inclusion criteria: patients with gout and major cardiovascular coexisting conditions Key exclusion criteria: secondary hyperuricemia due to myeloproliferative disorder, xanthinuria, active peptic ulcer disease, history of cancer, receiving urate-lowering therapy Interventions N=3098 febuxostat (adjusted according to serum urate) N=3092 allopurinol (adjusted according to kidney function) Primary outcome CV death, nonfatal MI, nonfatal CVA, or UA requiring urgent revascularization 10.8 % 10.8 10.4 8.1 % https://web.pathway.md/studies/recC9STYXflKFyvqG 1/2 6/28/23, 12:03 AM CARES Pathway 5.4 % Difference not exceeding nonferiority margin 2.7 % 0.0 % Febuxostat Allopurinol Difference not exceeding nonferiority margin in CV death, nonfatal MI, nonfatal CVA, or UA requiring urgent revascularization (10.8% vs. 10.4%; HR 1.03, 95% CI 0.38 to 1.68) Secondary outcomes Significant increase in death from any cause (7.8% vs. 6.4%; HR 1.22, 95% CI 1.01 to 1.47) Significant increase in cardiovascular death (4.3% vs. 3.2%; HR 1.34, 95% CI 1.03 to 1.73) Safety outcomes No significant difference in overall rates of adverse major cardiovascular events. Conclusion In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to CV death, nonfatal MI, nonfatal CVA, or UA requiring urgent revascularization. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. Reference White WB, Saag KG, Becker MA et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018 Mar 29;378(13):1200-1210. Open reference URL https://web.pathway.md/studies/recC9STYXflKFyvqG 2/2

6/28/23, 12:03 AM CARP Pathway Feedback Search Clinical Topics Home Studies CARP CARP Disease Coronary artery disease Trial question What is the role of coronary artery revascularization in patients at increased risk for perioperative cardiac complications and clinically significant coronary artery disease? Study design Multi-center Open label RCT Population 510 patients Inclusion criteria: patients at increased risk for perioperative cardiac complications and clinically significant coronary artery disease Key exclusion criteria: need for urgent or emergency surgery, a severe coexisting illness, or prior revascularization without evidence of recurrent ischemia Interventions N=258 coronary artery revascularization (either PCI or bypass surgery) N=252 no revascularization (no PCI or bypass surgery) Primary outcome Rate of death at a mean follow-up of 2.7 years 23.0 % 23 22 17.3 % 11.5 % 5.8 % No significant difference 0.0 % Coronary artery revascularization No revascularization https://web.pathway.md/studies/recKrNdn8xep0ciT4 1/2 6/28/23, 12:03 AM CARP Pathway No significant difference in the rate of death at a mean follow-up of 2.7 years (22% vs. 23%; RR 0.98, 95% CI 0.7 to 1.37) Secondary outcomes No significant difference in the rate of postoperative myocardial infarction, within 30 days of vascular operation (12% vs. 14%; RR 0.86, 95% CI -1 to 2.72) Conclusion In patients at increased risk for perioperative cardiac complications and clinically significant coronary artery disease, coronary artery revascularization was not superior to no revascularization with respect to the rate of death at a mean follow-up of 2.7 years. Reference McFalls EO, Ward HB, Moritz TE et al. Coronary-artery revascularization before elective major vascular surgery. N Engl J Med. 2004 Dec 30;351(27):2795-804. Open reference URL https://web.pathway.md/studies/recKrNdn8xep0ciT4 2/2

6/28/23, 12:03 AM CASS Pathway Feedback Search Clinical Topics Home Studies CASS CASS Disease Sepsis and septic shock Trial question What is the role of induced hypothermia among patients with septic shock and ventilator- dependent respiratory failure? Study design Multi-center Open label RCT Population Characteristics of study participants 40.4% female N = 436 59.6% male 436 patients (173 female, 259 male) Inclusion criteria: patients with at least 50 years of age admitted to the ICU for at least 24 hours with severe sepsis or septic shock who were on mechanical ventilation Key exclusion criteria: uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission Interventions N=217 induced hypothermia (a target temperature of 32-34 degree Celsius for 24 hours and subsequent normothermia) N=215 control (routine thermal management) Primary outcome Rate of death from all causes by day 30 44.2 % 44.2 https://web.pathway.md/studies/recWcq6McvaiMH4C2 1/2 6/28/23, 12:03 AM CASS Pathway 35.8 33.2 % 22.1 % 11.1 % Borderline significant increase 0.0 % Induced hypothermia Control Borderline significant increase in the rate of death from all causes by day 30 (44.2% vs. 35.8%; RR 1.2, 95% CI 1 to 1.6) Secondary outcomes No significant difference in death at day 180 (56.2% vs. 50.7%; RR 1.1, 95% CI 0.9 to 1.3) Safety outcomes No significant differences in delirium, need for blood transfusion and surgery. Significant differences in Sequential Organ Failure Assessment score at 72 hours (11 vs. 9), > 30% decrease in CRP (33.3% vs. 50.3%). Conclusion In patients with at least 50 years of age admitted to the ICU for at least 24 hours with severe sepsis or septic shock who were on mechanical ventilation, induced hypothermia was inferior to control with respect to the rate of death from all causes by day 30. Reference Theis Skovsgaard Itenov, Maria Egede Johansen, Morten Bestle et al. Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial. Lancet Respir Med. 2018 Mar;6(3):183-192. Open reference URL https://web.pathway.md/studies/recWcq6McvaiMH4C2 2/2

6/28/23, 12:04 AM CASSINI Pathway Feedback Search Clinical Topics Home Studies CASSINI CASSINI Disease Cancer-associated thrombosis Trial question What is the role of rivaroxaban in high-risk ambulatory patients with cancer? Study design Multi-center Double blinded RCT Population Characteristics of study participants 49.0% female N = 841 51.0% male 841 patients (413 female, 428 male) Inclusion criteria: high-risk ambulatory adults with cancer Key exclusion criteria: primary brain tumor or known brain metastases; active bleeding or at risk for bleeding; ECOG performance-status score of 3 Interventions N=420 rivaroxaban (a dose of 10 mg daily for 6 months) N=421 placebo (matching placebo daily for 6 months) Primary outcome Thrombotic events at 6 months 8.8 % 8.8 6.6 % 6 4 4 % https://web.pathway.md/studies/rec5v70paFtB83aAQ 1/2 6/28/23, 12:04 AM CASSINI Pathway 4.4 % 2.2 % No significant difference 0.0 % Rivaroxaban Placebo No significant difference in thrombotic events at 6 months (6% vs. 8.8%; HR 0.66, 95% CI 0.4 to 1.09) Secondary outcomes No significant difference in death at day 180 (20% vs. 23.8%; HR 0.83, 95% CI 0.62 to 1.11) No significant difference in symptomatic proximal deep vein thrombosis in the lower limb at day 180 (2.1% vs. 1.9%; HR 1.12, 95% CI 0.43 to 2.91) No significant difference in symptomatic distal deep vein thrombosis in the lower limb at day 180 (0.5% vs. 1.2%; HR 0.4, 95% CI 0.08 to 2.07) Safety outcomes No significant differences in major bleeding, clinically relevant nonmajor bleeding, adverse and serious adverse events. Conclusion In high-risk ambulatory adults with cancer, rivaroxaban was not superior to placebo with respect to thrombotic events at 6 months. Reference Alok A Khorana, Gerald A Soff, Ajay K Kakkar et al. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. N Engl J Med. 2019 Feb 21;380(8):720-728. Open reference URL https://web.pathway.md/studies/rec5v70paFtB83aAQ 2/2

6/28/23, 12:04 AM CASTLE-AF Pathway Feedback Search Clinical Topics Home Studies CASTLE AF CASTLE AF Disease Disease Atrial fibrillation Heart failure Trial question What is the role of catheter ablation for AF in patients with HF who are otherwise receiving appropriate treatment? Study design Multi-center Open label RCT Population Characteristics of study participants 14.3% female N = 398 85.7% male 398 patients (52 female, 311 male) Inclusion criteria: patients with symptomatic paroxysmal or persistent AF and HF who did not respond to antiarrhythmic drugs Key exclusion criteria: candidacy for heart transplantation or planned cardiovascular intervention Interventions N=179 catheter ablation (to restore sinus rhythm) N=184 medical therapy alone (for rate or rhythm control) Primary outcome Death or hospitalization for worsening HF 44.6 % 44.6 https://web.pathway.md/studies/recbUTrx9UP6gzymr 1/2 6/28/23, 12:04 AM CASTLE-AF Pathway 33.5 % 28.5 22.3 % Significant decrease 11.2 % NNT = 6 0.0 % Catheter ablation Medical therapy alone Significant decrease in death or hospitalization for worsening HF (28.5% vs. 44.6%; HR 0.62, 95% CI 0.43 to 0.87) Secondary outcomes Significant decrease in death from any cause (13.4% vs. 25%; HR 0.53, 95% CI 0.32 to 0.86) Significant decrease in hospitalization for worsening HF (20.7% vs. 35.9%; HR 0.56, 95% CI 0.37 to 0.83) Significant decrease in cardiovascular death (11.2% vs. 22.3%; HR 0.49, 95% CI 0.29 to 0.84) Safety outcomes Significant differences in pericardial effusion and severe bleeding (3 vs. 0 in each),. Conclusion In patients with symptomatic paroxysmal or persistent AF and HF who did not respond to antiarrhythmic drugs, catheter ablation was superior to medical therapy alone with respect to death or hospitalization for worsening HF. Reference Marrouche NF, Brachmann J, Andresen D et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med. 2018 Feb 1;378(5):417-427. Open reference URL https://web.pathway.md/studies/recbUTrx9UP6gzymr 2/2

6/28/23, 12:05 AM CATCO Pathway Feedback Search Clinical Topics Home Studies CATCO CATCO Disease COVID 19 infection Trial question What is the role of remdesivir in patients with COVID-19 infection across Canada? Study design Multi-center Open label RCT Population Characteristics of study participants 40.0% female N = 1281 60.0% male 1281 patients (515 female, 766 male) Inclusion criteria: hospitalized adults with laboratory-confirmed COVID-19 infection Key exclusion criteria: allergy to study drug; anticipated transfer to a nonstudy site; expected to not survive beyond 24 hours; already receiving remdesivir at time of enrolment Interventions N=634 remdesivir (IV dose of 200 mg on day 0, followed by 100 mg daily for 10 days plus standard care) N=648 standard care (standard care alone) Primary outcome Death at day 28 22.6 % 22.6 18.7 17.0 % https://web.pathway.md/studies/rec1c9XBbrIBqnkRV 1/2 6/28/23, 12:05 AM CATCO Pathway 11.3 % 5.7 % No significant difference 0.0 % Remdesivir Standard care No significant difference in death at day 28 (18.7% vs. 22.6%; RR 0.83, 95% CI 0.67 to 1.03) Secondary outcomes Borderline significant decrease in need for mechanical ventilation (8% vs. 15%; RR 0.53, 95% CI 0.38 to 0.75) No significant difference in death at day 60 (24.8% vs. 28.2%; RR 0.88, 95% CI 0.72 to 1.07) Significant increase in oxygen-free days at day 28 (15.9 days vs. 14.2 days; AD 1.7 days, 95% CI 0.4 to 3) Safety outcomes No significant differences in need for dialysis, creatinine levels, new hepatic dysfunction. Conclusion In hospitalized adults with laboratory-confirmed COVID-19 infection, remdesivir was not superior to standard care with respect to death at day 28. Reference Karim Ali, Tanweer Azher, Mahin Baqi et al. Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial. CMAJ. 2022 Feb 22;194(7):E242-E251. Open reference URL https://web.pathway.md/studies/rec1c9XBbrIBqnkRV 2/2

6/28/23, 12:26 AM Catecholamines in pediatric cold shock Pathway Feedback Search Clinical Topics Home Studies Catecholamines in pediatric cold shock Catecholamines in pediatric cold shock Disease Sepsis and septic shock Trial question Is a combination of norepinephrine and dobutamine superior to epinephrine in children with fluid- refractory cold septic shock? Study design Single center Open label RCT Population Characteristics of study participants 43.0% female N = 67 57.0% male 67 patients (29 female, 38 male) Inclusion criteria: children 2 months to < 18 years old with fluid refractory cold septic shock Key exclusion criteria: fulminant myocarditis; congenital heart disease; severe acute malnutrition; CKD; receipt of vasoactive agents Interventions N=34 norepinephrine plus dobutamine (dose titration of 0.1-0.3 and 10-20 g/kg/min, respectively) N=33 epinephrine (dose titration of 0.1-0.3 g/kg/min) Primary outcome Shock resolution at 1 hour of therapy 17.6 % 17.6 https://web.pathway.md/studies/recmBlbBoRcyExsP5 1/2 6/28/23, 12:26 AM Catecholamines in pediatric cold shock Pathway 13.2 % 9 8.8 % 4.4 % No significant difference 0.0 % Norepinephrine plus dobutamine Epinephrine No significant difference in shock resolution at 1 hour of therapy (17.6% vs. 9%; RR 2, 95% CI 0.54 to 7.35) Secondary outcomes No significant difference in shock resolution at 6 hours of therapy (76.4% vs. 54.5%; RR 1.69, 95% CI 0.92 to 3.13) Significant decrease in time to attain shock resolution (3 hours vs. 6 hours; HR 0.54, 95% CI 0.32 to 0.9) No significant difference in death at day 28 (23.5% vs. 39.3%; RR 0.59, 95% CI 0.28 to 1.25) Safety outcomes No significant difference in adverse events. Conclusion In children 2 months to < 18 years old with fluid refractory cold septic shock, norepinephrine plus dobutamine was not superior to epinephrine with respect to shock resolution at 1 hour of therapy. Reference Kiran Kumar Banothu, Jhuma Sankar, U Vijaya Kumar et al. A Randomized Controlled Trial of Norepinephrine Plus Dobutamine Versus Epinephrine As First-Line Vasoactive Agents in Children With Fluid Refractory Cold Septic Shock. Crit Care Explor. 2022 Dec 28;5(1):e0815. eCollection 2023 Jan. Open reference URL https://web.pathway.md/studies/recmBlbBoRcyExsP5 2/2

6/28/23, 12:05 AM CATT Pathway Feedback Search Clinical Topics Home Studies CATT CATT Reference CATT Research Group, Martin DF, Maguire MG et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011 May 19;364(20):1897-908. Open reference URL https://web.pathway.md/studies/rec14LmhumMmG8QJk 1/1

6/28/23, 12:26 AM Ceftriaxone prophylaxis in cirrhosis with GI bleeding Pathway Feedback Search Clinical Topics Home Studies Ceftriaxone prophylaxis in cirrhosis with GI bleeding Ceftriaxone prophylaxis in cirrhosis with GI bleeding Disease Disease Liver cirrhosis Variceal hemorrhage Trial question What is the role of ceftriaxone in the prophylaxis of bacterial infections in patients with advanced cirrhosis and hemorrhage? Study design Multi-center Open label RCT Population Characteristics of study participants 23.0% female N = 111 77.0% male 111 patients (25 female, 86 male) Inclusion criteria: patients with advanced cirrhosis (at least 2 of the following: ascites, severe malnutrition, encephalopathy, or bilirubin > 3 mg/dL) and gastrointestinal hemorrhage Key exclusion criteria: allergy to cephalosporins or quinolones, pneumonia, previously diagnosed advanced HCC, and human immunodeficiency virus (HIV) infection Interventions N=54 ceftriaxone (intravenous dosage of 1 g/day for 7 days) N=57 norfloxacin (oral dosage of 400 mg BID for 7 days) Primary outcome Proved or possible infections at 10 days 33.0 % 33 https://web.pathway.md/studies/rectPQdlsWq6rKBrH 1/2 6/28/23, 12:26 AM Ceftriaxone prophylaxis in cirrhosis with GI bleeding Pathway 24.8 % 16.5 % Significant decrease 11 8.3 % NNT = 5 0.0 % Ceftriaxone Norfloxacin Significant decrease in proved or possible infections at 10 days (11% vs. 33%; RR 0.33, 95% CI 0.11 to 0.55) Secondary outcomes Significant decrease in proved infections (11% vs. 26%; RR 0.42, 95% CI 0.04 to 0.8) Significant decrease in spontaneous bacteremia or SBP (2% vs. 12%; RR 0.17, 95% CI 0.02 to 0.32) Safety outcomes No significant difference in hospital mortality. Conclusion In patients with advanced cirrhosis (at least 2 of the following: ascites, severe malnutrition, encephalopathy, or bilirubin > 3 mg/dL) and gastrointestinal hemorrhage, ceftriaxone was superior to norfloxacin with respect to proved or possible infections at 10 days. Reference Fernandez J, Ruiz del Arbol L, Gomez C et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology. 2006 Oct;131(4):1049-56. Open reference URL https://web.pathway.md/studies/rectPQdlsWq6rKBrH 2/2

6/28/23, 12:26 AM Celecoxib vs. diclofenac in arthritis with recent ulcer bleeding Pathway Feedback Search Clinical Topics Home Studies Celecoxib vs. diclofenac in arthritis with recent ulcer bleeding Celecoxib vs. diclofenac in arthritis with recent ulcer bleeding Disease Disease Disease Ankylosing spondylitis Chronic arthritic pain Hand o Trial question What is the role of celecoxib in patients with arthritis and a recent history of ulcer bleeding? Study design Single center Double blinded RCT Population Characteristics of study participants 56.0% female N = 287 44.0% male 287 patients (161 female, 126 male) Inclusion criteria: patients with arthritis and a recent history of ulcer bleeding Key exclusion criteria: concomitant use of anticoagulant agents or corticosteroids; a history of gastric or duodenal surgery other than a patch repair; and the presence of erosive esophagitis, gastric outlet obstruction, renal failure, terminal illness, or cancer Interventions N=144 celecoxib (200 mg BID plus omeprazole placebo daily for 6 months) N=143 diclofenac plus omeprazole (75 mg ER diclofenac BID plus 20 mg of omeprazole daily for 6 months) Primary outcome Rate of probability of recurrent bleeding during the 6-month period 6.4 6.4 % 4 9 https://web.pathway.md/studies/recRrSVOg3pwWuJYE 1/2 6/28/23, 12:26 AM Celecoxib vs. diclofenac in arthritis with recent ulcer bleeding Pathway 4.9 4.8 % 3.2 % Difference not exceeding nonferiority margin 1.6 % 0.0 % Celecoxib Diclofenac plus omeprazole Difference not exceeding nonferiority margin in the rate of probability of recurrent bleeding during the 6-month period (4.9% vs. 6.4%; AD -1.5%, 95% CI -6.8 to 3.8) Safety outcomes Significant differences in renal adverse events, including hypertension, peripheral edema, and renal failure (24.3% vs. 30.8%). Conclusion In patients with arthritis and a recent history of ulcer bleeding, celecoxib was noninferior to diclofenac plus omeprazole with respect to the rate of probability of recurrent bleeding during the 6-month period. Reference Chan FK, Hung LC, Suen BY et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 2002 Dec 26;347(26):2104-10. Open reference URL https://web.pathway.md/studies/recRrSVOg3pwWuJYE 2/2

6/28/23, 12:05 AM CENSER Pathway Feedback Search Clinical Topics Home Studies CENSER CENSER Disease Sepsis and septic shock Trial question What is the role of early use of norepinephrine in patients with septic shock? Study design Single center Double blinded RCT Population Characteristics of study participants 52.0% female N = 310 48.0% male 310 patients (162 female, 148 male) Inclusion criteria: adult patients diagnosed with sepsis with hypotension Key exclusion criteria: septic shock diagnostic criteria for > 1 hour before randomization, acute cerebral vascular event, acute coronary syndrome, acute pulmonary edema, active gastrointestinal hemorrhage Interventions N=155 early norepinephrine (infusion of a dose of 0.05 g/kg/min of body weight plus fluid resuscitation) N=155 placebo (5% dextrose in water plus standard treatment) Primary outcome Shock control rate by 6 hours after initiation of resuscitation 76.1 % 76.1 https://web.pathway.md/studies/recseFcqChB57SsKX 1/2 6/28/23, 12:05 AM CENSER Pathway 57.1 % 48.4 38.0 % Significant increase 19.0 % NNH = 4 0.0 % Early norepinephrine Placebo Significant increase in shock control rate by 6 hours after initiation of resuscitation (76.1% vs. 48.4%; OR 3.4, 95% CI 2.09 to 5.53) Secondary outcomes No significant difference in the rate of death by day 28 (15.5% vs. 21.9%; RR 0.79, 95% CI 0.53 to 1.11) No significant difference in hospital death (22.6% vs. 24.5%; RR 0.95, 95% CI 0.72 to 1.24) Significant increase in achievement of target mean arterial BP by 6 hours (86.5% vs. 67.1%; RR 3.13, 95% CI 1.77 to 5.53) Safety outcomes No significant differences in limb ischemia, intestinal ischemia, ARDS, hospital-acquired infection, upper gastrointestinal hemorrhage, skin necrosis. Significant differences in cardiogenic pulmonary edema (14.4% vs. 27.7%), new-onset arrhythmia (11% vs. 20%). Conclusion In adult patients diagnosed with sepsis with hypotension, early norepinephrine was superior to placebo with respect to shock control rate by 6 hours after initiation of resuscitation. Reference Chairat Permpikul, Surat Tongyoo, Tanuwong Viarasilpa et al. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med. 2019 May 1;199(9):1097-1105. Open reference URL https://web.pathway.md/studies/recseFcqChB57SsKX 2/2

6/28/23, 12:05 AM CHAMPION PHOENIX Pathway Feedback Search Clinical Topics Home Studies CHAMPION PHOENIX CHAMPION PHOENIX Disease Disease Disease Coronary artery disease Non-ST-elevation myocardial inf ST-elev Trial question What is the effect of cangrelor in patients who were undergoing either urgent or elective PCI? Study design Multi-center Double blinded RCT Population Characteristics of study participants 27.6% female N = 11145 72.4% male 11145 patients (3051 female, 7891 male) Inclusion criteria: patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy Key exclusion criteria: pregnancy, age < 18 years, receipt of a P2Y12 inhibitor or abciximab at any time in the 7 days before randomization and receipt of eptifibatide or tirofiban or fibrinolytic therapy in the 12 hours before randomization Interventions N=5472 cangrelor (a bolus of 30 g/kg body weight followed by an infusion of 4 g/kg/minute) N=5470 clopidogrel (600 mg or 300 mg loading dose) Primary outcome Stent thrombosis at 48 hours 1.4 % 1.4 https://web.pathway.md/studies/recULL516VI0PPstl 1/2 6/28/23, 12:05 AM CHAMPION PHOENIX Pathway 1.0 % 0.8 0.7 % Significant decrease 0.3 % NNT = 167 0.0 % Cangrelor Clopidogrel Significant decrease in stent thrombosis at 48 hours (0.8% vs. 1.4%; OR 0.62, 95% CI 0.43 to 0.9) Secondary outcomes Significant decrease in intraprocedural stent thrombosis (0.6% vs. 1%; OR 0.65, 95% CI 0.42 to 0.99) Significant decrease in use of rescue therapy with a glycoprotein IIb/IIIa inhibitor (2.3% vs. 3.5%; OR 0.65, 95% CI 0.52 to 0.82) Safety outcomes No significant differences in GUSTO-defined severe bleeding, adverse events. Significant differences in procedural complications (3.4% vs. 4.5%), transient dyspnea (1.2% vs. 0.3%). Conclusion In patients who were undergoing either urgent or elective PCI and were receiving guideline- recommended therapy, cangrelor was superior to clopidogrel with respect to stent thrombosis at 48 hours. Reference Bhatt DL, Stone GW, Mahaffey KW et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013 Apr 4;368(14):1303-13. Open reference URL https://web.pathway.md/studies/recULL516VI0PPstl 2/2

6/28/23, 12:06 AM CHANCE-HF Pathway Feedback Search Clinical Topics Home Studies CHANCE HF CHANCE HF Disease Heart failure Trial question What is the role of carbohydrate antigen-125-guided therapy in patients with acute HF? Study design Multi-center Open label RCT Population Characteristics of study participants 44.0% female N = 380 56.0% male 380 patients (168 female, 212 male) Inclusion criteria: patients discharged for acute HF and high carbohydrate antigen-125 Key exclusion criteria: life expectancy < 12 months due to other diseases different from HF; pregnancy; angina pectoris higher than class II; VHD already scheduled for surgical intervention Interventions N=187 carbohydrate antigen-125-guided therapy (treatment measures aimed to keep carbohydrate antigen-125 35 U/mL) N=193 standard of care (therapy based on established European current guidelines) Primary outcome Death or acute heart failure readmission at 1 year, restricted mean survival time 0.7 years 0.74 0.66 0 6 https://web.pathway.md/studies/reci2bSLqXgwt6wBb 1/2 6/28/23, 12:06 AM 0.6 years CHANCE-HF Pathway 0.4 years 0.2 years Significant increase 0.0 years Carbohydrate antigen-125-guided therapy Standard of care Significant increase in death or acute HF readmission at 1 year, restricted mean survival time (0.74 years vs. 0.66 years; AD 0.08 years, 95% CI 0.02 to 0.15) Secondary outcomes No significant difference in death or any rehospitalization at 1 year, restricted mean survival time (0.67 years vs. 0.61 years; AD 0.054 years, 95% CI -0.02 to 0.13) No significant difference in the rate of death from all causes and days alive and out of the hospital (16.6% vs. 18.1%; HR 0.92, 95% CI 0.57 to 1.49) Significant decrease in the incidence of recurrent hospitalizations (0.67 events/person-year vs. 1.06 events/person-year; RR 0.63, 95% CI 0.5 to 0.8) Safety outcomes No significant differences in hospitalizations due to hyperkalemia, hypokalemia or acute renal failure. Conclusion In patients discharged for acute HF and high carbohydrate antigen-125, carbohydrate antigen- 125-guided therapy was superior to standard of care with respect to death or acute HF readmission at 1 year, restricted mean survival time. Reference Julio N ez, Pau Ll cer, Vicente Bertomeu-Gonz lez et al. Carbohydrate Antigen-125-Guided Therapy in Acute Heart Failure: CHANCE-HF: A Randomized Study. JACC Heart Fail. 2016 Nov;4(11):833-843. Open reference URL https://web.pathway.md/studies/reci2bSLqXgwt6wBb 2/2

6/28/23, 12:05 AM CHANCE Pathway Feedback Search Clinical Topics Home Studies CHANCE CHANCE Disease Disease Acute ischemic stroke Transient ischemic attack Trial question What is the role of combination of clopidogrel with aspirin in patients with acute minor stroke or TIA? Study design Multi-center Double blinded RCT Population Characteristics of study participants 34.0% female N = 5170 66.0% male 5170 patients (1750 female, 3420 male) Inclusion criteria: patients after the onset of minor ischemic stroke or high-risk TIA Key exclusion criteria: hemorrhage, VM, tumor, abscess, isolated sensory symptoms (e.g., numbness), isolated visual changes, or isolated dizziness or vertigo without evidence of acute infarction on baseline CT or MRI of the head Interventions N=2584 clopidogrel-aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) N=2586 aspirin alone (placebo plus aspirin 75 mg per day for 90 days) Primary outcome Stroke 11.7 % 11.7 https://web.pathway.md/studies/recrMgxz2ZUkVIBus 1/2 6/28/23, 12:05 AM CHANCE Pathway 8.8 % 8.2 5.8 % Significant decrease 2.9 % NNT = 29 0.0 % Clopidogrel-aspirin Aspirin alone Significant decrease in stroke (8.2% vs. 11.7%; HR 0.68, 95% CI 0.57 to 0.81) Secondary outcomes Significant decrease in vascular events (8.4% vs. 11.9%; HR 0.69, 95% CI 0.58 to 0.82) Significant decrease in ischemic stroke (7.9% vs. 11.4%; HR 0.67, 95% CI 0.56 to 0.81) No significant difference in hemorrhagic stroke (0.3% vs. 0.3%; HR 1.01, 95% CI 0.38 to 2.7) Safety outcomes No significant differences in adverse events (5.8% vs. 5.0%) and serious adverse events (1.0% vs. 0.8%) and moderate or severe hemorrhage (0.3% vs. 0.3%, p=0.73). Significant differences in any bleeding (2.3% vs. 1.6%, p = 0.09). Conclusion In patients after the onset of minor ischemic stroke or high-risk TIA, clopidogrel-aspirin was superior to aspirin alone with respect to stroke. Reference Wang Y, Wang Y, Zhao X et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013 Jul 4;369(1):11-9. Open reference URL https://web.pathway.md/studies/recrMgxz2ZUkVIBus 2/2

6/28/23, 12:06 AM CHARISMA Pathway Feedback Search Clinical Topics Home Studies CHARISMA CHARISMA Disease Disease Disease Acute ischemic stroke Coronary artery disease Non-ST Trial question What is the effect of combination of clopidogrel and aspirin in patients with high-risk for atherothrombotic events? Study design Multi-center Double blinded RCT Population Characteristics of study participants 30.0% female N = 15603 70.0% male 15603 patients (4644 female, 10959 male) Inclusion criteria: patients with either clinically evident CVD or multiple risk factors for atherothrombotic events Key exclusion criteria: receipt of oral antithrombotic medications or nonsteroidal antiinflammatory drugs on a long-term basis, recent acute coronary syndrome, or requirement of clopidogrel after revascularization procedure Interventions N=7802 clopidogrel and aspirin (clopidogrel 75 mg/day and aspirin 75-162 mg/day) N=7801 aspirin (aspirin 75-162 mg/day plus matching placebo) Primary outcome Myocardial infarction, stroke, or death from cardiovascular causes 7.3 7 3 % 6 8 https://web.pathway.md/studies/rect4idwT0Gy2Nud6 1/2 6/28/23, 12:06 AM CHARISMA Pathway 7.3 % 6.8 5.5 % 3.6 % 1.8 % No significant difference 0.0 % Clopidogrel and aspirin Aspirin No significant difference in myocardial infarction, stroke, or death from cardiovascular causes (6.8% vs. 7.3%; RR 0.93, 95% CI 0.83 to 1.05) Secondary outcomes Significant decrease in hospitalizations for ischemic events (16.7% vs. 17.9%; RR 0.92, 95% CI 0.86 to 0.99) No significant difference in myocardial infarction, stroke, or death from cardiovascular causes, in patients with multiple risk factors (6.6% vs. 5.5%; RR 1.2, 95% CI 0.91 to 1.59) Safety outcomes Significant differences in severe bleeding (1.7% vs. 1.3%, p = 0.09; RR 1.25, 95% CI 0.97-1.61). Conclusion In patients with either clinically evident CVD or multiple risk factors for atherothrombotic events, clopidogrel and aspirin were not superior to aspirin with respect to myocardial infarction, stroke, or death from cardiovascular causes. Reference Bhatt DL, Fox KA, Hacke W et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006 Apr 20;354(16):1706-17. Open reference URL https://web.pathway.md/studies/rect4idwT0Gy2Nud6 2/2

6/28/23, 12:06 AM CHARM (adalimumab-eow) Pathway Feedback Search Clinical Topics Home Studies CHARM (adalimumab-eow) CHARM (adalimumab-eow) Disease Crohn's disease Trial question What is the role of adalimumab, every other week in patients with Crohn's disease? Study design Multi-center Double blinded RCT Population 521 patients Inclusion criteria: adult patients with moderately to severely active Crohn's disease who were responders of adalimumab induction therapy through week 0 and week 2 Key exclusion criteria: ulcerative colitis; symptomatic obstructive disease; bowel resection within the past 6 months; ostomy; extensive small bowel resection; short bowel syndrome; history of cancer Interventions N=260 adalimumab-eow (a dose of 40 mg every other week through week 56 plus induction therapy) N=261 placebo (matching placebo through week 56 plus induction therapy) Primary outcome Percentage of week-4 induction therapy responders who achieved remission at week 26 40.0 % 40 30.0 % 20.0 % 17 Significant increase 10.0 % NNT = 4 0.0 % https://web.pathway.md/studies/recx5morH6R5z4bfm 1/2 6/28/23, 12:06 AM CHARM (adalimumab-eow) Pathway 0 0 % Adalimumab-eow Placebo Significant increase in the percentage of week-4 induction therapy responders who achieved remission at week 26 (40% vs. 17%; AD 23%, 95% CI 9.35 to 36.65) Secondary outcomes Significant increase in the percentage of week-4 responders who achieved remission at week 56 (36% vs. 12%; AD 24%, 95% CI 9.76 to 38.24) Significant increase in the percentage of patients experiencing 70 points reduction in Crohn's disease activity index at week 56 (43% vs. 17.6%; AD 25.4%, 95% CI 10.33 to 40.47) Significant increase in the percentage of patients experiencing 100 points reduction in Crohn's disease activity index at week 56 (41.3% vs. 16.5%; AD 24.8%, 95% CI 10.08 to 39.52) Safety outcomes Significant differences in adverse events leading to study drug discontinuation (6.9% vs. 13.4%), serious adverse events (9.2% vs. 15.3%). Conclusion In adult patients with moderately to severely active Crohn's disease who were responders of adalimumab induction therapy through week 0 and week 2, adalimumab-eow was superior to placebo with respect to the percentage of week-4 induction therapy responders who achieved remission at week 26. Reference Jean-Fr d ric Colombel, William J Sandborn, Paul Rutgeerts et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007 Jan;132(1):52-65. Open reference URL https://web.pathway.md/studies/recx5morH6R5z4bfm 2/2

6/28/23, 12:07 AM CHARM (adalimumab-weekly) Pathway Feedback Search Clinical Topics Home Studies CHARM (adalimumab-weekly) CHARM (adalimumab-weekly) Disease Crohn's disease Trial question What is the role of adalimumab weekly in patients with Crohn's disease? Study design Multi-center Double blinded RCT Population Characteristics of study participants 62.0% female N = 518 38.0% male 518 patients (482 female, 296 male) Inclusion criteria: adult patients with moderately to severely active crohn's disease Key exclusion criteria: ulcerative colitis; symptomatic obstructive disease; bowel resection within the past 6 months; ostomy; extensive small bowel resection; short bowel syndrome; history of cancer Interventions N=257 adalimumab weekly (matching placebo through week 56 plus induction therapy) N=261 placebo (matching placebo through week 56 plus induction therapy) Primary outcome Percentage of week-4 induction therapy responders who achieved remission at week 26 47.0 % 47 35.3 % https://web.pathway.md/studies/recbsXdMDkgRmQNZZ 1/2 6/28/23, 12:07 AM 35 3 % CHARM (adalimumab-weekly) Pathway 23.5 % Significant increase 17 11.8 % NNT = 3 0.0 % Adalimumab weekly Placebo Significant increase in the percentage of week-4 induction therapy responders who achieved remission at week 26 (47% vs. 17%; AD 30%, 95% CI 12.2 to 47.8) Secondary outcomes Significant increase in the percentage of week-4 induction therapy responders who achieved remission at week 56 (41% vs. 12%; AD 29%, 95% CI 11.79 to 46.21) Significant increase in the percentage of patients experiencing 70 points reduction in Crohn's disease activity index at week 56 (49% vs. 17.6%; AD 31.4%, 95% CI 12.77 to 50.03) Significant increase in the percentage of patients experiencing 100 points reduction in Crohn's disease activity index at week 56 (47.8% vs. 16.5%; AD 31.3%, 95% CI 12.73 to 49.87) Safety outcomes Significant differences in adverse events leading to study drug discontinuation (4.7% vs. 13.4%), serious adverse events (8.2% vs. 15.3%). Conclusion In adult patients with moderately to severely active crohn's disease, adalimumab weekly was superior to placebo with respect to the percentage of week-4 induction therapy responders who achieved remission at week 26. Reference Jean-Fr d ric Colombel, William J Sandborn, Paul Rutgeerts et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007 Jan;132(1):52-65. Open reference URL https://web.pathway.md/studies/recbsXdMDkgRmQNZZ 2/2

6/28/23, 12:07 AM CHARM-Added Pathway Feedback Search Clinical Topics Home Studies CHARM Added CHARM Added Disease Heart failure Trial question What is the role of candesartan in patients with chronic HF and reduced left-ventricular systolic function taking ACEIs? Study design Multi-center Double blinded RCT Population Characteristics of study participants 21.0% female N = 2548 79.0% male 2548 patients (542 female, 2006 male) Inclusion criteria: patients with chronic HF and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors Key exclusion criteria: life-threatening adverse event; known bilateral renal artery stenosis; current symptomatic hypotension; persistent systolic or diastolic hypertension; stroke, acute myocardial infarction, or open heart surgery within the last 4 weeks; or previous heart transplant or heart transplant expected to be performed within the next 6 months Interventions N=1276 candesartan (target dose 32 mg once daily) N=1272 placebo (matching placebo) Primary outcome Cardiovascular death or hospital admission for CHF https://web.pathway.md/studies/recIoSXG7Rwk1eocu 1/2 6/28/23, 12:07 AM CHARM-Added Pathway 42.0 % 42 38 31.5 % 21.0 % Significant decrease 10.5 % NNT = 25 0.0 % Candesartan Placebo Significant decrease in cardiovascular death or hospital admission for CHF (38% vs. 42%; HR 0.85, 95% CI 0.75 to 0.96) Secondary outcomes Significant decrease in cardiovascular death, hospital admission for CHF, and MI (38.8% vs. 43.2%; HR 0.85, 95% CI 0.76 to 0.96) Safety outcomes Significant differences in drug discontinuation due to adverse event or abnormal laboratory value (24% vs. 18%, p = 0.0003). Conclusion In patients with chronic HF and reduced left-ventricular systolic function taking angiotensin- converting-enzyme inhibitors, candesartan was superior to placebo with respect to cardiovascular death or hospital admission for CHF. Reference McMurray JJ, Ostergren J, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003 Sep 6;362(9386):767-71. Open reference URL https://web.pathway.md/studies/recIoSXG7Rwk1eocu 2/2

6/28/23, 12:07 AM CHARM-Preserved Pathway Feedback Search Clinical Topics Home Studies CHARM Preserved CHARM Preserved Disease Heart failure Trial question What is the role of candesartan in patients with chronic HF and preserved left-ventricular ejection fraction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 40.0% female N = 3023 60.0% male 3023 patients (1212 female, 1811 male) Inclusion criteria: patients with chronic HF and preserved left-ventricular ejection fraction Key exclusion criteria: life-threatening adverse event; known bilateral renal artery stenosis; current symptomatic hypotension; persistent systolic or diastolic hypertension; stroke, acute myocardial infarction, or open heart surgery within the last 4 weeks; or previous heart transplant or heart transplant expected to be performed within the next 6 months Interventions N=1514 candesartan (target dose 32 mg once daily) N=1509 placebo (matching placebo daily) Primary outcome Cardiovascular death or admission to hospital for CHF 24 24 0 % 22 https://web.pathway.md/studies/recUc3ap5LC2KVloG 1/2 6/28/23, 12:07 AM 24.0 % CHARM-Preserved Pathway 22 18.0 % 12.0 % 6.0 % Borderline significant decrease 0.0 % Candesartan Placebo Borderline significant decrease in cardiovascular death or admission to hospital for CHF (22% vs. 24%; aHR 0.86, 95% CI 0.74 to 1) Secondary outcomes Significant decrease in nonfatal myocardial infarction and nonfatal stroke (26% vs. 28%; aHR 0.86, 95% CI 0.75 to 0.99) Significant decrease in hospital admission for chronic HF (15.9% vs. 18.3%; aHR 0.84, 95% CI 0.7 to 1) No significant difference in cardiovascular death (11.2% vs. 11.3%; aHR 0.95, 95% CI 0.76 to 1.18) Safety outcomes Significant difference in drug discontinuation due to adverse event or laboratory abnormality (17.8% vs. 13.5%). Conclusion In patients with chronic HF and preserved left-ventricular ejection fraction, candesartan was superior to placebo with respect to cardiovascular death or admission to hospital for CHF. Reference Yusuf S, Pfeffer MA, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003 Sep 6;362(9386):777-81. Open reference URL https://web.pathway.md/studies/recUc3ap5LC2KVloG 2/2

6/28/23, 12:26 AM CheckMate-057 Pathway Feedback Search Clinical Topics Home Studies CheckMate-057 CheckMate-057 Disease Non-small cell lung cancer Trial question What is the role of nivolumab in patients with advanced non-squamous non-small cell lung cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 45.0% female N = 582 55.0% male 582 patients (263 female, 319 male) Inclusion criteria: patients with non-squamous non-small cell lung cancer that had progressed during or after platinum-based doublet chemotherapy Key exclusion criteria: autoimmune disease, symptomatic ILD, systemic immunosuppression, prior treatment with immune-stimulatory antitumor agents including checkpoint-targeted agents, or docetaxel Interventions N=292 nivolumab (intravenous dose of 3 mg/kg every 2 weeks) N=290 docetaxel (intravenous dose of 75 mg/m every 3 weeks) Primary outcome Overall survival 12.2 months 12.2 https://web.pathway.md/studies/recUMAF4dYxeHInMz 1/2 6/28/23, 12:26 AM CheckMate-057 Pathway 9.4 9.1 months 6.1 months 3.0 months Significant increase 0.0 months Nivolumab Docetaxel Significant increase in overall survival (12.2 months vs. 9.4 months; HR 1.37, 95% CI 1.13 to 1.69) Secondary outcomes No significant difference in median progression free survival (2.3 months vs. 4.2 months; HR 0.92, 95% CI 0.77 to 1.1) Significant increase in objective response (19% vs. 12%; OR 1.7, 95% CI 0.27 to 3.13) Safety outcomes No significant differences in all-causality and any-grade adverse events, but fewer grade 3-4 adverse events were reported with nivolumab than docetaxel. Conclusion In patients with non-squamous non-small cell lung cancer that had progressed during or after platinum-based doublet chemotherapy, nivolumab was superior to docetaxel with respect to overall survival. Reference Borghaei H, Paz-Ares L, Horn L et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. Open reference URL https://web.pathway.md/studies/recUMAF4dYxeHInMz 2/2

6/28/23, 12:08 AM CHECKMATE-816 Pathway Feedback Search Clinical Topics Home Studies CHECKMATE 816 CHECKMATE 816 Disease Non-small cell lung cancer Trial question What is the role of neoadjuvant nivolumab plus chemotherapy in patients with resectable non- small cell lung cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 29.0% female N = 358 71.0% male 358 patients (103 female, 255 male) Inclusion criteria: patients with stage IB to IIIA resectable non-small cell lung cancer Key exclusion criteria: known ALK translocations or epidermal growth factor receptor mutations; locally advanced, inoperable or metastatic disease; active, known or suspected autoimmune disease Interventions N=179 nivolumab plus chemotherapy (nivolumab 360 mg plus platinum-doublet chemotherapy, followed by resection) N=179 chemotherapy alone (platinum-doublet chemotherapy alone, followed by resection) Primary outcome Event-free survival 31.6 months 31.6 https://web.pathway.md/studies/recF0uB1mOG2Mx2wE 1/2 6/28/23, 12:08 AM CHECKMATE-816 Pathway 23.7 months 20.8 15.8 months 7.9 months Significant increase 0.0 months Nivolumab plus chemotherapy Chemotherapy alone Significant increase in event-free survival (31.6 months vs. 20.8 months; AD 10.8 months, 95% CI 3.27 to 18.33) Secondary outcomes Significant increase in pathological complete response (24% vs. 2.2%; AD 21.8%, 95% CI 15.2 to 28.7) Borderline significant increase in major pathological response (36.9% vs. 8.9%; OR 5.7, 95% CI 3.16 to 10.26) Safety outcomes No significant differences in adverse events, grade 3 or 4 treatment-related adverse events. Conclusion In patients with stage IB to IIIA resectable non-small cell lung cancer, nivolumab plus chemotherapy was superior to chemotherapy alone with respect to a event-free survival. Reference Patrick M Forde, Jonathan Spicer, Shun Lu et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985. Open reference URL https://web.pathway.md/studies/recF0uB1mOG2Mx2wE 2/2

6/28/23, 12:08 AM CHEST-1 Pathway Feedback Search Clinical Topics Home Studies CHEST 1 CHEST 1 Disease Chronic thromboembolic pulmo Trial question What is the role of riociguat, a soluble guanylate cyclase stimulator, in patients with chronic thromboembolic pulmonary hypertension? Study design Multi-center Double blinded RCT Population Characteristics of study participants 66.0% female N = 261 34.0% male 261 patients (172 female, 89 male) Inclusion criteria: patients with inoperable chronic thromboembolic pulmonary hypertension, or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy Key exclusion criteria: receipt of an endothelin-receptor antagonist, prostacyclin analogue, phosphodiesterase type 5 inhibitor, or nitric oxide donor within the 3 months before study entry Interventions N=173 riociguat (an oral dose of 1-2.5 mg TID for 16 weeks) N=88 placebo (matching placebo TID for 16 weeks) Primary outcome Significant increase in improvement in 6-minute walk distance at week 16 (39 m vs. -6 m; MD 46, 95% CI 25 to 67) t https://web.pathway.md/studies/rectBS9P9bWgihKa0 S d 1/2 6/28/23, 12:08 AM CHEST-1 Pathway Secondary outcomes Significant decrease in elevation of pulmonary vascular resistance at week 16 (-226 dyn s/cm vs. 23 dyn s/cm ; MD -246, 95% CI -303 to -190) Significant decrease in improvement in N-terminal pro-BNP level at week 16 (-291 pg/mL vs. 76 pg/mL; MD -444, 95% CI -843 to -45) Significant increase in quality of life as measured by the EuroQol-5D questionnaire (0.06 vs. -0.08; MD 0.13, 95% CI 0.06 to 0.21) Safety outcomes No significant differences in clinical worsening, RV failure, syncope, other adverse events. Conclusion In patients with inoperable chronic thromboembolic pulmonary hypertension, or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy, riociguat was superior to placebo with respect to improvement in 6-minute walk distance at week 16. Reference Hossein-Ardeschir Ghofrani, Andrea M D'Armini, Friedrich Grimminger et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013 Jul 25;369(4):319-29. Open reference URL https://web.pathway.md/studies/rectBS9P9bWgihKa0 2/2

6/28/23, 12:08 AM CHIPS Pathway Feedback Search Clinical Topics Home Studies CHIPS CHIPS Disease Preeclampsia Trial question What is the effect of less-tight control of hypertension during pregnancy? Study design Multi-center Open label RCT Population 987 female patients Inclusion criteria: women at 14-34 weeks gestation with nonproteinuric preexisting or gestational hypertension Key exclusion criteria: proteinuria, used an angiotensin-converting-enzyme (ACE) inhibitor at 14 weeks 0 days of gestation or later, contraindication to either trial group because of a preexisting condition, known multiple gestation or a fetus with a major anomaly or chromosomal abnormality, had plans to terminate the pregnancy, Interventions N=493 less-tight control (target diastolic BP, 100 mmHg) N=488 tight control (target diastolic BP, 85 mmHg) Primary outcome Rate of pregnancy loss or requirement for high-level neonatal care for > 48 hours during the first 28 postnatal days 31.4 % 31.4 30.7 23.5 % 15.7 % 7.8 % No significant difference 0.0 % Less-tight control Tight control https://web.pathway.md/studies/recaDwJmsp6dDfMHu 1/2 6/28/23, 12:08 AM CHIPS Pathway No significant difference in the rate of pregnancy loss or requirement for high-level neonatal care for > 48 hours during the first 28 postnatal days (31.4% vs. 30.7%; aOR 1.02, 95% CI 0.77 to 1.35) Secondary outcomes Significant increase in serious maternal complications (3.7% vs. 2%; aOR 1.74, 95% CI 0.79 to 3.84) Significant increase in severe hypertension (40.6% vs. 27.5%; aOR 1.8, 95% CI 1.34 to 2.38) Conclusion In women at 14-34 weeks gestation with nonproteinuric preexisting or gestational hypertension, less-tight control was not superior to tight control with respect to the rate of pregnancy loss or requirement for high-level neonatal care for > 48 hours during the first 28 postnatal days. Reference Magee LA, von Dadelszen P, Rey E et al. Less-tight versus tight control of hypertension in pregnancy. N Engl J Med. 2015 Jan 29;372(5):407-17. Open reference URL https://web.pathway.md/studies/recaDwJmsp6dDfMHu 2/2

6/28/23, 12:08 AM CHLAZIDOXY Pathway Feedback Search Clinical Topics Home Studies CHLAZIDOXY CHLAZIDOXY Disease Chlamydia trachomatis infection Trial question Is doxycycline superior to azithromycin in women with concurrent anorectal and vaginal Chlamydia trachomatis infection? Study design Multi-center Open label RCT Population 357 female patients Inclusion criteria: adult women positive for anorectal and vaginal Chlamydia trachomatis infection Key exclusion criteria: symptoms suggestive of pelvic inflammatory disease; receipt of antibiotic with antichlamydial activity within 21 days of screening; breast-feeding; severe liver or cardiac disease Interventions N=184 doxycycline (100 mg twice per day for 7 days) N=173 azithromycin (a single 1 g dose) Primary outcome Microbiological anorectal cure 94.0 % 94 85 70.5 % 47.0 % Significant increase 23.5 % NNH = 11 0.0 % Doxycycline Azithromycin https://web.pathway.md/studies/recCueJfPxDdoFEMd 1/2 6/28/23, 12:08 AM CHLAZIDOXY Pathway Significant increase in microbiological anorectal cure (94% vs. 85%; OR 2.33, 95% CI 1.1 to 4.76) Safety outcomes No significant difference in adverse events including gastrointestinal disorders; serious adverse effects. Conclusion In adult women positive for anorectal and vaginal Chlamydia trachomatis infection, doxycycline was superior to azithromycin with respect to microbiological anorectal cure. Reference Olivia Peuchant, Edouard Lhomme, Pervenche Martinet et al. Doxycycline versus azithromycin for the treatment of anorectal Chlamydia trachomatis infection in women concurrent with vaginal infection (CHLAZIDOXY study): a multicentre, open-label, randomised, controlled, superiority trial. Lancet Infect Dis. 2022 May 9;S1473-3099(22)00148-7. Open reference URL https://web.pathway.md/studies/recCueJfPxDdoFEMd 2/2

6/28/23, 12:08 AM CHOICE (alteplase) Pathway Feedback Search Clinical Topics Home Studies CHOICE (alteplase) CHOICE (alteplase) Disease Acute ischemic stroke Trial question What is the effect of intra-arterial alteplase in patients with large vessel occlusion acute ischemic stroke? Study design Multi-center Double blinded RCT Population Characteristics of study participants 46.0% female N = 113 54.0% male 113 patients (52 female, 61 male) Inclusion criteria: patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy Key exclusion criteria: contraindication to the use of intravenous alteplase; NIHSS score on admission > 25; complete clinical recovery in the angiography suite during the procedure Interventions N=61 alteplase (intra-arterial infusion of a dose of 0.225 mg/kg over 15-30 minutes) N=52 placebo (intra-arterial infusion of a matching placebo over 15 minutes) Primary outcome Percentage of patients with modified Rankin Scale score of 0 or 1 at 90 days 59.0 % 59 https://web.pathway.md/studies/recsEsvuL2OQ8OUvO 1/2 6/28/23, 12:08 AM CHOICE (alteplase) Pathway 44.3 % 40.4 29.5 % Significant increase 14.8 % NNH = 5 0.0 % Alteplase Placebo Significant increase in the percentage of patients with mRS score of 0 or 1 at 90 days (59% vs. 40.4%; AD 18.4%, 95% CI 0.3 to 36.4) Secondary outcomes No significant difference in the percentage of patients with improved angiographic eTICI score (8.5% vs. 7.7%; AD 0.6%, 95% CI -9.5 to 10.7) No significant difference in the percentage of patients with infarct expansion (63.9% vs. 74.5%; ARD -8.9, 95% CI -25.6 to 7.9) No significant difference in the percentage of patients with ischemic worsening (1.6% vs. 5.8%; ARD -4.9, 95% CI -18 to 8.3) Safety outcomes No significant differences in symptomatic intracranial hemorrhage, death at day 90. Conclusion In patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, alteplase was superior to placebo with respect to the percentage of patients with mRS score of 0 or 1 at 90 days. Reference Arturo Ren , M nica Mill n, Luis San Rom n et al. Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial. JAMA. 2022 Mar 1;327(9):826-835. Open reference URL https://web.pathway.md/studies/recsEsvuL2OQ8OUvO 2/2

6/28/23, 12:08 AM CHOICE Pathway Feedback Search Clinical Topics Home Studies CHOICE CHOICE Disease Pregnancy termination Reference Secura GM, Madden T, McNicholas C et al. Provision of no-cost, long-acting contraception and teenage pregnancy. N Engl J Med. 2014 Oct 2;371(14):1316-23. Open reference URL https://web.pathway.md/studies/rec9fHLJs2kheWpd6 1/1

6/28/23, 12:09 AM CHOIR Pathway Feedback Search Clinical Topics Home Studies CHOIR CHOIR Disease Disease Anemia of chronic kidney disease Chronic kidney disease Trial question What is the role of epoetin alfa in patients with anemia of CKD? Study design Multi-center Open label RCT Population Characteristics of study participants 55.0% female N = 1432 45.0% male 1432 patients (790 female, 642 male) Inclusion criteria: patients with anemia of CKD Key exclusion criteria: uncontrolled hypertension, active gastrointestinal bleeding, an iron- overload state, a history of frequent transfusions in the previous 6 months, refractory iron- deficiency anemia, active cancer, or previous therapy with epoetin alfa Interventions N=715 high-Hgb (administration of epoetin alfa for a target Hgb level of 13.5 g/dL) N=717 low-Hgb (administration of epoetin alfa for a target Hgb level of 11.3 g/dL) Primary outcome Death, myocardial infarction, hospitalization for congestive heart failure, or stroke. 17.5 % 17.5 13.5 13.1 % https://web.pathway.md/studies/recg6srjTwdrFYMbS 1/2 6/28/23, 12:09 AM CHOIR Pathway 8.8 % Significant increase 4.4 % NNH = 25 0.0 % High-hemoglobin Low-hemoglobin Significant increase in death, myocardial infarction, hospitalization for congestive HF, or stroke. (17.5% vs. 13.5%; HR 1.34, 95% CI 1.03 to 1.74) Secondary outcomes No significant difference in death (7.3% vs. 5%; HR 1.48, 95% CI 0.97 to 2.27) No significant difference in hospitalization for congestive HF (9% vs. 6.6%; HR 1.41, 95% CI 0.97 to 2.05) Significant increase in hospitalization for cardiovascular causes (32.6% vs. 27.5%; HR 1.23, 95% CI 1.01 to 1.48) Safety outcomes No significant difference in adverse event and thrombovascular event. Significant difference in serious adverse event (54.8% vs. 48.5%) and congestive HF (11.2% vs. 7.4%). Conclusion In patients with anemia of CKD, high-Hgb was inferior to low-Hgb with respect to death, myocardial infarction, hospitalization for congestive HF, or stroke Reference Singh AK, Szczech L, Tang KL et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006 Nov 16;355(20):2085-98. Open reference URL https://web.pathway.md/studies/recg6srjTwdrFYMbS 2/2

6/28/23, 12:09 AM CIBIS Pathway Feedback Search Clinical Topics Home Studies CIBIS CIBIS Disease Heart failure Trial question What is the role of -blockade therapy with bisoprolol in patients with chronic HF of various etiologies and a LVEF of < 40% on diuretic and vasodilator therapy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 17.0% female N = 641 83.0% male 641 patients (112 female, 529 male) Inclusion criteria: patients with chronic HF of various etiologies and an LVEF < 40% on diuretic and vasodilator therapy Key exclusion criteria: LV diastolic dysfunction, coronary heart disease awaiting bypass surgery or a recent history of myocardial infarction < 3 months, insulin-dependent diabetes, asthma, renal insufficiency hypothyroidism or hyperthyroidism, or malignant disease Interventions N=320 -blockade therapy with bisoprolol (recommended dose increment or at one of the dose levels of 1.25, 2.5, 3.75, or 5 mg/d) N=321 placebo (matching placebo) Primary outcome Death https://web.pathway.md/studies/recEklJnj1TGOez9x 1/2 6/28/23, 12:09 AM CIBIS Pathway 20.9 % 20.9 16.6 15.7 % 10.4 % 5.2 % No significant difference 0.0 % Beta-blockade therapy with bisoprolol Placebo No significant difference in death (16.6% vs. 20.9%; RR 0.8, 95% CI 0.56 to 1.15) Secondary outcomes Significant decrease in hospitalization for cardiac decompensation (19.1% vs. 28%; RR 0.68, 95% CI 0.16 to 1.2) Significant increase in reduction by at least one NYHA functional class (21.3% vs. 15%; RR 1.42, 95% CI 0.06 to 2.78) Safety outcomes No significant difference in premature treatment withdrawals. Conclusion In patients with chronic HF of various etiologies and an LVEF < 40% on diuretic and vasodilator therapy, -blockade therapy with bisoprolol was not superior to placebo with respect to death. Reference CIBIS Investigators. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees. Circulation. 1994 Oct;90(4):1765-73. Open reference URL https://web.pathway.md/studies/recEklJnj1TGOez9x 2/2

6/28/23, 12:26 AM Ciclesonide-COVID Pathway Feedback Search Clinical Topics Home Studies Ciclesonide-COVID Ciclesonide-COVID Disease COVID 19 infection Trial question What is the effect of inhaled ciclesonide in nonhospitalized participants with symptomatic COVID-19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 55.0% female N = 400 45.0% male 400 patients (221 female, 179 male) Inclusion criteria: nonhospitalized participants with symptomatic COVID-19 infection Key exclusion criteria: life-threatening co-morbidity; cystic fibrosis; hypersensitivity to ciclesonide; use of inhaled or intranasal corticosteroid; receipt of oral corticosteroids; receipt of hydroxychloroquine or chloroquine Interventions N=197 ciclesonide metered dose inhaler (160 g per actuation, 2 actuations BID for 30 days) N=203 placebo metered dose inhaler (matching placebo inhaler, 2 actuations BID for 30 days) Primary outcome Time to alleviate all COVID-19 related symptoms by day 30 19.0 days 19 19 14 3 days https://web.pathway.md/studies/recD56IcE1fHDN7OF 1/2 6/28/23, 12:26 AM 14.3 days Ciclesonide-COVID Pathway 9.5 days 4.8 days No significant difference 0.0 days Ciclesonide metered dose inhaler Placebo metered dose inhaler No significant difference in time to alleviate all COVID-19 related symptoms by day 30 (19 days vs. 19 days; HR 1.08, 95% CI 0.84 to 1.38) Secondary outcomes Significant decrease in the rate of COVID-19 related emergency department visits or hospital admissions by day 30 (1% vs. 5.4%; OR 0.18, 95% CI 0.04 to 0.85) No significant difference in the rate of hospital admission or death by day 30 (1.5% vs. 3.4%; OR 0.45, 95% CI 0.11 to 1.84) No significant difference in COVID-19 symptoms reduction by day 30 (70.6% vs. 63.5%; OR 1.28, 95% CI 0.84 to 1.97) Safety outcomes No significant difference in adverse events. Conclusion In nonhospitalized participants with symptomatic COVID-19 infection, ciclesonide metered dose inhaler was not superior to placebo metered dose inhaler with respect to time to alleviate all COVID-19 related symptoms by day 30. Reference Brian M Clemency, Renoj Varughese, Yaneicy Gonzalez-Rojas et al. Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA Intern Med. 2022 Jan 1;182(1):42-49. Open reference URL https://web.pathway.md/studies/recD56IcE1fHDN7OF 2/2

6/28/23, 12:27 AM Ciprofloxacin for 7 vs. 14 days in pyelonephritis Pathway Feedback Search Clinical Topics Home Studies Ciprofloxacin for 7 vs. 14 days in pyelonephritis Ciprofloxacin for 7 vs. 14 days in pyelonephritis Disease Acute pyelonephritis Trial question Is ciprofloxacin for 7 days noninferior to 14 days ciprofloxacin in women with acute pyelonephritis? Study design Multi-center Double blinded RCT Population 248 female patients Inclusion criteria: non-pregnant women with acute pyelonephritis Key exclusion criteria: pregnancy or lactation; inadequate contraception for women of childbearing age; known hypersensitivity to fluoroquinolones; systemic antibiotic treatment within the preceding 72 h; presence of an indwelling urinary catheter or clean intermittent catheterization of the bladder Interventions N=126 treatment with ciprofloxacin for 7 days (500 mg BID for 7 days followed by placebo for next 7 days) N=122 treatment with ciprofloxacin for 14 days (500 mg BID for 14 days) Primary outcome Short-term clinical cure 97.0 % 97 96 72.8 % 48.5 % Difference not exceeding nonferiority margin 24.3 % 0.0 % Treatment with ciprofloxacin for 7 days Treatment with ciprofloxacin for 14 days https://web.pathway.md/studies/recj3Zfhpvw35fTnd 1/2 6/28/23, 12:27 AM Ciprofloxacin for 7 vs. 14 days in pyelonephritis Pathway Difference not exceeding nonferiority margin in short-term clinical cure (97% vs. 96%; ARD -0.9, 90% CI -6.5 to 4.8) Safety outcomes No significant difference in adverse events (5% vs. 6%). Significant differences in mucosal candida infection (0 vs. 5, p = 0.036). Conclusion In non-pregnant women with acute pyelonephritis, treatment with ciprofloxacin for 7 days were noninferior to treatment with ciprofloxacin for 14 days with respect to a short-term clinical cure. Reference Sandberg T, Skoog G, Hermansson AB et al. Ciprofloxacin for 7 days versus 14 days in women with acute pyelonephritis: a randomised, open-label and double-blind, placebo-controlled, non- inferiority trial. Lancet. 2012 Aug 4;380(9840):484-90. Open reference URL https://web.pathway.md/studies/recj3Zfhpvw35fTnd 2/2

6/28/23, 12:09 AM CIRT Pathway Feedback Search Clinical Topics Home Studies CIRT CIRT Disease Disease Coronary artery disease Diabetes mellitus type 2 Trial question What is the role of low-dose methotrexate in patients with previous MI or MVCAD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 19.0% female N = 4786 81.0% male 4786 patients (898 female, 3888 male) Inclusion criteria: patients with previous MI or multivessel CAD and either T2DM or metabolic syndrome Key exclusion criteria: history of chronic infection, tuberculosis, pulmonary fibrosis, alcohol abuse, hepatic or renal dysfunction and women of childbearing potential Interventions N=2391 low-dose methotrexate (15 to 20 mg weekly, with 1 mg folate daily) N=2395 placebo (matching tablet weekly, with 1 mg folate daily) Primary outcome Incidence of nonfatal MI, nonfatal CVA, CV death, or hospitalization for UA requiring urgent revascularization 4.3/100 py 4.31 4.13 3 2/100 py https://web.pathway.md/studies/recNLBmLBV0zB52Ob 1/2 6/28/23, 12:09 AM 3.2/100 py CIRT Pathway 2.2/100 py 1.1/100 py No significant difference 0.0/100 py Low-dose methotrexate Placebo No significant difference in the incidence of nonfatal MI, nonfatal CVA, CV death, or hospitalization for UA requiring urgent revascularization (4.13 /100 py vs. 4.31 /100 py; HR 0.96, 96% CI 0.79 to 1.16) Secondary outcomes No significant difference in the incidence of nonfatal MI, nonfatal CVA, or CV death (3.46 /100 py vs. 3.43 /100 py; HR 1.01, 95% CI 0.82 to 1.25) Safety outcomes No significant differences in serious adverse events, including bleeding and infection. Leukopenia, elevated liver enzymes and increased incidence of non-basal-cell skin cancer was noted in methotrexate group than in placebo. Conclusion In patients with previous MI or multivessel CAD and either T2DM or metabolic syndrome, low- dose methotrexate was not superior to placebo with respect to the incidence of nonfatal MI, nonfatal CVA, CV death, or hospitalization for UA requiring urgent revascularization. Reference Ridker PM, Everett BM, Pradhan A et al. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2019 Feb 21;380(8):752-762. Open reference URL https://web.pathway.md/studies/recNLBmLBV0zB52Ob 2/2

6/28/23, 12:10 AM CITRIS-ALI Pathway Feedback Search Clinical Topics Home Studies CITRIS ALI CITRIS ALI Disease Disease Acute respiratory distress syndr Sepsis and septic shock Trial question What is the effect of vitamin C infusion in patients with sepsis and severe acute respiratory failure? Study design Multi-center Double blinded RCT Population Characteristics of study participants 46.0% female N = 167 54.0% male 167 patients (77 female, 90 male) Inclusion criteria: patients with sepsis and ARDS present for < 24 hours Key exclusion criteria: known allergy to vitamin C; > 48 hours elapsed since ARDS; moribund and not expected to survive 24 hours; ILD, diffuse alveolar hemorrhage, diabetic ketoacidosis, or an active kidney stone Interventions N=84 vitamin C (intravenous infusion of 50 mg/kg of body weight in dextrose 5% in water every 6 hours for 96 hours) N=83 placebo (intravenous infusion of dextrose 5% in water only every 6 hours for 96 hours) Primary outcome Change in modified Sequential Organ Failure Assessment scores from enrollment to 96 hours 3.5 points 3.5 https://web.pathway.md/studies/rec5OXjXCoxndqGZ9 1/2 6/28/23, 12:10 AM CITRIS-ALI Pathway 3 2.6 points 1.8 points 0.9 points No significant difference 0.0 points Vitamin C Placebo No significant difference in change in modified Sequential Organ Failure Assessment scores from enrollment to 96 hours (3 points vs. 3.5 points; AD -0.1 points, 95% CI -1.23 to 1.03) Secondary outcomes No significant difference in CRP levels at 168 hours (54.1 g/mL vs. 46.1 g/mL; AD 7.94 g/mL, 95% CI -8.23 to 24.1) No significant difference in thrombomodulin levels at 168 hours (14.5 ng/mL vs. 13.8 ng/mL; AD 0.69 ng/mL, 95% CI -2.8 to 4.2) Significant increase in death at day 28 (29.8% vs. 46.3%; ARD 16.58, 95% CI 2 to 31.1) Safety outcomes No significant difference in ventilator-free days. Significant differences in hospital-free days (22.6 days vs. 15.5 days), ICU-free days (10.7 days vs. 7.7 days), transfer out of ICU by hour 168 (25% vs. 12.5%). Conclusion In patients with sepsis and ARDS present for < 24 hours, vitamin C was not superior to placebo with respect to change in modified Sequential Organ Failure Assessment scores from enrollment to 96 hours. Reference Alpha A Fowler rd, Jonathon D Truwit, R Duncan Hite et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019 Oct 1;322(13):1261-1270. Open reference URL https://web.pathway.md/studies/rec5OXjXCoxndqGZ9 2/2

6/28/23, 12:28 AM Clarity AD Pathway Feedback Search Clinical Topics Home Studies Clarity AD Clarity AD Disease Alzheimer's disease Trial question What is the role of lecanemab in patients with early Alzheimer's disease? Study design Multi-center Double blinded RCT Population Characteristics of study participants 52.0% female N = 1734 48.0% male 1734 patients (907 female, 827 male) Inclusion criteria: participants 50-90 years of age with early Alzheimer's disease with evidence of amyloid on positron-emission tomography or by CSF testing Key exclusion criteria: any neurological condition that may be contributing to cognitive impairment above and beyond that caused by participant's Alzheimer's disease; history of TIAs, stroke, seizures within 12 months of screening; any psychiatric diagnosis or symptoms Interventions N=859 lecanemab (an intravenous dose of 10 mg/kg every 2 weeks) N=875 placebo (matching placebo every 2 weeks) Primary outcome Reduction in clinical dementia rating-sum of boxes at 18 months 1.7 1.66 https://web.pathway.md/studies/recTq7cu4CChfHOXR 1/2 6/28/23, 12:28 AM Clarity AD Pathway 1.2 1.21 0.8 0.4 Significant decrease 0.0 Lecanemab Placebo Significant decrease in reduction in the clinical dementia rating-sum of boxes at 18 months (1.21 vs. 1.66; ARD -0.45, 95% CI -0.67 to -0.23) Secondary outcomes Significant decrease in reduction in 14-item Cognitive Subscale of the Alzheimer's Disease Assessment Scale (4.14 vs. 5.58; ARD -1.44, 95% CI -2.27 to -0.61) Significant decrease in reduction in Alzheimer's disease composite score (0.164 vs. 0.214; ARD -0.05, 95% CI -0.07 to -0.03) Significant increase in improvement in Alzheimer's disease cooperative study-activities of daily living scale for mild cognitive impairment score (-3.5 vs. -5.5; AD 2, 95% CI 1.2 to 2.8) Safety outcomes No significant difference in adverse events and serious adverse events including death. Conclusion In participants 50-90 years of age with early Alzheimer's disease with evidence of amyloid on positron-emission tomography or by CSF testing, lecanemab was superior to placebo with respect to reduction in the clinical dementia rating-sum of boxes at 18 months. Reference Christopher H van Dyck, Chad J Swanson, Paul Aisen et al. Lecanemab in Early Alzheimer's Disease. N Engl J Med. 2023 Jan 5;388(1):9-21. Open reference URL https://web.pathway.md/studies/recTq7cu4CChfHOXR 2/2

6/28/23, 12:10 AM CLARITY Pathway Feedback Search Clinical Topics Home Studies CLARITY CLARITY Disease COVID 19 infection Trial question What is the role of ARBs in patients with COVID-19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 787 64.0% male 787 patients (282 female, 505 male) Inclusion criteria: adult patients admitted to the hospital for the management of COVID-19 Key exclusion criteria: previous treatment with a renin-angiotensin system blockade; hyperkalemia or unrecorded serum potassium; low eGFR; or unrecorded kidney function Interventions N=393 ARB (predominantly oral telmisartan at a starting dose of 40 mg/day for 28 days) N=394 placebo (matching placebo for 28 days) Primary outcome World Health Organization Scale score at day 14 1.0 1 1 0.8 0.5 https://web.pathway.md/studies/recGmL4ZNMLc1p86G 1/2 6/28/23, 12:10 AM CLARITY Pathway 0.3 Borderline significant increase 0.0 Angiotensin receptor blocker Placebo Borderline significant increase in WHO Scale score at day 14 (1 vs. 1; OR 1.51, 95% CI 1.02 to 2.23) Secondary outcomes No significant difference in death at day 28 (2.5% vs. 1.5%; OR 1.74, 95% CI 0.62 to 5.25) No significant difference in respiratory failure (6.6% vs. 5.1%; HR 1.32, 95% CI 0.74 to 2.43) Safety outcomes No significant differences in hyperkalemia, hypotension, AKI. Conclusion In adult patients admitted to the hospital for the management of COVID-19, ARB was not superior to placebo with respect to WHO Scale score at day 14. Reference Meg J Jardine, Sradha S Kotwal, Abhinav Bassi et al. Angiotensin receptor blockers for the treatment of covid-19: pragmatic, adaptive, multicentre, phase 3, randomised controlled trial. BMJ. 2022 Nov 16;379:e072175. Open reference URL https://web.pathway.md/studies/recGmL4ZNMLc1p86G 2/2

6/28/23, 12:10 AM CLASSIC Pathway Feedback Search Clinical Topics Home Studies CLASSIC CLASSIC Disease Sepsis and septic shock Trial question What is the role of intravenous fluid restriction in ICU patients with septic shock? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 1545 59.0% male 1545 patients (627 female, 904 male) Inclusion criteria: patients with septic shock in the ICU who received at least 1 L of intravenous fluid Key exclusion criteria: septic shock for > 12 hours; life-threatening bleeding; acute burn injury involving > 10% of BSA; pregnancy Interventions N=764 restrictive fluid (no intravenous fluids administration unless extenuating circumstances occur) N=781 standard fluid (no upper limit for the use of intravenous fluids) Primary outcome Death at day 90 42.3 % 42.3 42.1 31 7 % https://web.pathway.md/studies/recfN08vkDI5Wkeas 1/2 6/28/23, 12:10 AM 31.7 % CLASSIC Pathway 21.1 % 10.6 % No significant difference 0.0 % Restrictive fluid Standard fluid No significant difference in death at day 90 (42.3% vs. 42.1%; AD 0.1%, 95% CI -4.7 to 4.9) Secondary outcomes No significant difference in serious adverse reaction (4.1% vs. 4.1%; ARD -0.1, 99% CI -2.8 to 2.6) No significant difference in days alive and out of the hospital (21 days vs. 33 days; ARD -12, 95% CI -30 to 6) Conclusion In patients with septic shock in the ICU who received at least 1 L of intravenous fluid, restrictive fluid was not superior to standard fluid with respect to death at day 90. Reference Tine S Meyhoff, Peter B Hjortrup, J rn Wetterslev et al. Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med. 2022 Jun 30;386(26):2459-2470. Open reference URL https://web.pathway.md/studies/recfN08vkDI5Wkeas 2/2

6/28/23, 12:11 AM CLEAR Harmony Pathway Feedback Search Clinical Topics Home Studies CLEAR Harmony CLEAR Harmony Disease Disease Disease Coronary artery disease Dyslipidemia Familia Trial question What is the role of bempedoic acid in patients with increased LDL cholesterol levels? Study design Multi-center Double blinded RCT Population Characteristics of study participants 27.0% female N = 2230 73.0% male 2230 patients (602 female, 1628 male) Inclusion criteria: patients taking the maximum tolerated dose of statin therapy with ASCVD Key exclusion criteria: use of gemfibrozil or simvastatin at doses > 40 mg/day; total fasting triglyceride 500 mg/dL; BMI 50 kg/m ; use of a proprotein convertase subtilisin/kexin 9 within the past 4 weeks Interventions N=1488 bempedoic acid (at an oral dose of 180 mg once daily) N=742 placebo (matching placebo tablet taken PO once daily) Primary outcome Adverse events 78.7 % 78.5 78.7 59.0 % https://web.pathway.md/studies/recFQneg6S8gUMIdX 1/2 6/28/23, 12:11 AM CLEAR Harmony Pathway 39.4 % 19.7 % No significant difference 0.0 % Bempedoic acid Placebo No significant difference in adverse events (78.5% vs. 78.7%; ARD -0.2, 95% CI -3.39 to 2.99) Secondary outcomes Significant decrease in change in the low-density lipoprotein cholesterol level at week 12 (-16.5% vs. 1.6%; ARD -18.1, 95% CI -20 to -16.1) Significant decrease in change in the low-density lipoprotein cholesterol level at week 24 (-14.9% vs. 1.2%; ARD -16.1, 95% CI -18.2 to -14) Significant decrease in total cholesterol level elevation at week 12 (-10.3% vs. 0.8%; ARD -11.1, 95% CI -12.5 to -9.8) Safety outcomes No significant difference in serious adverse events. Significant differences in adverse events leading to discontinuation of trial agent (10.9% vs. 7.1%), gout (1.2% vs. 0.3%), new-onset or worsening diabetes (3.3% vs. 5.4%). Conclusion In patients taking the maximum tolerated dose of statin therapy with ASCVD, bempedoic acid was not superior to placebo with respect to adverse events. Reference Kausik K Ray, Harold E Bays, Alberico L Catapano et al. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019 Mar 14;380(11):1022-1032. Open reference URL https://web.pathway.md/studies/recFQneg6S8gUMIdX 2/2

6/28/23, 12:11 AM CLEAR Outcomes Pathway Feedback Search Clinical Topics Home Studies CLEAR Outcomes CLEAR Outcomes Disease Disease Disease Coronary artery disease Dyslipidemia Familia Trial question What is the role of bempedoic acid in patients with statin-intolerant patients? Study design Multi-center Double blinded RCT Population Characteristics of study participants 48.0% female N = 13970 52.0% male 13970 patients (6740 female, 7230 male) Inclusion criteria: patients who were unable or unwilling to take statins owing to unacceptable adverse effects and had or were at high risk for CVD Key exclusion criteria: fasting blood triglycerides > 500 mg/dL; recent history of major cardiovascular events, TIA, or unstable or symptomatic cardiac arrhythmia; history of severe HF; uncontrolled hypertension or uncontrolled diabetes Interventions N=6992 bempedoic acid (an oral dose of 180 mg daily) N=6978 placebo (matching placebo) Primary outcome Major adverse cardiovascular events 13.3 % 13.3 11.7 10 0 % https://web.pathway.md/studies/recrX8Cn3Yxp3ECUX 1/2 6/28/23, 12:11 AM 10.0 % CLEAR Outcomes Pathway 6.7 % Significant decrease 3.3 % NNT = 62 0.0 % Bempedoic acid Placebo Significant decrease in major adverse cardiovascular events (11.7% vs. 13.3%; HR 0.87, 95% CI 0.79 to 0.96) Secondary outcomes Significant decrease in composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (8.2% vs. 9.5%; HR 0.85, 95% CI 0.76 to 0.96) Significant decrease in fatal or nonfatal myocardial infarction (3.7% vs. 4.8%; HR 0.77, 95% CI 0.66 to 0.91) Significant decrease in coronary revascularization (6.2% vs. 7.6%; HR 0.81, 95% CI 0.72 to 0.92) Safety outcomes No significant difference in adverse and serious adverse events. Significant difference in hyperuricemia (10.9% vs. 5.6%). Conclusion In patients who were unable or unwilling to take statins owing to unacceptable adverse effects and had or were at high risk for CVD, bempedoic acid was superior to placebo with respect to major adverse cardiovascular events. Reference Steven E Nissen, A Michael Lincoff, Danielle Brennan et al. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023 Apr 13;388(15):1353-1364. Open reference URL https://web.pathway.md/studies/recrX8Cn3Yxp3ECUX 2/2

6/28/23, 12:11 AM CLEOPATRA Pathway Feedback Search Clinical Topics Home Studies CLEOPATRA CLEOPATRA Trial question What is the effect of pertuzumab in addition to trastuzumab and docetaxel in patients with HER2- positive metastatic breast cancer? Study design Multi-center Double blinded RCT Population 808 female patients Inclusion criteria: patients with metastatic breast cancer that is positive for HER2 (HER2) Key exclusion criteria: central-nervous-system metastases, LVEF was < 50% during or after previous trastuzumab therapy, or received other anticancer therapy (with the exception of one previous hormonal regimen) or had a cumulative exposure > 360 mg of doxorubicin/m of BSA or its equivalent Interventions N=402 pertuzumab (plus trastuzumab and docetaxel) N=406 placebo (plus trastuzumab and docetaxel) Primary outcome Median overall survival 56.5 months 56.5 42.4 months 40.8 28.3 months 14.1 months Significant increase 0.0 months Pertuzumab Placebo Significant increase in median overall survival (56.5 months vs. 40.8 months; HR 1.47, 95% CI 1.19 to 1.79) Secondary outcomes Significant increase in median progression-free survival (18.7 months vs. 12.4 months; HR 1.47, 95% CI 0.6 to 2.34) https://web.pathway.md/studies/recJfn0uhOkBUmLfp 1/2 6/28/23, 12:11 AM CLEOPATRA Pathway Safety outcomes Significant differences in diarrhea (28.1% vs. 14.2%), rash (18.3% vs. 8.0%), muscle spasm (7.8% vs. 2.3%), pruritus (13.7% vs. 5.7%), and upper respiratory tract infection (18.3% vs. 12.3%). Conclusion In patients with metastatic breast cancer that is positive for HER2 (HER2), pertuzumab was superior to placebo with respect to median overall survival. Reference Swain SM, Baselga J, Kim SB et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34. Open reference URL https://web.pathway.md/studies/recJfn0uhOkBUmLfp 2/2

6/28/23, 12:11 AM CLICK Pathway Feedback Search Clinical Topics Home Studies CLICK CLICK Disease Disease Chronic kidney disease Hypertension Trial question What is the role of chlorthalidone in patients with advanced CKD and poorly controlled hypertension? Study design Multi-center Double blinded RCT Population Characteristics of study participants 22.8% female N = 160 77.2% male 160 patients (36 female, 124 male) Inclusion criteria: patients with stage 4 CKD and poorly controlled hypertension Key exclusion criteria: 24-hour ambulatory systolic BP 160 mmHg or diastolic BP 100 mmHg; history of stroke or myocardial infarction; receipt of high-dose loop diuretics; receipt of thiazide or thiazide-like drugs within 12 weeks Interventions N=81 chlorthalidone (initial dose of 12.5 mg/day, doubled every 4 weeks to a maximum dose of 50 mg/day, for 12 weeks) N=79 placebo (matching placebo for 12 weeks) Primary outcome 24-hour ambulatory systolic blood pressure reduction at week 12 11.0 mmHg 11 https://web.pathway.md/studies/recUw7lUATGAofJEt 1/2 6/28/23, 12:11 AM CLICK Pathway 8.3 mmHg 5.5 mmHg 2.8 mmHg Significant increase 0.5 0.0 mmHg Chlorthalidone Placebo Significant increase in 24-hour ambulatory systolic BP reduction at week 12 (11 mmHg vs. 0.5 mmHg; AD 10.5 mmHg, 95% CI 14.6 to 6.4) Secondary outcomes Significant increase in urine albumin/creatinine ratio reduction at week 12 (52% vs. 4%; AD 50%, 95% CI 60 to 37) Significant increase in N-terminal pro-B-type natriuretic peptide reduction at week 12 (30% vs. 11%; AD 21%, 95% CI 35 to 4) Significant increase in eGFR improvement at week 12 (2.7 mL/min/1.73 m vs. 0.5 mL/min/1.73 m ; AD 2.2 mL/min/1.73 m , 95% CI 3.3 to 1) Safety outcomes No significant difference in serious adverse events. Conclusion In patients with stage 4 CKD and poorly controlled hypertension, chlorthalidone was superior to placebo with respect to a 24-hour ambulatory systolic BP reduction at week 12. Reference Rajiv Agarwal, Arjun D Sinha, Andrew E Cramer et al. Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease. N Engl J Med. 2021 Dec 30;385(27):2507-2519. Open reference URL https://web.pathway.md/studies/recUw7lUATGAofJEt 2/2

6/28/23, 12:11 AM CLOROTIC Pathway Feedback Search Clinical Topics Home Studies CLOROTIC CLOROTIC Disease Heart failure Trial question What is the effect of hydrochlorothiazide addition to loop diuretic therapy in patients with acute HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 48.0% female N = 230 52.0% male 230 patients (111 female, 119 male) Inclusion criteria: hospitalized adult patients with acute decompensated HF Key exclusion criteria: unstable on admission; treatment with inotropic agents; or any thiazide diuretic during the month before admission Interventions N=114 hydrochlorothiazide (at a dose of 25-100 mg/day, adjusted according to GFR, plus intravenous furosemide regimen) N=116 placebo (matching placebo plus intravenous furosemide regimen) Primary outcome Weight reduction at 72 hours 2.3 kg 2.3 https://web.pathway.md/studies/recSbGBntcqPrJOqR 1/2 6/28/23, 12:11 AM CLOROTIC Pathway 1.7 kg 1.5 1.1 kg 0.6 kg Significant increase 0.0 kg Hydrochlorothiazide Placebo Significant increase in weight reduction at 72 hours (2.3 kg vs. 1.5 kg; AD 1.14 kg, 95% CI 0.42 to 1.84) Secondary outcomes No significant difference in patient-reported dyspnea using area under curve for the VAS at 72 hours (960 vs. 720; AD 240, 95% CI -436.98 to 916.98) Significant increase in weight reduction at 96 hours (2.5 kg vs. 1.5 kg; AD 1.57 kg, 95% CI 0.76 to 2.35) No significant difference in patient-reported dyspnea using area under curve for the VAS at 96 hours (1500 vs. 1320; AD 180, 95% CI -389.96 to 749.96) Safety outcomes No significant difference in reduction in eGFR > 50%. Significant differences in impaired renal function (46.5% vs. 17.2%), elevation in creatinine > 26.5 mol/L (46.5% vs. 17.2%). Conclusion In hospitalized adult patients with acute decompensated HF, hydrochlorothiazide was superior to placebo with respect to weight reduction at 72 hours. Reference Joan Carles Trull s, Jos Luis Morales-Rull, Jes s Casado et al. Combining loop with thiazide diuretics for decompensated heart failure: the CLOROTIC trial. Eur Heart J. 2022 Nov 24;ehac689. Open reference URL https://web.pathway.md/studies/recSbGBntcqPrJOqR 2/2

6/28/23, 12:11 AM CLOSURE I Pathway Feedback Search Clinical Topics Home Studies CLOSURE I CLOSURE I Disease Disease Disease Acute ischemic stroke Patent foramen ovale Transie Reference Furlan AJ, Reisman M, Massaro J et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med. 2012 Mar 15;366(11):991-9. Open reference URL https://web.pathway.md/studies/recdwF3QJQp3u3B4q 1/1

6/28/23, 12:12 AM CLOT Pathway Feedback Search Clinical Topics Home Studies CLOT CLOT Disease Disease Disease Cancer-associated thrombosis Deep vein thrombosis Pulmon Trial question Is LMWH superior to coumarin for the prevention of recurrent VTE in patients with cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 51.0% female N = 676 49.0% male 676 patients (348 female, 328 male) Inclusion criteria: patients with cancer who had acute, symptomatic proximal deep vein thrombosis, PE, or both Key exclusion criteria: weight 40 kg, ECOG performance status score of 3 or 4, receipt of OAC therapy, serious bleeding within the previous two weeks, high risk of serious bleeding, contraindications to heparin therapy, or pregnancy Interventions N=338 subcutaneous dalteparin (200 IU of dalteparin per kilogram once daily for the first month and approximately 150 IU per kilogram for the remaining 5 months) N=338 oral anticoagulation (dalteparin at a dose of 200 IU per kilogram of body weight SC once daily for 5-7 days and vitamin K antagonist for 6 months) Primary outcome Recurrent venous thromboembolism at 6 months https://web.pathway.md/studies/recGqmUJW68h59km3 1/2 6/28/23, 12:12 AM CLOT Pathway 17.0 % 17 12.8 % 9 8.5 % Significant decrease 4.3 % NNT = 13 0.0 % Subcutaneous dalteparin Oral anticoagulation Significant decrease in recurrent VTE at 6 months (9% vs. 17%; HR 0.48, 95% CI 0.3 to 0.77) Secondary outcomes No significant difference in death (39% vs. 41%; RR 0.95, 95% CI -1.94 to 3.84) Safety outcomes No significant difference in rate of major bleeding (6% vs. 4%) or any bleeding (14% vs. 19%). Conclusion In patients with cancer who had acute, symptomatic proximal deep vein thrombosis, PE, or both, subcutaneous dalteparin was superior to oral anticoagulation with respect to recurrent VTE at 6 months. Reference Lee AY, Levine MN, Baker RI et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53. Open reference URL https://web.pathway.md/studies/recGqmUJW68h59km3 2/2

6/28/23, 12:12 AM CLOVERS Pathway Feedback Search Clinical Topics Home Studies CLOVERS CLOVERS Disease Sepsis and septic shock Trial question Is restrictive fluid strategy superior to liberal fluid strategy in patients with sepsis-induced hypotension? Study design Multi-center Open label RCT Population Characteristics of study participants 47.0% female N = 1563 53.0% male 1563 patients (737 female, 826 male) Inclusion criteria: adult patients within 4 hours of a suspected or confirmed infection and sepsis-induced hypotension Key exclusion criteria: relapse of > 4 hours of meeting the criteria for sepsis-induced hypotension; elapse of > 24 hours since presentation at the hospital; previous receipt of > 3,000 mL of intravenous fluid during this episode; presence of fluid overload; severe volume depletion from nonseptic causes Interventions N=782 restrictive fluid strategy (early vasopressors, rescue fluids permitted for prespecified indications) N=781 liberal fluid strategy (initial 2,000 mL intravenous infusion of isotonic crystalloid, followed by fluid boluses administered on the basis of clinical triggers) P i t https://web.pathway.md/studies/recInxJ2LCodMtdka 1/2 6/28/23, 12:12 AM CLOVERS Pathway Primary outcome Death from any causes before discharge home at day 90 14.9 % 14.9 14 11.2 % 7.5 % 3.7 % No significant difference 0.0 % Restrictive fluid strategy Liberal fluid strategy No significant difference in death from any causes before discharge home at day 90 (14% vs. 14.9%; ARD -0.9, 95% CI -4.4 to 2.6) Secondary outcomes No significant difference in the number of days free from organ-support therapy at 28 days (24 days vs. 23.6 days; AD 0.3 days, 95% CI -0.5 to 1.2) No significant difference in the number of days free from ventilator use at 28 days (23.4 days vs. 22.8 days; AD 0.6 days, 95% CI -0.4 to 1.6) No significant difference in the number of days free from RRT at 28 days (24.1 days vs. 23.9 days; AD 0.2 days, 95% CI -0.8 to 1.2) Safety outcomes No significant difference in serious adverse events. Conclusion In adult patients within 4 hours of a suspected or confirmed infection and sepsis-induced hypotension, restrictive fluid strategy was not superior to liberal fluid strategy with respect to death from any causes before discharge home at day 90. Reference National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network et al. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023 Feb 9;388(6):499-510. Open reference URL https://web.pathway.md/studies/recInxJ2LCodMtdka 2/2

6/28/23, 12:13 AM COACT Pathway Feedback Search Clinical Topics Home Studies COACT COACT Disease Cardiac arrest Trial question What is the role of immediate coronary angiography and PCI in patients who have been successfully resuscitated after out-of-hospital cardiac arrest in the absence of STEMI? Study design Multi-center Open label RCT Population Characteristics of study participants 23.0% female N = 552 77.0% male 552 patients (127 female, 425 male) Inclusion criteria: out-of-hospital cardiac arrest patients without signs of STEMI Key exclusion criteria: signs of STEMI on ECG, shock, noncoronary cause of arrest, severe renal dysfunction (GFR< 30 ml/min), pregnancy Interventions N=273 immediate coronary angiography (initiated within 2 hours after randomization in addition to PCI, if indicated) N=265 delayed coronary angiography (performed after neurologic recovery in addition to PCI, if indicated) Primary outcome Rate of survival at 90-days 67.2 67.2 % 64 5 https://web.pathway.md/studies/rece8m8EaSNnDQs4Q 1/2 6/28/23, 12:13 AM 67.2 % COACT Pathway 64.5 50.4 % 33.6 % 16.8 % No significant difference 0.0 % Immediate coronary angiography Delayed coronary angiography No significant difference in the rate of survival at 90-days (64.5% vs. 67.2%; OR 0.89, 95% CI 0.62 to 1.27) Safety outcomes No significant difference in remaining secondary end points. Conclusion In out-of-hospital cardiac arrest patients without signs of STEMI, immediate coronary angiography was not superior to delayed coronary angiography with respect to the rate of survival at 90-days. Reference Lemkes JS, Janssens GN, van der Hoeven NW et al. Coronary Angiography after Cardiac Arrest without ST-Segment Elevation. N Engl J Med. 2019 Apr 11;380(15):1397-1407. Open reference URL https://web.pathway.md/studies/rece8m8EaSNnDQs4Q 2/2

6/28/23, 12:13 AM COAPT Pathway Feedback Search Clinical Topics Home Studies COAPT COAPT Disease Disease Heart failure Mitral regurgitation Trial question What is the role of transcatheter mitral valve repair in patients with HF and symptomatic moderate-to-severe or severe secondary MR? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 614 64.0% male 614 patients (219 female, 393 male) Inclusion criteria: patients with HF and symptomatic moderate-to-severe or severe secondary MR despite the use of maximal doses of guideline-directed medical therapy Key exclusion criteria: untreated clinically significant coronary artery disease requiring revascularization, CABG, PCI or TAVR within the prior 30 days, cerebrovascular accident within prior 30 days, severe symptomatic carotid stenosis, carotid surgery or stenting within prior 30 days Interventions N=302 transcatheter mitral valve repair (with MitraClip device within 14 days after randomization plus guideline-directed medical therapy) N=312 control (guideline-directed medical therapy alone) Primary outcome https://web.pathway.md/studies/recmgeqzmLkCrS0xy 1/2 6/28/23, 12:13 AM COAPT Pathway All hospitalizations for heart failure within 24 months 67.9 % / p-y 67.9 50.9 % / p-y 35.8 34.0 % / p-y 17.0 % / p-y Significant decrease 0.0 % / p-y Transcatheter mitral valve repair Control Significant decrease in all hospitalizations for HF within 24 months (35.8% / p-y vs. 67.9% / p-y; HR 0.53, 95% CI 0.4 to 0.7) Secondary outcomes Significant decrease in death from any cause at 2 years (29.1% vs. 46.1%; HR 0.62, 95% CI 0.46 to 0.82) Conclusion In patients with HF and symptomatic moderate-to-severe or severe secondary MR despite the use of maximal doses of guideline-directed medical therapy, transcatheter mitral valve repair was superior to control with respect to all hospitalizations for HF within 24 months. Reference Stone GW, Lindenfeld J, Abraham WT et al. Transcatheter Mitral-Valve Repair in Patients with Heart Failure. N Engl J Med. 2018 Dec 13;379(24):2307-2318. Open reference URL https://web.pathway.md/studies/recmgeqzmLkCrS0xy 2/2

6/28/23, 12:13 AM COCA Pathway Feedback Search Clinical Topics Home Studies COCA COCA Disease Cardiac arrest Trial question What is the effect of intravenous or intraosseous administration of calcium in adults with out-of- hospital cardiac arrest? Study design Multi-center Double blinded RCT Population Characteristics of study participants 29.0% female N = 391 71.0% male 391 patients (114 female, 277 male) Inclusion criteria: adult patients with out-of-hospital cardiac arrest who received at least 1 dose of epinephrine during the cardiac arrest Key exclusion criteria: traumatic cardiac arrest, pregnancy, prior enrollment in the trial, receipt of epinephrine outside the trial, or clinical indication for calcium Interventions N=193 calcium (up to 2 doses of intravenous or intraosseous calcium chloride, 5 mmol) N=198 saline (up to 2 doses of intravenous or intraosseous 9 mg/mL sodium chloride) Primary outcome Sustained return of spontaneous circulation 27.0 % 27 https://web.pathway.md/studies/reckeOCA4CY2n1LsJ 1/2 6/28/23, 12:13 AM COCA Pathway 20.3 % 19 13.5 % 6.8 % No significant difference 0.0 % Calcium Saline No significant difference in sustained ROSC (19% vs. 27%; RR 0.72, 95% CI 0.49 to 1.03) Secondary outcomes No significant difference in survival at day 30 (5.2% vs. 9.1%; RR 0.57, 95% CI 0.27 to 1.18) No significant difference in favorable neurological outcome at day 30 (3.6% vs. 7.6%; RR 0.48, 95% CI 0.2 to 1.12) Borderline significant decrease in favorable neurological outcome at day 90 (3.6% vs. 9.1%; RR 0.4, 95% CI 0.17 to 0.91) Conclusion In adult patients with out-of-hospital cardiac arrest who received at least 1 dose of epinephrine during the cardiac arrest, calcium was not superior to saline with respect to sustained ROSC. Reference Mikael Fink Vallentin, Asger Granfeldt, Carsten Meilandt et al. Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of- Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2021 Dec 14;326(22):2268-2276. Open reference URL https://web.pathway.md/studies/reckeOCA4CY2n1LsJ 2/2

6/28/23, 12:13 AM CODA Pathway Feedback Search Clinical Topics Home Studies CODA CODA Disease Acute appendicitis Trial question Is antibiotic therapy noninferior to appendectomy in patients with appendicitis? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 1552 63.0% male 1552 patients (576 female, 976 male) Inclusion criteria: adult patients with appendicitis Key exclusion criteria: septic shock; diffuse peritonitis; recurrent appendicitis; severe phlegmon on imaging; walled-off abscess; free air or more than minimal free fluid; evidence suggestive of neoplasm Interventions N=776 antibiotics (intravenous antibiotics for 24 hours followed by oral antibiotics for 10 days) N=776 appendectomy (use of laparoscopic and conventional surgical approaches) Primary outcome Mean improvement in health status at day 30 as measured by european quality of life-5 dimension questionnaire score 0.9 0.92 0.91 0 7 https://web.pathway.md/studies/recn9Bi4fqoM3JTKj 1/2 6/28/23, 12:13 AM CODA Pathway 0.7 0.5 Difference not exceeding nonferiority margin 0.2 0.0 Antibiotics Appendectomy Difference not exceeding nonferiority margin in mean improvement in health status at day 30 as measured by the european quality of life-5 dimension questionnaire score (0.92 vs. 0.91; MD 0.01, 95% CI 0 to 0.03) Secondary outcomes No significant difference in resolution of symptoms at day 30 (68% vs. 70%; RR 0.97, 95% CI 0.91 to 1.04) Borderline significant increase in the rate of emergency department or urgent care clinic visit after index treatment within 90 days (9% vs. 4%; RR 2.07, 95% CI 1.32 to 3.25) No significant difference in days from randomization to discharge for index treatment (1.33 vs. 1.3; RR 1, 95% CI 0.89 to 1.13) Safety outcomes No significant difference in serious adverse events. Significant difference in complications at day 90 (8.1 per 100 participants vs. 3.5 per 100 participants). Conclusion In adult patients with appendicitis, antibiotics were noninferior to appendectomy with respect to mean improvement in health status at day 30 as measured by the european quality of life-5 dimension questionnaire score. Reference CODA Collaborative, David R Flum, Giana H Davidson et al. A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis. N Engl J Med. 2020 Nov 12;383(20):1907-1919. Open reference URL https://web.pathway.md/studies/recn9Bi4fqoM3JTKj 2/2

6/28/23, 12:28 AM CodeBreak 200 Pathway Feedback Search Clinical Topics Home Studies CodeBreak 200 CodeBreak 200 Disease Non-small cell lung cancer Trial question Is sotorasib superior to docetaxel in previously treated patients with advanced non-small cell lung cancer with KRASG12C mutation? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 345 59.0% male 345 patients (141 female, 204 male) Inclusion criteria: adult patients with KRASG12C-mutated advanced non-small cell lung cancer, who progressed after previous platinum-based chemotherapy and a programmed cell death protein-1 or programmed cell death-ligand 1 inhibitor Key exclusion criteria: new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available; previous treatment with docetaxel; previous treatment with a direct KRASG12C inhibitor; systemic anticancer therapy within 28 days of study day 1; and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation Interventions N=171 sotorasib (an oral dose of 960 mg/day) N=174 docetaxel (an intravenous dose of 75 mg/m2 once every 3 weeks) P i t https://web.pathway.md/studies/rec2cxkYZ82BXlKkE 1/2 6/28/23, 12:28 AM CodeBreak 200 Pathway Primary outcome Median progression-free survival 5.6 months 5.6 4.5 4.2 months 2.8 months 1.4 months Significant increase 0.0 months Sotorasib Docetaxel Significant increase in median progression-free survival (5.6 months vs. 4.5 months; HR 1.515, 95% CI 1.16 to 1.96) Secondary outcomes Significant increase in overall response rate (28.1% vs. 13.2%; AD 14.8%, 95% CI 6.4 to 23.1) Safety outcomes No significant difference in treatment-emergent adverse events. Conclusion In adult patients with KRASG12C-mutated advanced non-small cell lung cancer, who progressed after previous platinum-based chemotherapy and a programmed cell death protein-1 or programmed cell death-ligand 1 inhibitor, sotorasib was superior to docetaxel with respect to median progression-free survival. Reference Adrianus Johannes de Langen, Melissa L Johnson, Julien Mazieres et al. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial. Lancet. 2023 Mar 4;401(10378):733-746. Open reference URL https://web.pathway.md/studies/rec2cxkYZ82BXlKkE 2/2

6/28/23, 12:13 AM COGENT Pathway Feedback Search Clinical Topics Home Studies COGENT COGENT Disease Disease Disease Acute ischemic stroke Coronary artery disease Periphe Trial question What is the role of prophylactic omeprazole among patients with an indication for dual antiplatelet therapy (aspirin and clopidogrel)? Study design Multi-center Double blinded RCT Population Characteristics of study participants 32.0% female N = 3873 68.0% male 3873 patients (1196 female, 2563 male) Inclusion criteria: patients with an indication for dual antiplatelet therapy Key exclusion criteria: short-term or long-term use of a PPI, an H2-receptor antagonist, sucralfate, or misoprostol; preexisting erosive esophagitis or esophageal or gastric variceal disease or previous nonendoscopic gastric surgery; receipt of clopidogrel or another thienopyridine for > 21 days before randomization; or recent fibrinolytic therapy Interventions N=1876 omeprazole (omeprazole 20 mg plus clopidogrel 75 mg and aspirin 75-325 mg daily) N=1885 placebo (clopidogrel 75 mg and aspirin 75-325 mg daily) Primary outcome Overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation https://web.pathway.md/studies/recNDZKIDnEYHzp70 1/2 6/28/23, 12:13 AM COGENT Pathway 2.9 % 2.9 2.2 % 1.4 % Significant decrease 1.1 0.7 % NNT = 56 0.0 % Omeprazole Placebo Significant decrease in overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation (1.1% vs. 2.9%; HR 0.34, 95% CI 0.18 to 0.63) Secondary outcomes Significant decrease in overt upper gastrointestinal bleeding (0.2% vs. 1.2%; HR 0.13, 95% CI 0.03 to 0.56) No significant difference in cardiovascular event (4.9% vs. 5.7%; HR 0.99, 99% CI 0.68 to 1.44) Safety outcomes No significant differences in rate of serious adverse events (10.1% vs. 9.4%, p=0.48) and overall adverse events (41.3% vs. 42.8%, p=0.33). Significant differences in risk of diarrhea (3.0% vs. 1.8%, p = 0.01). Conclusion In patients with an indication for dual antiplatelet therapy, omeprazole was superior to placebo with respect to overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. Reference Bhatt DL, Cryer BL, Contant CF et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010 Nov 11;363(20):1909-17. Open reference URL https://web.pathway.md/studies/recNDZKIDnEYHzp70 2/2

6/28/23, 12:14 AM COIITSS Pathway Feedback Search Clinical Topics Home Studies COIITSS COIITSS Disease Sepsis and septic shock Trial question Is intensive insulin therapy superior to conventional insulin therapy in patients treated with hydrocortisone for septic shock? Study design Multi-center Open label RCT Population Characteristics of study participants 35.0% female N = 509 65.0% male 509 patients (179 female, 330 male) Inclusion criteria: adult patients with septic shock who were treated with hydrocortisone Key exclusion criteria: pregnancy; life expectancy below 24 hours Interventions N=255 intensive insulin therapy (continuous insulin infusion to maintain blood glucose levels between 4-6 mmol/L plus hydrocortisone 50 mg intravenous bolus every 6 hours for 7 days) N=254 conventional insulin therapy (conventional glycemic control plus hydrocortisone 50 mg intravenous bolus every 6 hours for 7 days) Primary outcome Death in hospital 45.9 % 45.9 42.9 34 4 % https://web.pathway.md/studies/recwfsx7eoylEjKJo 1/2 6/28/23, 12:14 AM 34.4 % COIITSS Pathway 22.9 % 11.5 % No significant difference 0.0 % Intensive insulin therapy Conventional insulin therapy No significant difference in death in the hospital (45.9% vs. 42.9%; RR 1.07, 95% CI 0.88 to 1.3) Secondary outcomes No significant difference in median mechanical ventilation-free days within 28 days (10 days vs. 13 days; MD -3, 95% CI -11.71 to 5.71) No significant difference in sequential organ failure assessment score < 8 at day 7 (64.3% vs. 60.6%; AD 3.7%, 95% CI -4.45 to 11.85) Safety outcomes No significant difference in superinfections. Significant difference in severe hypoglycemia (16.4% vs. 7.8%). Conclusion In adult patients with septic shock who were treated with hydrocortisone, intensive insulin therapy was not superior to conventional insulin therapy with respect to death in the hospital. Reference COIITSS Study Investigators, Djillali Annane, Alain Cariou et al. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010 Jan 27;303(4):341-8. Open reference URL https://web.pathway.md/studies/recwfsx7eoylEjKJo 2/2

6/28/23, 12:14 AM COLCOT Pathway Feedback Search Clinical Topics Home Studies COLCOT COLCOT Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the effect of low-dose colchicine in patients after a myocardial infarction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 19.0% female N = 4745 81.0% male 4745 patients (909 female, 3836 male) Inclusion criteria: adult patients who had a myocardial infarction within 30 days of enrollment Key exclusion criteria: severe HF, stroke within the previous 3 months, IBD or chronic diarrhea, neuromuscular disease, severe renal disease, severe hepatic disease, a history of clinically significant sensitivity to colchicine Interventions N=2366 colchicine (at a dose of 0.5 mg once daily) N=2379 placebo (matching 0.5 mg sugar pill once daily) Primary outcome Death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization 7.1 7.1 % 5 5 https://web.pathway.md/studies/rec5ikA6cDV6BUP4j 1/2 6/28/23, 12:14 AM COLCOT Pathway 5.5 5.3 % 3.5 % Significant decrease NNT = 63 1.8 % 0.0 % Colchicine Placebo Significant decrease in death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization (5.5% vs. 7.1%; HR 0.77, 95% CI 0.61 to 0.96) Secondary outcomes No significant difference in death from cardiovascular causes, cardiac arrest, myocardial infarction, or stroke (4.7% vs. 5.5%; HR 0.85, 95% CI 0.66 to 1.1) No significant difference in deep vein thrombosis or PE (0.4% vs. 0.3%; HR 1.43, 95% CI 0.54 to 3.75) Safety outcomes No significant differences in adverse events, serious adverse events, diarrhea. Significant differences in pneumonia (0.9% vs. 0.4%), nausea (1.8% vs. 1.0%). Conclusion In adult patients who had a myocardial infarction within 30 days of enrollment, colchicine was superior to placebo with respect to death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. Reference Jean-Claude Tardif, Simon Kouz, David D Waters et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019 Dec 26;381(26):2497-2505. Open reference URL https://web.pathway.md/studies/rec5ikA6cDV6BUP4j 2/2

6/28/23, 12:14 AM COLONPREV Pathway Feedback Search Clinical Topics Home Studies COLONPREV COLONPREV Disease Disease Colon cancer Rectal cancer Trial question Is FITing noninferior to colonoscopy for colorectal cancer screening in average-risk adults? Study design Multi-center Open label RCT Population Characteristics of study participants 53.8% female N = 57404 46.2% male 57404 patients (28729 female, 24573 male) Inclusion criteria: asymptomatic adults 50 to 69 years of age Key exclusion criteria: personal history of colorectal cancer, adenoma, or IBD, a family history of hereditary or familial colorectal cancer, a severe coexisting illness, and previous colectomy Interventions N=26599 FITing (single stool sample every 2 years) N=26703 colonoscopy (one-time colonoscopy with bowel cleansing and sedation) Primary outcome Colorectal cancer 0.1 % 0.1 0.1 0.1 % 0.1 % https://web.pathway.md/studies/reco84XJPr74Rtfkc 1/2 6/28/23, 12:14 AM COLONPREV Pathway Difference not exceeding nonferiority margin 0.0 % 0.0 % Fecal immunochemical testing Colonoscopy Difference not exceeding nonferiority margin in colorectal cancer (0.1% vs. 0.1%; OR 0.99, 99% CI 0.61 to 1.64) Secondary outcomes Significant increase in advanced adenomas (0.9% vs. 1.9%; OR 2.3, 95% CI 1.97 to 2.69) Significant increase in nonadvanced adenomas (0.4% vs. 4.2%; OR 9.8, 95% CI 8.1 to 11.85) Significant decrease in participation (34.2% vs. 24.6%; OR 0.63, 95% CI 0.6 to 0.65) Safety outcomes Significant difference in major complications (0.1% vs. 0.5%). Conclusion In asymptomatic adults 50 to 69 years of age, FITing was noninferior to colonoscopy with respect to colorectal cancer. Reference Quintero E, Castells A, Bujanda L et al. Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening. N Engl J Med. 2012 Feb 23;366(8):697-706. Open reference URL https://web.pathway.md/studies/reco84XJPr74Rtfkc 2/2

6/28/23, 12:14 AM COLOR II Pathway Feedback Search Clinical Topics Home Studies COLOR II COLOR II Disease Rectal cancer Trial question Is laparoscopic surgery noninferior to open surgery in patients with rectal cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 37.0% female N = 1044 63.0% male 1044 patients (385 female, 659 male) Inclusion criteria: adult patients with rectal cancer within 15 cm from the anal verge without evidence of distant metastases Key exclusion criteria: T4 tumors or T3 tumors within 2 mm of the endopelvic fascia; T1 tumors treated by local excision; signs of acute intestinal obstruction; > 1 colorectal tumor Interventions N=699 laparoscopic surgery (laparoscopic-assisted rectal resection) N=345 open surgery (open laparotomy and rectal resection) Primary outcome Disease-free survival at 3 years 74.8 % 74.8 70.8 56.1 % https://web.pathway.md/studies/recx2VYsRGF3tDYnw 1/2 6/28/23, 12:14 AM COLOR II Pathway 37.4 % 18.7 % No significant difference 0.0 % Laparoscopic surgery Open surgery No significant difference in disease-free survival at 3 years (74.8% vs. 70.8%; AD 4%, 95% CI -1.9 to 9.9) Secondary outcomes No significant difference in overall survival at 3 years (86.7% vs. 83.6%; AD 3.1%, 95% CI -1.6 to 7.8) Conclusion In adult patients with rectal cancer within 15 cm from the anal verge without evidence of distant metastases, laparoscopic surgery was noninferior to open surgery with respect to a disease-free survival at 3 years. Reference H Jaap Bonjer, Charlotte L Deijen, Gabor A Abis et al. A Randomized Trial of Laparoscopic versus Open Surgery for Rectal Cancer. N Engl J Med. 2015 Apr 2;372(14):1324-32. Open reference URL https://web.pathway.md/studies/recx2VYsRGF3tDYnw 2/2

6/28/23, 12:14 AM COLOR Pathway Feedback Search Clinical Topics Home Studies COLOR COLOR Disease Hand osteoarthritis Trial question What is the role of colchicine in adults with symptomatic hand OA? Study design Single center Double blinded RCT Population Characteristics of study participants 69.0% female N = 100 31.0% male 100 patients (69 female, 31 male) Inclusion criteria: adults with symptomatic hand OA and finger pain of at least 40 mm on a 100 mm VAS Key exclusion criteria: other known medical diseases that may affect joints; known cutaneous deposition diseases; known blood dyscrasias and coagulation disorders; known malignancy Interventions N=50 colchicine (an oral dose of 0.5 mg BID for 12 weeks) N=50 placebo (matching placebo tablet BID for 12 weeks) Primary outcome Reduction in finger pain at week 12 13.9 mm 13.9 13.5 10.4 mm https://web.pathway.md/studies/recauv5XQYAo6X2k0 1/2 6/28/23, 12:14 AM COLOR Pathway 7.0 mm 3.5 mm No significant difference 0.0 mm Colchicine Placebo No significant difference in reduction in finger pain at week 12 (13.9 mm vs. 13.5 mm; AD 0.4 mm, 95% CI -6.7 to 7.6) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In adults with symptomatic hand OA and finger pain of at least 40 mm on a 100 mm VAS, colchicine was not superior to placebo with respect to reduction in finger pain at week 12. Reference Anna D ssing, Prof Marius Henriksen, Karen Ellegaard et al. Colchicine twice a day for hand osteoarthritis (COLOR): a double-blind, randomised, placebo-controlled trial. Lancet Rheumatol. 2023 Apr 4;5(5):E254-E262. Open reference URL https://web.pathway.md/studies/recauv5XQYAo6X2k0 2/2

6/28/23, 12:15 AM COMET Pathway Feedback Search Clinical Topics Home Studies COMET COMET Disease Heart failure Trial question Is carvedilol superior to metoprolol on clinical outcomes in patients with chronic HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 20.0% female N = 3029 80.0% male 3029 patients (612 female, 2417 male) Inclusion criteria: patients chronic HF (NYHA II-IV), previous cardiovascular admission, and LVEF < 35% on optimal medical treatment Key exclusion criteria: contraindication to use of -blockers, history of asthma or COPD, peripheral arterial disease with symptoms at rest, or unstable insulin-dependent diabetes mellitus Interventions N=1511 carvedilol (target dose 25 mg BID) N=1518 metoprolol (target dose 50 mg BID) Primary outcome All-cause death 40.0 % 40 34 https://web.pathway.md/studies/recsNr6cfMRquAO4E 1/2 6/28/23, 12:15 AM COMET Pathway 30.0 % 20.0 % Significant decrease 10.0 % NNT = 17 0.0 % Carvedilol Metoprolol Significant decrease in all-cause death (34% vs. 40%; HR 0.83, 95% CI 0.74 to 0.93) Secondary outcomes No significant difference in death or hospital admission (74% vs. 76%; HR 0.94, 95% CI 0.86 to 1.02) Safety outcomes No significant difference in incidence of side-effects and drug withdrawals. Conclusion In patients chronic HF (NYHA II-IV), previous cardiovascular admission, and LVEF < 35% on optimal medical treatment, carvedilol was superior to metoprolol with respect to a all-cause death. Reference Poole-Wilson PA, Swedberg K, Cleland JG et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003 Jul 5;362(9377):7-13. Open reference URL https://web.pathway.md/studies/recsNr6cfMRquAO4E 2/2

6/28/23, 12:15 AM COMMIT Pathway Feedback Search Clinical Topics Home Studies COMMIT COMMIT Disease Disease Non-ST-elevation myocardial inf ST-elevation myocardial infarction Trial question What is the role of metoprolol in patients suspected of acute myocardial infarction? Study design Multi-center Double blinded RCT Population Characteristics of study participants 28.0% female N = 45852 72.0% male 45852 patients (12759 female, 33093 male) Inclusion criteria: patients suspected of acute myocardial infarction Key exclusion criteria: scheduled for primary PCI, life-threatening disease, persistently low BP, low HR, heart block, or cardiogenic shock Interventions N=22929 metoprolol (up to 15 mg IV then 200 mg oral daily) N=22923 placebo (matching placebo) Primary outcome Death, reinfarction, or cardiac arrest 9.9 % 9.9 9.4 7.4 % 5.0 % https://web.pathway.md/studies/recqSeWcTcx0cn7vS 1/2 6/28/23, 12:15 AM COMMIT Pathway 2.5 % No significant difference 0.0 % Metoprolol Placebo No significant difference in death, reinfarction, or cardiac arrest (9.4% vs. 9.9%; OR 0.96, 96% CI 0.9 to 1.01) Secondary outcomes No significant difference in death (7.7% vs. 7.8%; OR 0.99, 99% CI 0.92 to 1.05) Significant decrease in reinfarction (2% vs. 2.5%; OR 0.82, 95% CI 0.72 to 0.92) Significant decrease in VF (2.5% vs. 3%; OR 0.83, 95% CI 0.75 to 0.93) Conclusion In patients suspected of acute myocardial infarction, metoprolol was not superior to placebo with respect to death, reinfarction, or cardiac arrest. Reference Chen ZM, Pan HC, Chen YP et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005 Nov 5;366(9497):1622-32. Open reference URL https://web.pathway.md/studies/recqSeWcTcx0cn7vS 2/2

6/28/23, 12:28 AM Compare-Acute Pathway Feedback Search Clinical Topics Home Studies Compare-Acute Compare-Acute Disease Disease Coronary artery disease ST-elevation myocardial infarction Trial question What is the effect of fractional flow reserve-guided multivessel angioplasty in patients with ST- segment elevation myocardial infarction and multivessel disease who underwent primary PCI of an infarct-related coronary artery? Study design Multi-center Single blinded RCT Population Characteristics of study participants 23.0% female N = 885 77.0% male 885 patients (202 female, 683 male) Inclusion criteria: patients with STEMI and multivessel disease who had undergone primary PCI of an infarct-related coronary artery Key exclusion criteria: left main coronary artery disease, chronic total occlusion, severe stenosis, with a Thrombolysis in Myocardial Infarction (TIMI) flow grade of 2 in the non- infarct-related coronary artery, suboptimal result or complications after treatment of an infarct- related coronary artery, severe valve dysfunction, and Killip class III or IV Interventions N=295 complete percutaneous coronary revascularization (fractional flow reserve-guided complete revascularization of non-infarct-related coronary arteries) N=590 infarct artery-only percutaneous coronary revascularization (no revascularization of non-infarct-related coronary arteries) https://web.pathway.md/studies/rectwLE3jzavGquyC 1/2 6/28/23, 12:28 AM Compare-Acute Pathway Primary outcome All-cause death, nonfatal myocardial infarction, revascularization and cerebrovascular events at 12 months 20.5 % 20.5 15.4 % 10.3 % Significant decrease 7.8 5.1 % NNT = 8 0.0 % Complete percutaneous coronary revascularization Infarct artery-only percutaneous coronary revascularization Significant decrease in all-cause death, nonfatal myocardial infarction, revascularization and cerebrovascular events at 12 months (7.8% vs. 20.5%; HR 0.35, 95% CI 0.22 to 0.55) Secondary outcomes No significant difference in death from any cause (1.4% vs. 1.7%; HR 0.8, 95% CI 0.25 to 2.56) Safety outcomes Significant difference in FFR-related serious adverse event (0 vs. 0.2%). Conclusion In patients with STEMI and multivessel disease who had undergone primary PCI of an infarct- related coronary artery, complete percutaneous coronary revascularization was superior to infarct artery-only percutaneous coronary revascularization with respect to a all-cause death, nonfatal myocardial infarction, revascularization and cerebrovascular events at 12 months. Reference Smits PC, Abdel-Wahab M, Neumann FJ et al. Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction. N Engl J Med. 2017 Mar 30;376(13):1234-1244. Open reference URL https://web.pathway.md/studies/rectwLE3jzavGquyC 2/2

6/28/23, 12:16 AM COMPASS-NCB Pathway Feedback Search Clinical Topics Home Studies COMPASS NCB COMPASS NCB Disease Disease Disease Acute ischemic stroke Coronary artery disease Periphe Trial question What is the net clinical benefit of low-dose rivaroxaban plus aspirin in a prespecified subpopulation of patients with chronic vascular disease within the COMPASS study? Study design Multi-center Double blinded RCT Population Characteristics of study participants 22.0% female N = 18278 78.0% male 18278 patients (4048 female, 14230 male) Inclusion criteria: patients with chronic vascular disease Key exclusion criteria: a high bleeding risk; a recent stroke or previous hemorrhagic or lacunar stroke; severe HF; advanced stable kidney disease; use of dual antiplatelet therapy, anticoagulation, or other antithrombotic therapy Interventions N=9152 low-dose rivaroxaban plus aspirin (rivaroxaban 2.5 mg BID plus aspirin 100 mg once daily) N=9126 aspirin monotherapy (aspirin 100 mg alone) Primary outcome Incidence of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ https://web.pathway.md/studies/reczGHeIRqssZqAPa 1/2 6/28/23, 12:16 AM COMPASS-NCB Pathway 3.1 % / y 3.1 2.5 2.3 % / y 1.6 % / y 0.8 % / y Significant decrease 0.0 % / y Low-dose rivaroxaban plus aspirin Aspirin monotherapy Significant decrease in the incidence of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ (2.5% / y vs. 3.1% / y; HR 0.8, 95% CI 0.7 to 0.91) Secondary outcomes Significant decrease in the incidence of stroke (0.5% / y vs. 0.8% / y; HR 0.58, 95% CI 0.44 to 0.76) Significant decrease in the incidence of cardiovascular death (0.9% / y vs. 1.2% / y; HR 0.78, 95% CI 0.64 to 0.96) No significant difference in the incidence of myocardial infarction (1% / y vs. 1.2% / y; HR 0.86, 95% CI 0.7 to 1.05) Safety outcomes No significant difference in fatal bleeding and symptomatic bleeding into critical organ. Conclusion In patients with chronic vascular disease, low-dose rivaroxaban plus aspirin was superior to aspirin monotherapy with respect to the incidence of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ. Reference Jan Steffel, John W Eikelboom, Sonia S Anand et al. The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared With Aspirin in Patients With Chronic Vascular Disease. Circulation. 2020 Jul 7;142(1):40-48. Open reference URL https://web.pathway.md/studies/reczGHeIRqssZqAPa 2/2

6/28/23, 12:16 AM CONFIRM Pathway Feedback Search Clinical Topics Home Studies CONFIRM CONFIRM Disease Hepatorenal syndrome Trial question What is the role of terlipressin in patients with type 1 hepatorenal syndrome? Study design Multi-center Double blinded RCT Population Characteristics of study participants 40.0% female N = 300 60.0% male 300 patients (121 female, 179 male) Inclusion criteria: adult patients with type 1 hepatorenal syndrome Key exclusion criteria: serum creatinine level > 7.0 mg/dL; 1 large-volume paracenteses of 4 L within 2 days before randomization; sepsis or uncontrolled bacterial infection for which antibiotic treatment was administered for < 2 days Interventions N=199 terlipressin (intravenous bolus injection of terlipressin plus albumin) N=101 placebo (matching placebo solution for injection plus albumin) Primary outcome Verified reversal of hepatorenal syndrome 32.0 % 32 24.0 % https://web.pathway.md/studies/rechnX8jfKVuaoedx 1/2 6/28/23, 12:16 AM CONFIRM Pathway 17 16.0 % Significant increase 8.0 % NNT = 7 0.0 % Terlipressin Placebo Significant increase in verified reversal of hepatorenal syndrome (32% vs. 17%; AD 15%, 95% CI 4.31 to 25.69) Secondary outcomes Significant increase in hepatorenal syndrome reversal (39% vs. 18%; AD 21%, 95% CI 8.54 to 33.46) Significant increase in the rate of hepatorenal syndrome reversal with no RRT through day 30 (34% vs. 17%; AD 17%, 95% CI 6.91 to 27.09) Significant increase in hepatorenal syndrome reversal in patients with systemic inflammatory response syndrome (37% vs. 6%; AD 31%, 95% CI 12.61 to 49.39) Safety outcomes No significant difference in adverse events. Significant differences in adverse events leading to discontinuation of trial regimen (12% vs. 5%), respiratory failure (10% vs. 3%). Conclusion In adult patients with type 1 hepatorenal syndrome, terlipressin was superior to placebo with respect to verified reversal of hepatorenal syndrome. Reference Florence Wong, S Chris Pappas, Michael P Curry et al. Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome. N Engl J Med. 2021 Mar 4;384(9):818-828. Open reference URL https://web.pathway.md/studies/rechnX8jfKVuaoedx 2/2

6/28/23, 12:16 AM CONSENSUS Pathway Feedback Search Clinical Topics Home Studies CONSENSUS CONSENSUS Disease Heart failure Trial question What is the role of enalapril in patients with congestive HF and NYHA class IV symptoms? Study design Multi-center Double blinded RCT Population Characteristics of study participants 30.0% female N = 253 70.0% male 253 patients (75 female, 178 male) Inclusion criteria: patients with congestive HF and NYHA class IV symptoms who were taking conventional treatment for HF Key exclusion criteria: acute pulmonary edema, hemodynamically important aortic or mitral valve stenosis, myocardial infarction within the previous two months, or unstable angina Interventions N=127 enalapril (initial dose of 5 mg BID, maximum dose of 20 mg BID) N=126 placebo (matching placebo BID) Primary outcome Death at 6 months 44.0 % 44 33.0 % https://web.pathway.md/studies/recVNcwpGKN9vdbYP 1/2 6/28/23, 12:16 AM CONSENSUS Pathway 26 22.0 % Significant decrease 11.0 % NNT = 6 0.0 % Enalapril Placebo Significant decrease in death at 6 months (26% vs. 44%; RR 0.65, 95% CI 0.24 to 1.06) Secondary outcomes Significant decrease in cardiac death due to progression of congestive HF (17.3% vs. 34.9%; RR 0.5, 95% CI 0.2 to 0.8) Safety outcomes No significant difference in overall withdrawal rates. Significant difference in hypotension requiring withdrawal (7 vs. 0). Conclusion In patients with congestive HF and NYHA class IV symptoms who were taking conventional treatment for HF, enalapril was superior to placebo with respect to death at 6 months. Reference CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987 Jun 4;316(23):1429-35. Open reference URL https://web.pathway.md/studies/recVNcwpGKN9vdbYP 2/2

6/28/23, 12:16 AM COPE Pathway Feedback Search Clinical Topics Home Studies COPE COPE Disease Acute pericarditis Trial question Is conventional therapy plus colchicine superior to conventional therapy alone in patients with a first episode of acute pericarditis? Study design Multi-center Open label RCT Population Characteristics of study participants 55.0% female N = 120 45.0% male 120 patients (66 female, 54 male) Inclusion criteria: patients with a first episode of acute pericarditis Key exclusion criteria: tuberculous, neoplastic, or purulent causes, severe liver disease, myopathy, blood dyscrasias or gastrointestinal disease, or pregnant and lactating women Interventions N=60 conventional therapy plus colchicine (1.0 to 2.0 mg for the first day and then a maintenance dose of 0.5 to 1.0 mg daily for 3 months plus aspirin) N=60 conventional therapy alone (aspirin 800 mg PO every 6 or 8 hours for 7 to 10 days with gradual tapering over 3 to 4 weeks) Primary outcome Recurrence at 18 months 32.3 % 32.3 https://web.pathway.md/studies/recAfrPSVmfbLfUkh 1/2 6/28/23, 12:16 AM COPE Pathway 24.2 % 16.1 % Significant decrease 10.7 8.1 % NNT = 5 0.0 % Conventional therapy plus colchicine Conventional therapy alone Significant decrease in recurrence at 18 months (10.7% vs. 32.3%; RR 0.33, 95% CI 3.1 to 10) Secondary outcomes Significant decrease in symptom persistence at 72 hours (11.7% vs. 36.7%; RR 0.32, 95% CI 0.11 to 0.53) Safety outcomes Significant difference in therapy discontinuation due to side-effects (8.3% vs. 0%). Conclusion In patients with a first episode of acute pericarditis, conventional therapy plus colchicine was superior to conventional therapy alone with respect to recurrence at 18 months. Reference Imazio M, Bobbio M, Cecchi E et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation. 2005 Sep 27;112(13):2012-6. Open reference URL https://web.pathway.md/studies/recAfrPSVmfbLfUkh 2/2

6/28/23, 12:16 AM COPERNICUS Pathway Feedback Search Clinical Topics Home Studies COPERNICUS COPERNICUS Disease Heart failure Trial question What is the role of carvedilol on the morbidity of patients with severe chronic HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 21.0% female N = 2289 79.0% male 2289 patients (470 female, 1819 male) Inclusion criteria: patients with symptoms of HF at rest or on minimal exertion and with an ejection fraction < 25% (but not volume-overloaded) Key exclusion criteria: HF caused by uncorrected primary valvular disease or a reversible form of cardiomyopathy; severe primary pulmonary, renal, or hepatic disease; or contraindication to -blocker therapy Interventions N=1156 carvedilol (target dose of 25 mg BID for an average of 10.4 months) N=1133 placebo (matching placebo for an average of 10.4 months) Primary outcome Death or hospitalization for a cardiovascular reason 41.6 % 41.6 https://web.pathway.md/studies/rec4NvXjaiEdZ5IF0 1/2 6/28/23, 12:16 AM COPERNICUS Pathway 31.2 % 30.2 20.8 % Significant decrease 10.4 % NNT = 9 0.0 % Carvedilol Placebo Significant decrease in death or hospitalization for a cardiovascular reason (30.2% vs. 41.6%; RR 0.73, 95% CI 0.63 to 0.84) Secondary outcomes Significant decrease in death or hospitalization for HF (25.5% vs. 37.9%; RR 0.69, 95% CI 0.59 to 0.81) Safety outcomes Significant differences in serious adverse event (39.0% vs. 45.5%, p = 0.002). Conclusion In patients with symptoms of HF at rest or on minimal exertion and with an ejection fraction < 25% (but not volume-overloaded), carvedilol was superior to placebo with respect to death or hospitalization for a cardiovascular reason. Reference Packer M, Fowler MB, Roecker EB et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002 Oct 22;106(17):2194-9. Open reference URL https://web.pathway.md/studies/rec4NvXjaiEdZ5IF0 2/2

6/28/23, 12:17 AM CORAL Pathway Feedback Search Clinical Topics Home Studies CORAL CORAL Disease Disease Disease Chronic kidney disease Hypertension Renal a Trial question What is the role of renal artery stenting in people with atherosclerotic renal artery stenosis and hypertension or CKD? Study design Multi-center Open label RCT Population Characteristics of study participants 50.0% female N = 947 50.0% male 947 patients (466 female, 465 male) Inclusion criteria: people with atherosclerotic renal artery stenosis and either systolic hypertension while taking 2 antihypertensive drugs or CKD Key exclusion criteria: renal artery stenosis due to FMD, CKD from a cause other than ischemic nephropathy or associated with a serum creatinine level > 4.0 mg/dL, kidney length < 7 cm, and a lesion that could not be treated with the use of a single stent Interventions N=467 renal artery stenting plus medical therapy (placement of a Palmaz Genesis stent (Cordis) plus candesartan, hydrochlorothiazide, and atorvastatin-amlodipine) N=480 medical therapy alone (with candesartan, hydrochlorothiazide, and atorvastatin- amlodipine) Primary outcome https://web.pathway.md/studies/rec2WNf51FYMPxySj 1/2 6/28/23, 12:17 AM CORAL Pathway Death from any cause 16.1 % 16.1 13.7 12.1 % 8.1 % 4.0 % No significant difference 0.0 % Renal artery stenting plus medical therapy Medical therapy alone No significant difference in death from any cause (13.7% vs. 16.1%; HR 0.8, 95% CI 0.58 to 1.12) Secondary outcomes No significant difference in stroke (3.5% vs. 4.9%; HR 0.68, 95% CI 0.36 to 1.28) No significant difference in progressive renal insufficiency (16.8% vs. 18.9%; HR 0.86, 95% CI 0.64 to 1.17) Conclusion In people with atherosclerotic renal artery stenosis and either systolic hypertension while taking 2 antihypertensive drugs or CKD, renal artery stenting plus medical therapy was not superior to medical therapy alone with respect to death from any cause. Reference Cooper CJ, Murphy TP, Cutlip DE et al. Stenting and medical therapy for atherosclerotic renal- artery stenosis. N Engl J Med. 2014 Jan 2;370(1):13-22. Open reference URL https://web.pathway.md/studies/rec2WNf51FYMPxySj 2/2

6/28/23, 12:17 AM CORONA Pathway Feedback Search Clinical Topics Home Studies CORONA CORONA Disease Disease Disease Dilated cardiomyopathy Dyslipidemia Heart f Trial question What is the role of rosuvastatin in older patients with systolic HF (NYHA class II, III or IV) secondary to ischemic cardiomyopathy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 24.0% female N = 5011 76.0% male 5011 patients (1180 female, 3831 male) Inclusion criteria: patients with systolic HF (NYHA class II, III or IV) secondary to ischemic cardiomyopathy Key exclusion criteria: previous statin-induced myopathy or hypersensitivity reaction; decompensated HF or a need for inotropic therapy; myocardial infarction within the past 6 months; unstable angina or stroke within the past 3 months; PCI, CABG, or the implantation of a cardioverter-defibrillator or biventricular pacemaker within the past 3 months Interventions N=2514 rosuvastatin (10 mg PO once daily) N=2497 placebo (matching placebo once daily) Primary outcome Death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke https://web.pathway.md/studies/recUTv9yPgrBZnNhp 1/2 6/28/23, 12:17 AM CORONA Pathway 14.6 % 14.6 13.8 10.9 % 7.3 % 3.6 % No significant difference 0.0 % Rosuvastatin Placebo No significant difference in death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke (13.8% vs. 14.6%; HR 0.92, 95% CI 0.83 to 1.02) Secondary outcomes No significant difference in the incidence of death from any cause (11.6 /100 py vs. 12.2 /100 py; HR 0.95, 95% CI 0.86 to 1.05) No significant difference in coronary event (9.3 vs. 10; HR 0.92, 95% CI 0.82 to 1.04) Safety outcomes No significant difference in muscle-related adverse events or other adverse events. Conclusion In patients with systolic HF (NYHA class II, III or IV) secondary to ischemic cardiomyopathy, rosuvastatin was not superior to placebo with respect to death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke. Reference Kjekshus J, Apetrei E, Barrios V et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med. 2007 Nov 29;357(22):2248-61. Open reference URL https://web.pathway.md/studies/recUTv9yPgrBZnNhp 2/2

6/28/23, 12:17 AM CORP Pathway Feedback Search Clinical Topics Home Studies CORP CORP Disease Acute pericarditis Trial question What is the role of colchicine in patients with a first recurrence of pericarditis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 47.5% female N = 120 52.5% male 120 patients (57 female, 63 male) Inclusion criteria: patients with a first recurrence of pericarditis Key exclusion criteria: pericarditis with tuberculous, purulent, or neoplastic causes; known severe liver disease; known myopathy; known blood dyscrasias; gastrointestinal disease; or known hypersensitivity to colchicine Interventions N=60 colchicine (1.0-2.0 mg on the first day followed by a maintenance dose of 0.5-1.0 mg/d for 6 months in addition to conventional treatment) N=60 placebo (matching placebo daily for 6 months in addition to conventional treatment) Primary outcome Recurrence at 18 months 55.0 % 55 https://web.pathway.md/studies/recTXMA4agLsJOvNZ 1/2 6/28/23, 12:17 AM CORP Pathway 41.3 % 27.5 % 24 Significant decrease 13.8 % NNT = 3 0.0 % Colchicine Placebo Significant decrease in recurrence at 18 months (24% vs. 55%; RR 0.44, 95% CI 0.27 to 0.73) Secondary outcomes Significant decrease in persistence of symptoms at 72 hours (23% vs. 53%; RR 0.43, 95% CI 0.26 to 0.63) Significant increase in remission at 1 week (82% vs. 48%; RR 1.71, 95% CI 0.7 to 2.72) Significant increase in time to recurrence (2.5 vs. 1; MD 1.5, 90% CI 0 to 19.1) Safety outcomes No significant differences in side effects (7% vs. 7%, p > 0.99) and drug withdrawal (8% vs. 5%, p=0.89). Conclusion In patients with a first recurrence of pericarditis, colchicine was superior to placebo with respect to recurrence at 18 months. Reference Imazio M, Brucato A, Cemin R et al. Colchicine for recurrent pericarditis (CORP): a randomized trial. Ann Intern Med. 2011 Oct 4;155(7):409-14. Open reference URL https://web.pathway.md/studies/recTXMA4agLsJOvNZ 2/2

6/28/23, 12:28 AM Corticosteroid injection for AT Pathway Feedback Search Clinical Topics Home Studies Corticosteroid injection for AT Corticosteroid injection for AT Disease Achilles tendinopathy Trial question What is the role of US-guided corticosteroid injection in patients with Achilles tendinopathy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 40.0% female N = 100 60.0% male 100 patients (40 female, 60 male) Inclusion criteria: adult patients with ultrasound-verified Achilles tendinopathy for 3 months Key exclusion criteria: Achilles tendon rupture or surgery in the symptomatic lower limb; known medical diseases; corticosteroid injection for Achilles tendon pain within the past 6 months; BMI > 30 Interventions N=48 US-guided corticosteroid injection (1-3 injections of 1 mL methylprednisolone acetate 40 mg/mL and 1 mL lidocaine 10 mg/mL over 3 months plus exercise therapy) N=52 US-guided placebo injection (1-3 injections of 1 mL intralipid and 1 mL lidocaine 10 mg/mL over 3 months plus exercise therapy) Primary outcome Improvement in Victorian Institute of Sports Assessment-Achilles score at 6 months 39.0 39 https://web.pathway.md/studies/recTdCXKPucvfwihj 1/2 6/28/23, 12:28 AM Corticosteroid injection for AT Pathway 29.3 22 19.5 9.8 Significant increase 0.0 Ultrasound-guided corticosteroid injection Ultrasound-guided placebo injection Significant increase in improvement in Victorian Institute of Sports Assessment-Achilles score at 6 months (39 vs. 22; AD 17.7, 95% CI 8.4 to 27) Secondary outcomes Significant increase in improvement in the ultrasound-measured thickness of Achilles tendon at 3 months (2.6 vs. 0.6; AD 2.2, 95% CI 1.5 to 3) Significant increase in improvement in morning pain on Visual Analog Scale at 2 months (34 vs. 18; AD 15.6, 95% CI 2.6 to 28.6) Safety outcomes No significant difference in injection pain. Conclusion In adult patients with ultrasound-verified Achilles tendinopathy for 3 months, US-guided corticosteroid injection was superior to US-guided placebo injection with respect to improvement in Victorian Institute of Sports Assessment-Achilles score at 6 months. Reference Finn Johannsen, Jens Lykkegaard Olesen, Tommy Frisgaard hlenschl ger et al. Effect of Ultrasonography-Guided Corticosteroid Injection vs Placebo Added to Exercise Therapy for Achilles Tendinopathy: A Randomized Clinical Trial. JAMA Netw Open. 2022 Jul 1;5(7):e2219661. Open reference URL https://web.pathway.md/studies/recTdCXKPucvfwihj 2/2

6/28/23, 12:17 AM CORTICUS Pathway Feedback Search Clinical Topics Home Studies CORTICUS CORTICUS Disease Sepsis and septic shock Trial question What is the role of hydrocortisone therapy in patients with septic shock? Study design Multi-center Double blinded RCT Population Characteristics of study participants 33.0% female N = 499 67.0% male 499 patients (167 female, 332 male) Inclusion criteria: patients with septic shock Key exclusion criteria: underlying disease with a poor prognosis, a life expectancy of < 24 hours, immunosuppression, and treatment with long-term corticosteroids within the past 6 months or short-term corticosteroids within the past 4 weeks Interventions N=251 hydrocortisone (intravenous 50 mg every 6 hours for 5 days) N=248 placebo (identical placebo intravenous every 6 hours for 5 days) Primary outcome Death at 28 days, among corticotropin non-responders 39.2 % 39.2 36.1 29.4 % https://web.pathway.md/studies/recTNWh0easoznNaB 1/2 6/28/23, 12:17 AM CORTICUS Pathway 19.6 % 9.8 % No significant difference 0.0 % Hydrocortisone Placebo No significant difference in death at 28 days, among corticotropin non-responders (39.2% vs. 36.1%; RR 1.09, 95% CI 0.77 to 1.52) Secondary outcomes No significant difference in death at 28 days, among corticotropin responders (28.8% vs. 28.7%; RR 1, 95% CI 0.68 to 1.49) No significant difference in death at 28 days (34.3% vs. 31.5%; RR 1.09, 95% CI 0.84 to 1.41) Significant decrease in time to reversal of shock (3.3 days vs. 5.8 days; AD -2.5 days, 95% CI -3.98 to -1.02) Safety outcomes Significant differences in new sepsis (3% vs. 1%), new shock (6% vs. 2%), new hyperglycemia (85% vs. 72%), and new hypernatremia (29% vs. 18%). Conclusion In patients with septic shock, hydrocortisone was not superior to placebo with respect to death at 28 days, among corticotropin non-responders. Reference Sprung CL, Annane D, Keh D et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med. 2008 Jan 10;358(2):111-24. Open reference URL https://web.pathway.md/studies/recTNWh0easoznNaB 2/2

6/28/23, 12:17 AM COURAGE Pathway Feedback Search Clinical Topics Home Studies COURAGE COURAGE Disease Coronary artery disease Trial question What is the role of PCI as an initial management strategy in patients with stable coronary artery disease? Study design Multi-center Open label RCT Population Characteristics of study participants 15.0% female N = 2287 85.0% male 2287 patients (338 female, 1947 male) Inclusion criteria: patients who had objective evidence of myocardial ischemia and significant coronary artery disease Key exclusion criteria: severe angina, a markedly positive stress test, refractory HF, cardiogenic shock, ejection fraction < 30%, or revascularization within 6 months Interventions N=1149 PCI (plus optimal medical therapy) N=1138 medical therapy (optimal medical therapy alone) Primary outcome Rate of death or nonfatal myocardial infarction at 4.6 years follow-up 19.0 % 19 18.5 14 3 % https://web.pathway.md/studies/recSHasUo6lbAuG04 1/2 6/28/23, 12:17 AM 14.3 % COURAGE Pathway 9.5 % 4.8 % No significant difference 0.0 % Percutaneous coronary intervention Medical therapy No significant difference in the rate of death or nonfatal myocardial infarction at 4.6 years follow- up (19% vs. 18.5%; HR 1.05, 95% CI 0.87 to 1.27) Secondary outcomes No significant difference in death, myocardial infarction and stroke (20% vs. 19.5%; HR 1.05, 95% CI 0.87 to 1.27) No significant difference in hospitalization for acute coronary syndrome (12.4% vs. 11.8%; HR 1.07, 95% CI 0.84 to 1.37) No significant difference in myocardial infarction (13.2% vs. 12.3%; HR 1.13, 95% CI 0.89 to 1.43) Conclusion In patients who had objective evidence of myocardial ischemia and significant coronary artery disease, PCI was not superior to medical therapy with respect to the rate of death or nonfatal myocardial infarction at 4.6 years follow-up. Reference Boden WE, O'Rourke RA, Teo KK et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med. 2007 Apr 12;356(15):1503-16. Open reference URL https://web.pathway.md/studies/recSHasUo6lbAuG04 2/2

6/28/23, 12:17 AM COV-BARRIER Pathway Feedback Search Clinical Topics Home Studies COV BARRIER COV BARRIER Disease COVID 19 infection Trial question What is the role of baricitinib in critically ill hospitalized patients with COVID-19 requiring invasive mechanical ventilation or ECMO? Study design Multi-center Double blinded RCT Population Characteristics of study participants 46.0% female N = 101 54.0% male 101 patients (46 female, 55 male) Inclusion criteria: adults hospitalized with COVID-19 on invasive mechanical ventilation or ECMO Key exclusion criteria: receipt of high-dose corticosteroids in the month before study entry; receipt of convalescent plasma or IVIG for COVID-19; suspected serious active bacterial, fungal, or other infection Interventions N=51 baricitinib (oral dose of 4 mg plus standard of care) N=50 placebo (oral dose of matching placebo plus standard of care) Primary outcome Death from all causes at day 28 58.0 % 58 https://web.pathway.md/studies/recpgDg5YTjalzY7B 1/2 6/28/23, 12:17 AM COV-BARRIER Pathway 43.5 % 39 29.0 % Significant decrease 14.5 % NNT = 5 0.0 % Baricitinib Placebo Significant decrease in death from all causes at day 28 (39% vs. 58%; HR 0.54, 95% CI 0.31 to 0.96) Secondary outcomes Significant decrease in death from all causes at day 60 (45% vs. 62%; HR 0.56, 95% CI 0.33 to 0.97) No significant difference in ventilator-free days (8.1 days vs. 5.5 days; AD 2.36 days, 95% CI -1.38 to 6.09) Borderline significant decrease in duration of hospitalization (23.7 days vs. 26.1 days; AD -2.3 days, 95% CI -4.59 to 0) Safety outcomes No significant differences in infection, blood clot formation, and adverse cardiovascular events. Conclusion In adults hospitalized with COVID-19 on invasive mechanical ventilation or ECMO, baricitinib was superior to placebo with respect to death from all causes at day 28. Reference E Wesley Ely, Athimalaipet V Ramanan, Cynthia E Kartman et al. Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial. Lancet Respir Med. 2022 Apr;10(4):327-336. Open reference URL https://web.pathway.md/studies/recpgDg5YTjalzY7B 2/2

6/28/23, 12:18 AM COVI-PRONE Pathway Feedback Search Clinical Topics Home Studies COVI PRONE COVI PRONE Disease COVID 19 infection Trial question What is the role of awake prone positioning in patients with COVID-19 and acute respiratory failure? Study design Multi-center Open label RCT Population Characteristics of study participants 29.0% female N = 400 71.0% male 400 patients (117 female, 283 male) Inclusion criteria: nonintubated adult patients with acute hypoxemia and COVID-19 Key exclusion criteria: receipt of invasive mechanical ventilation; contraindications to prone positioning; at risk of complications from prone positioning; prior self-prone positioning Interventions N=205 prone positioning (awake prone positioning sessions for 8-10 hours/day with usual care) N=195 usual care (usual care alone) Primary outcome Rate of endotracheal intubation within 30 days 40.5 40.5 % 34.1 https://web.pathway.md/studies/rec4P3tV18UpSuhCN 1/2 6/28/23, 12:18 AM COVI-PRONE Pathway 30.4 % 20.3 % 10.1 % No significant difference 0.0 % Prone positioning Usual care No significant difference in the rate of endotracheal intubation within 30 days (34.1% vs. 40.5%; HR 0.81, 95% CI 0.59 to 1.12) Secondary outcomes No significant difference in death at day 60 (22% vs. 24%; HR 0.93, 95% CI 0.62 to 1.4) No significant difference in days free from invasive mechanical ventilation or noninvasive ventilation at day 30 (21.4% vs. 19.4%; MD 2.04, 95% CI -0.5 to 4.59) No significant difference in hospital free days at day 60 (34.4% vs. 30.8%; MD 3.52, 95% CI -1.05 to 8.08) Safety outcomes Significant difference in adverse events including musculoskeletal pain or discomfort from prone positioning (10% vs. 0%). Conclusion In nonintubated adult patients with acute hypoxemia and COVID-19, prone positioning was not superior to usual care with respect to the rate of endotracheal intubation within 30 days. Reference Waleed Alhazzani, Ken Kuljit S Parhar, Jason Weatherald et al. Effect of Awake Prone Positioning on Endotracheal Intubation in Patients With COVID-19 and Acute Respiratory Failure: A Randomized Clinical Trial. JAMA. 2022 Jun 7;327(21):2104-2113. Open reference URL https://web.pathway.md/studies/rec4P3tV18UpSuhCN 2/2

6/28/23, 12:19 AM COVID NT-300 Pathway Feedback Search Clinical Topics Home Studies COVID NT 300 COVID NT 300 Disease COVID 19 infection Trial question What is the role of nitazoxanide in outpatients with mild to moderate COVID-19? Study design Multi-center Double blinded RCT Population Characteristics of study participants 56.0% female N = 379 44.0% male 379 patients (214 female, 165 male) Inclusion criteria: patients presenting within 72-hour onset of mild or moderate COVID-19 Key exclusion criteria: signs or symptoms suggestive of severe COVID-19 including resting respiratory rate 30 breaths/min, resting pulse rate 125 beats/min, or blood oxygen saturation 93%; previous COVID-19 infection; immunodeficiency Interventions N=184 nitazoxanide (600 mg PO BID for 5 days) N=195 placebo (matching placebo tablets PO BID for 5 days) Primary outcome Time to sustained clinical recovery 13.3 days 13.3 12.4 10.0 days https://web.pathway.md/studies/rec7uh1wCjKwNLPl1 1/2 6/28/23, 12:19 AM COVID NT-300 Pathway 6.7 days 3.3 days No significant difference 0.0 days Nitazoxanide Placebo No significant difference in time to sustained clinical recovery (13.3 days vs. 12.4 days; AD 0.9 days, 95% CI -9.93 to 11.73) Secondary outcomes No significant difference in the percentage of patients who progressed to severe COVID-19 (0.5% vs. 3.6%; OR 5.6, 95% CI 0.7 to 46.1) No significant difference in composite outcome of hospitalization, emergency room visit, or death at 28 days (0.5% vs. 3.1%; OR 4.7, 95% CI 0.6 to 39.7) Safety outcomes No significant difference in adverse events. Conclusion In patients presenting within 72-hour onset of mild or moderate COVID-19, nitazoxanide was not superior to placebo with respect to time to sustained clinical recovery. Reference Jean-Fran ois Rossignol, Matthew C Bardin, Jessica Fulgencio et al. A randomized double-blind placebo-controlled clinical trial of nitazoxanide for treatment of mild or moderate COVID-19. EClinicalMedicine. 2022 Feb 28;45:101310. Open reference URL https://web.pathway.md/studies/rec7uh1wCjKwNLPl1 2/2

6/28/23, 12:19 AM COVID STEROID 2 Pathway Feedback Search Clinical Topics Home Studies COVID STEROID 2 COVID STEROID 2 Disease COVID 19 infection Trial question Is 12 mg/day of dexamethasone superior to 6 mg/day of dexamethasone in patients with COVID- 19 and severe hypoxemia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 31.0% female N = 982 69.0% male 982 patients (305 female, 677 male) Inclusion criteria: adult patients with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation Key exclusion criteria: receipt of corticosteroids 5 days or > 6 mg for other conditions, invasive fungal infection, active tuberculosis, hypersensitivity to dexamethasone, pregnancy Interventions N=503 high-dose dexamethasone (12 mg/day of intravenous dexamethasone for up to 10 days) N=497 low-dose dexamethasone (6 mg/day of intravenous dexamethasone for up to 10 days) Primary outcome Days alive without life support at day 28 22 22 0 days 20 5 https://web.pathway.md/studies/recfCiN1yHmjI3dfd 1/2 6/28/23, 12:19 AM 22.0 days COVID STEROID 2 Pathway 20.5 16.5 days 11.0 days 5.5 days Borderline significant increase 0.0 days High-dose dexamethasone Low-dose dexamethasone Borderline significant increase in days alive without life support at day 28 (22 days vs. 20.5 days; AD 1.3 days, 95% CI 0 to 2.6) Secondary outcomes No significant difference in death at day 28 (27.1% vs. 32.3%; aRR 0.86, 99% CI 0.68 to 1.08) No significant difference in death at day 90 (32% vs. 37.7%; aRR 0.87, 99% CI 0.7 to 1.07) No significant difference in days alive without life support at day 90 (84 days vs. 80 days; AD 4.4 days, 95% CI -1.6 to 10.4) Safety outcomes No significant difference in serious adverse reactions. Conclusion In adult patients with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation, high-dose dexamethasone was superior to low-dose dexamethasone with respect to days alive without life support at day 28. Reference COVID STEROID Trial Group, Marie W Munch, Sheila N Myatra et al. Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial. JAMA. 2021 Nov 9;326(18):1807-1817. Open reference URL https://web.pathway.md/studies/recfCiN1yHmjI3dfd 2/2

6/28/23, 12:19 AM COVID-19 PEP Pathway Feedback Search Clinical Topics Home Studies COVID 19 PEP COVID 19 PEP Disease COVID 19 infection Trial question What is the role of hydroxychloroquine as postexposure prophylaxis for COVID-19? Study design Multi-center Double blinded RCT Population Characteristics of study participants 52.0% female N = 821 48.0% male 821 patients (424 female, 397 male) Inclusion criteria: adults who had household or occupational exposure to someone with confirmed COVID-19 at a distance of < 6 feet for > 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure) Key exclusion criteria: age < 18 years, current hospitalization, allergy to hydroxychloroquine, retinal eye disease, known glucose-6 phosphate dehydrogenase deficiency, known CKD, structural or ischemic heart disease, personal or family history of prolonged QT syndrome Interventions N=414 hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days for a total course of 5 days) N=407 placebo (matching folate tablet in an identical regimen) Primary outcome https://web.pathway.md/studies/recaaUgd9TswfVq94 1/2 6/28/23, 12:19 AM COVID-19 PEP Pathway Incidence of either laboratory-confirmed coronavirus disease 2019 or illness compatible with coronavirus disease 2019 within 14 days 14.3 % 14.3 11.8 10.7 % 7.2 % 3.6 % No significant difference 0.0 % Hydroxychloroquine Placebo No significant difference in the incidence of either laboratory-confirmed COVID-19 or illness compatible with COVID-19 within 14 days (11.8% vs. 14.3%; ARD -2.4, 95% CI -7 to 2.2) Secondary outcomes No significant difference in all new symptoms (13.8% vs. 14.5%; ARD -0.7, 95% CI -7.05 to 5.65) Safety outcomes No significant differences in neurologic reaction (dizziness, irritability, vertigo), headache, skin reaction, fatigue, allergic reaction, dry mouth, or taste change. Significant differences in side-effects (40.1% vs. 16.8%), nausea or upset stomach (22.9% vs. 7.7%), gastrointestinal symptoms (23.2% vs. 4.3%). Conclusion In adults who had household or occupational exposure to someone with confirmed COVID-19 at a distance of < 6 feet for > 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure), hydroxychloroquine was not superior to placebo with respect to the incidence of either laboratory-confirmed COVID-19 or illness compatible with COVID-19 within 14 days. Reference David R Boulware, Matthew F Pullen, Ananta S Bangdiwala et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020 Aug 6;383(6):517-525. Open reference URL https://web.pathway.md/studies/recaaUgd9TswfVq94 2/2

6/28/23, 12:19 AM COVID-19 Phase 3 Prevention Pathway Feedback Search Clinical Topics Home Studies COVID 19 Phase 3 Prevention COVID 19 Phase 3 Prevention Disease COVID 19 infection Trial question What is the effect of subcutaneous casirivimab and imdevimab antibody combination in individuals with early asymptomatic COVID-19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 55.0% female N = 207 45.0% male 207 patients (113 female, 94 male) Inclusion criteria: asymptomatic individuals with positive RT-PCR for COVID-19 who are living with an infected household contact Key exclusion criteria: COVID-19 vaccination; history of prior COVID-19 positive test; active respiratory or non-respiratory symptoms consistent with COVID-19; nursing home resident; current hospitalization Interventions N=100 casirivimab and imdevimab (single subcutaneous dose of 1200 mg, 600 mg of each) N=104 placebo (matching saline solution) Primary outcome Progression to symptomatic COVID-19 disease 42.3 % 42.3 https://web.pathway.md/studies/recsRoimMWBZs0Iqy 1/2 6/28/23, 12:19 AM COVID-19 Phase 3 Prevention Pathway 31.7 % 29 21.1 % Significant decrease 10.6 % NNT = 8 0.0 % Casirivimab and imdevimab Placebo Significant decrease in progression to symptomatic COVID-19 disease (29% vs. 42.3%; OR 0.54, 95% CI 0.3 to 0.97) Secondary outcomes Significant decrease in the number of weeks of symptomatic COVID-19 infection per 1,000 participants (895.7 weeks vs. 1636.4 weeks; AD -741.7 weeks, 95% CI -1412.66 to -70.74) Significant decrease in the number of weeks of high viral load per 1,000 participants (489.8 weeks vs. 811.9 weeks; AD -322.1 weeks, 95% CI -513.22 to -130.98) Significant decrease in COVID-19 related hospitalizations or emergency visits (ARD -5.8, 95% CI -10.3 to -1.3) Conclusion In asymptomatic individuals with positive RT-PCR for COVID-19 who are living with an infected household contact, casirivimab and imdevimab were superior to placebo with respect to progression to symptomatic COVID-19 disease. Reference Meagan P O'Brien, Eduardo Forleo-Neto, Neena Sarkar et al. Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial. JAMA. 2022 Feb 1;327(5):432-441. Open reference URL https://web.pathway.md/studies/recsRoimMWBZs0Iqy 2/2

6/28/23, 12:19 AM COVID-19-MP Pathway Feedback Search Clinical Topics Home Studies COVID 19 MP COVID 19 MP Disease COVID 19 infection Trial question What is the role of intravenous methylprednisolone pulses in patients with severe COVID-19 pneumonia? Study design Multi-center Double blinded RCT Population Characteristics of study participants 28.0% female N = 301 72.0% male 301 patients (84 female, 217 male) Inclusion criteria: hospitalized patients with COVID-19 pneumonia Key exclusion criteria: requirement of invasive mechanical ventilation; shock or organ failure requiring an ICU admission; pregnancy; severe cardiac or renal failure; uncontrolled diabetes Interventions N=151 pulse methylprednisolone (1 g intravenous methylprednisolone for 3 consecutive days plus standard dexamethasone) N=150 placebo (matching placebo plus standard dexamethasone) Primary outcome Rate of the percentage of patients who were discharged without oxygen within 30 days 75.4 % 75.4 75.2 56 6 % https://web.pathway.md/studies/recZqIjjNJkVcO5zJ 1/2 6/28/23, 12:19 AM 56.6 % COVID-19-MP Pathway 37.7 % 18.9 % No significant difference 0.0 % Pulse methylprednisolone Placebo No significant difference in the rate of the percentage of patients who were discharged without oxygen within 30 days (75.4% vs. 75.2%; HR 1.09, 95% CI 0.83 to 1.41) Secondary outcomes No significant difference in the percentage of patients who were admitted to ICU and undergone orotracheal intubation or died (20% vs. 16.1%; HR 1.26, 95% CI 0.74 to 2.16) No significant difference in death from all causes (10% vs. 12.2%; HR 0.83, 95% CI 0.42 to 1.64) No significant difference in clinical worsening or death (45.7% vs. 40.3%; HR 1.17, 95% CI 0.73 to 1.89) Safety outcomes No significant difference in serious adverse events. Conclusion In hospitalized patients with COVID-19 pneumonia, pulse methylprednisolone was not superior to placebo with respect to the rate of the percentage of patients who were discharged without oxygen within 30 days. Reference Carlo Salvarani, Marco Massari, Massimo Costantini et al. Intravenous methylprednisolone pulses in hospitalised patients with severe COVID-19 pneumonia, A double-blind, randomised, placebo-controlled trial. Eur Respir J. 2022 Mar 31;2200025. Open reference URL https://web.pathway.md/studies/recZqIjjNJkVcO5zJ 2/2

6/28/23, 12:19 AM COVID-OUT (fluvoxamine) Pathway Feedback Search Clinical Topics Home Studies COVID OUT (fluvoxamine) COVID OUT (fluvoxamine) Disease COVID 19 infection Trial question What is the role of fluvoxamine in patients with COVID-19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 54.0% female N = 661 46.0% male 661 patients (358 female, 303 male) Inclusion criteria: nonhospitalized adults aged between 30 to 85 years with a confirmed diagnosis of COVID-19 within the past 3 days Key exclusion criteria: hospitalization for COVID-19 infection or other reasons; symptom onset > 7 days; immunocompromised patient; hepatic impairment; AUD; history of severe kidney disease Interventions N=334 fluvoxamine (fluvoxamine alone at a dose of 50 mg BID for 14 days or fluvoxamine in combination with metformin) N=327 placebo (matching placebo or metformin alone) Primary outcome Composite outcome of hypoxemia, emergency department visit, hospitalization, or death 24.9 24.9 % 24 https://web.pathway.md/studies/recbpJmmneolqUyqy 1/2 6/28/23, 12:19 AM 24.9 % COVID-OUT (fluvoxamine) Pathway 24 18.7 % 12.4 % 6.2 % No significant difference 0.0 % Fluvoxamine Placebo No significant difference in composite outcome of hypoxemia, emergency department visit, hospitalization, or death (24% vs. 24.9%; OR 0.94, 95% CI 0.66 to 1.36) Secondary outcomes No significant difference in hospitalization or death (1.8% vs. 1.5%; OR 1.11, 95% CI 0.33 to 3.76) No significant difference in hypoxemia (21.6% vs. 22.8%; OR 0.93, 95% CI 0.64 to 1.35) Conclusion In nonhospitalized adults aged between 30 to 85 years with a confirmed diagnosis of COVID-19 within the past 3 days, fluvoxamine was not superior to placebo with respect to the composite outcome of hypoxemia, emergency department visit, hospitalization, or death. Reference Carolyn T Bramante, Jared D Huling, Christopher J Tignanelli et al. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19. N Engl J Med. 2022 Aug 18;387(7):599- 610. Open reference URL https://web.pathway.md/studies/recbpJmmneolqUyqy 2/2

6/28/23, 12:20 AM COVID-OUT (ivermectin) Pathway Feedback Search Clinical Topics Home Studies COVID OUT (ivermectin) COVID OUT (ivermectin) Disease COVID 19 infection Trial question What is the role of ivermectin in patients with COVID-19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 55.0% female N = 808 45.0% male 808 patients (442 female, 366 male) Inclusion criteria: nonhospitalized adults aged between 30 to 85 years with a confirmed diagnosis of COVID-19 within the past 3 days Key exclusion criteria: hospitalization for COVID-19 infection or other reasons; symptom onset > 7 days; immunocompromised patient; hepatic impairment; AUD; history of severe kidney disease Interventions N=410 ivermectin (ivermectin alone at a dose of 390-470 g/kg/day for 3 days or ivermectin in combination with metformin) N=398 placebo (matching placebo or metformin alone) Primary outcome Composite outcome of hypoxemia, emergency department visit, hospitalization, or death 25.8 25 8 % 24 6 https://web.pathway.md/studies/rec7MDosqVHrjjcYY 1/2 6/28/23, 12:20 AM 25.8 % COVID-OUT (ivermectin) Pathway 24.6 19.4 % 12.9 % 6.5 % No significant difference 0.0 % Ivermectin Placebo No significant difference in composite outcome of hypoxemia, emergency department visit, hospitalization, or death (25.8% vs. 24.6%; aOR 1.05, 95% CI 0.76 to 1.45) Secondary outcomes No significant difference in composite outcome of emergency department visit, hospitalization, or death (5.7% vs. 4.1%; aOR 1.39, 95% CI 0.72 to 2.69) No significant difference in hospitalization or death (1% vs. 1.3%; aOR 0.73, 95% CI 0.19 to 2.77) No significant difference in hypoxemia (23.6% vs. 22.6%; aOR 1.04, 95% CI 0.75 to 1.46) Conclusion In nonhospitalized adults aged between 30 to 85 years with a confirmed diagnosis of COVID-19 within the past 3 days, ivermectin was not superior to placebo with respect to the composite outcome of hypoxemia, emergency department visit, hospitalization, or death. Reference Carolyn T Bramante, Jared D Huling, Christopher J Tignanelli et al. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19. N Engl J Med. 2022 Aug 18;387(7):599- 610. Open reference URL https://web.pathway.md/studies/rec7MDosqVHrjjcYY 2/2

6/28/23, 12:20 AM COVID-OUT (metformin) Pathway Feedback Search Clinical Topics Home Studies COVID OUT (metformin) COVID OUT (metformin) Disease COVID 19 infection Trial question What is the role of metformin in patients with COVID-19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 56.0% female N = 1323 44.0% male 1323 patients (741 female, 582 male) Inclusion criteria: nonhospitalized adults aged between 30 to 85 years with a confirmed diagnosis of COVID-19 within the past 3 days Key exclusion criteria: hospitalization for COVID-19 infection or other reasons; symptom onset > 7 days; immunocompromised patient; hepatic impairment; AUD; history of severe kidney disease Interventions N=663 metformin (immediate-release metformin alone, with an increase in dose over 6 days to 1,500 mg/day for 14 days, or metformin in combination with either fluvoxamine or ivermectin) N=660 placebo (receipt of placebo, fluvoxamine alone or ivermectin alone) Primary outcome Composite outcome of hypoxemia, emergency department visit, hospitalization, or death 27.4 % 27.4 https://web.pathway.md/studies/recz80nKsOgzVrLr9 1/2 6/28/23, 12:20 AM COVID-OUT (metformin) Pathway 23.6 20.5 % 13.7 % 6.8 % No significant difference 0.0 % Metformin Placebo No significant difference in composite outcome of hypoxemia, emergency department visit, hospitalization, or death (23.6% vs. 27.4%; OR 0.84, 95% CI 0.66 to 1.09) Secondary outcomes Borderline significant decrease in composite outcome of emergency department visit, hospitalization, or death (4.1% vs. 7.3%; OR 0.58, 95% CI 0.35 to 0.94) No significant difference in hospitalization or death from any cause (1.2% vs. 2.7%; OR 0.47, 95% CI 0.2 to 1.11) No significant difference in hypoxemia (22.6% vs. 24.3%; OR 0.94, 95% CI 0.72 to 1.22) Conclusion In nonhospitalized adults aged between 30 to 85 years with a confirmed diagnosis of COVID-19 within the past 3 days, metformin was not superior to placebo with respect to the composite outcome of hypoxemia, emergency department visit, hospitalization, or death. Reference Carolyn T Bramante, Jared D Huling, Christopher J Tignanelli et al. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19. N Engl J Med. 2022 Aug 18;387(7):599- 610. Open reference URL https://web.pathway.md/studies/recz80nKsOgzVrLr9 2/2

6/28/23, 12:20 AM COVID-PACT (anticoagulant therapy) Pathway Feedback Search Clinical Topics Home Studies COVID PACT (anticoagulant therapy) COVID PACT (anticoagulant therapy) Disease COVID 19 infection Trial question Is full-dose anticoagulation prophylaxis superior to standard-dose prophylactic anticoagulation in critically ill patients with COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 382 59.0% male 382 patients (156 female, 226 male) Inclusion criteria: adult patients with COVID-19 infection requiring ICU-level of care Key exclusion criteria: use of full-dose anticoagulation; contraindication to antithrombotic therapy; high risk of bleeding; heparin-induced thrombocytopenia; or ischemic stroke within the past 2 weeks Interventions N=191 full-dose anticoagulation strategy (intravenous UFH or subcutaneous LMWH) N=191 standard-dose prophylactic anticoagulation strategy (LMWH) Primary outcome Rate of death due to venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute https://web.pathway.md/studies/recsEiyJLcUmCKMEm 1/2 6/28/23, 12:20 AM COVID-PACT (anticoagulant therapy) Pathway limb ischemia, or clinically silent deep venous thrombosis, through hospital discharge or 28 days, time-to-first event analysis 15.2 % 15.2 11.4 % 9.9 Significant decrease 7.6 % NNT = 19 3.8 % 0.0 % Full-dose anticoagulation strategy Standard-dose prophylactic anticoagulation strategy Significant decrease in the rate of death due to venous or arterial thrombosis, PE, clinically evident DVT, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent DVT, through hospital discharge or 28 days, time-to-first event analysis (9.9% vs. 15.2%; HR 0.56, 95% CI 0.32 to 0.99) Secondary outcomes No significant difference in death attributable to venous or arterial thrombosis, PE, clinically evident DVT, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia (7.3% vs. 12%; HR 0.55, 95% CI 0.28 to 1.08) No significant difference in death from all causes (18.8% vs. 16.8%; HR 1.1, 95% CI 0.68 to 1.79) Safety outcomes No significant difference in fatal and life-threatening bleeding. Significant difference in GUSTO moderate and severe bleeding (7.9% vs. 0.5%). Conclusion In adult patients with COVID-19 infection requiring ICU-level of care, full-dose anticoagulation strategy was superior to standard-dose prophylactic anticoagulation strategy with respect to the rate of death due to venous or arterial thrombosis, PE, clinically evident DVT, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent DVT, through hospital discharge or 28 days, time-to-first event analysis. Reference Erin A Bohula, David D Berg, Mathew S Lopes et al. Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients with COVID-19: COVID-PACT. Circulation. 2022 Nov;146(18):1344-1356. Open reference URL https://web.pathway.md/studies/recsEiyJLcUmCKMEm 2/2

6/28/23, 12:20 AM COVID-PACT (antiplatelet therapy) Pathway Feedback Search Clinical Topics Home Studies COVID PACT (antiplatelet therapy) COVID PACT (antiplatelet therapy) Disease COVID 19 infection Trial question What is the role of clopidogrel in critically ill patients with COVID-19? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 290 59.0% male 290 patients (118 female, 172 male) Inclusion criteria: adult patients with COVID-19 infection requiring ICU-level of care Key exclusion criteria: use of full-dose anticoagulation; use of dual antiplatelet therapy, contraindication to antithrombotic therapy; high risk of bleeding; heparin-induced thrombocytopenia; or ischemic stroke within the past 2 weeks Interventions N=150 clopidogrel (300 mg on the day of randomization, followed by 75 mg/day on subsequent days) N=140 no clopidogrel (no antiplatelet therapy) Primary outcome Rate of death due to venous and arterial thrombotic events through hospital discharge or 28 days 15 15.0 % https://web.pathway.md/studies/recg4rWFzkFahhMBP 1/2 6/28/23, 12:20 AM COVID-PACT (antiplatelet therapy) Pathway 11.3 11.3 % 7.5 % 3.8 % No significant difference 0.0 % Clopidogrel No clopidogrel No significant difference in the rate of death due to venous and arterial thrombotic events through hospital discharge or 28 days (11.3% vs. 15%; HR 0.9, 95% CI 0.48 to 1.69) Secondary outcomes No significant difference in death due to clinically evident venous and arterial thrombotic events (10.7% vs. 9.3%; HR 1.29, 95% CI 0.62 to 2.66) No significant difference in death from all causes (16% vs. 24.3%; HR 0.87, 95% CI 0.51 to 1.49) No significant difference in venous thrombotic events (17 events vs. 21 events; HR 0.9, 95% CI 0.48 to 1.69) Safety outcomes No significant differences in fatal and life-threatening bleeding, GUSTO moderate and severe bleeding. Conclusion In adult patients with COVID-19 infection requiring ICU-level of care, clopidogrel was not superior to no clopidogrel with respect to the rate of death due to venous and arterial thrombotic events through hospital discharge or 28 days. Reference Erin A Bohula, David D Berg, Mathew S Lopes et al. Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients with COVID-19: COVID-PACT. Circulation. 2022 Nov;146(18):1344-1356. Open reference URL https://web.pathway.md/studies/recg4rWFzkFahhMBP 2/2

6/28/23, 12:21 AM CPA (itraconazole) Pathway Feedback Search Clinical Topics Home Studies CPA (itraconazole) CPA (itraconazole) Disease Invasive aspergillosis Trial question Is 12-month oral itraconazole superior to 6-month itraconazole in patients with chronic pulmonary aspergillosis? Study design Single center Open label RCT Population Characteristics of study participants 48.0% female N = 164 52.0% male 164 patients (78 female, 86 male) Inclusion criteria: adult patients with chronic pulmonary aspergillosis who were naive to antifungal treatment Key exclusion criteria: receipt of antifungal azoles for > 3 weeks in the preceding 6 months; active mycobacterium tuberculosis or NTM pulmonary disease; other forms of pulmonary aspergillosis Interventions N=83 12-month itraconazole (an oral dose of 400 mg/day for 12 months) N=81 6-month itraconazole (an oral dose of 400 mg/day for 6 months) Primary outcome Relapse at 2 years 38.0 % 38 https://web.pathway.md/studies/recLXBWWxGRV30tEd 1/2 6/28/23, 12:21 AM CPA (itraconazole) Pathway 28.5 % 19.0 % Significant decrease 10 9.5 % NNT = 4 0.0 % 12-month itraconazole 6-month itraconazole Significant decrease in relapse at 2 years (10% vs. 38%; ARD -29, 95% CI -16 to -40) Secondary outcomes Significant increase in time to first relapse (23 months vs. 18 months; AD 5 months, 95% CI 2.5 to 7.5) Safety outcomes No significant differences in nausea, anorexia, ankle edema, other adverse events. Conclusion In adult patients with chronic pulmonary aspergillosis who were naive to antifungal treatment, 12- month itraconazole was superior to 6-month itraconazole with respect to relapse at 2 years. Reference Inderpaul S Sehgal, Sahajal Dhooria, Valliappan Muthu et al. Efficacy of 12-months oral itraconazole versus 6-months oral itraconazole to prevent relapses of chronic pulmonary aspergillosis: an open-label, randomised controlled trial in India. Lancet Infect Dis. 2022 Jul;22(7):1052-1061. Open reference URL https://web.pathway.md/studies/recLXBWWxGRV30tEd 2/2

6/28/23, 12:28 AM Cranberry for prevention of pyuria and bacteriuria Pathway Feedback Search Clinical Topics Home Studies Cranberry for prevention of pyuria and bacteriuria Cranberry for prevention of pyuria and bacteriuria Disease Disease Acute cystitis Asymptomatic bacteriuria Trial question What is the effect of cranberry capsules on bacteriuria plus pyuria in older women living in nursing homes? Study design Multi-center Double blinded RCT Population 185 female patients Inclusion criteria: women aged 65 years or older, with or without bacteriuria plus pyuria at baseline, residing in nursing homes Key exclusion criteria: short term rehabilitation, pending discharge, terminal life expectancy < 1 month; on chronic suppressive antibiotic or anti-infective (i.e., mandelamine) therapy for recurrent UTI; on dialysis for end stage renal disease; unable to produce a baseline clean catch urine specimen; on warfarin therapy; history of nephrolithiasis; presence of an indwelling bladder catheter; allergy to cranberry products; or treatment with cranberry products Interventions N=92 cranberry capsules (2 oral capsules once daily, containing 72 mg total of the active ingredient proanthocyanidin, equivalent to 20 ounces of cranberry juice) N=93 placebo (two matching capsules once daily) Primary outcome Bacteriuria plus pyuria 29.1 % 29.1 29 21.8 % 14.6 % 7.3 % https://web.pathway.md/studies/recuExkcj6cwzFUgH 1/2 6/28/23, 12:28 AM Cranberry for prevention of pyuria and bacteriuria Pathway 0.0 % No significant difference Cranberry capsules Placebo No significant difference in bacteriuria plus pyuria (29.1% vs. 29%; OR 1.01, 95% CI 0.61 to 1.66) Conclusion In women aged 65 years or older, with or without bacteriuria plus pyuria at baseline, residing in nursing homes, cranberry capsules were not superior to placebo with respect to bacteriuria plus pyuria. Reference Juthani-Mehta M, Van Ness PH, Bianco L et al. Effect of Cranberry Capsules on Bacteriuria Plus Pyuria Among Older Women in Nursing Homes: A Randomized Clinical Trial. JAMA. 2016 Nov 8;316(18):1879-1887. Open reference URL https://web.pathway.md/studies/recuExkcj6cwzFUgH 2/2

6/28/23, 12:21 AM CRASH-2 Pathway Feedback Search Clinical Topics Home Studies CRASH 2 CRASH 2 Disease Traumatic hemorrhage Trial question What is the effect of tranexamic acid in trauma patients with significant hemorrhage? Study design Multi-center Double blinded RCT Population Characteristics of study participants 16.0% female N = 20211 84.0% male 20211 patients (3271 female, 16908 male) Inclusion criteria: adult trauma patients with, or at risk of, significant bleeding Key exclusion criteria: a clear indication for tranexamic acid, or a clear contraindication to tranexamic acid treatment Interventions N=10096 tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h IV) N=10115 placebo (matching placebo of 0.9% saline IV) Primary outcome All-cause death 16.0 % 16 14.5 12.0 % 8.0 % Si ifi t d https://web.pathway.md/studies/recU6k0jaHCrofV2P 1/2 6/28/23, 12:21 AM CRASH-2 Pathway Significant decrease 4.0 % NNT = 67 0.0 % Tranexamic acid Placebo Significant decrease in all-cause death (14.5% vs. 16%; RR 0.91, 95% CI 0.85 to 0.97) Secondary outcomes Significant decrease in death due to bleeding (4.9% vs. 5.7%; RR 0.85, 95% CI 0.76 to 0.96) No significant difference in death due to vascular occlusion (0.3% vs. 0.5%; RR 0.9, 95% CI 0.75 to 1.08) No significant difference in vascular occlusive events (1.7% vs. 2%; RR 0.84, 95% CI 0.68 to 1.02) Conclusion In adult trauma patients with, or at risk of, significant bleeding, tranexamic acid was superior to placebo with respect to a all-cause death. Reference CRASH- trial collaborators, Shakur H, Roberts I et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010 Jul 3;376(9734):23-32. Open reference URL https://web.pathway.md/studies/recU6k0jaHCrofV2P 2/2

6/28/23, 12:22 AM CRASH-3 Pathway Feedback Search Clinical Topics Home Studies CRASH 3 CRASH 3 Disease Traumatic brain injury Trial question What is the effect of tranexamic acid in patients with acute TBI? Study design Multi-center Double blinded RCT Population Characteristics of study participants 20.0% female N = 9202 80.0% male 9202 patients (1799 female, 7402 male) Inclusion criteria: adult patients with TBI who were within 3 hours of injury, had a Glasgow Coma Scale score 12 or any intracranial bleeding on CT scan, and no major extracranial bleeding Key exclusion criteria: the responsible clinician's 'uncertainty' as to the appropriateness of tranexamic acid treatment in a particular patient with TBI Interventions N=6406 tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 hours) N=6331 placebo (0.9% sodium chloride by intravenous infusion) Primary outcome Rate of head injury-related death in hospital within 28 days of injury 19.8 % 19.8 18.5 14 9 % https://web.pathway.md/studies/rec6awzUz1qIKQ0yZ 1/2 6/28/23, 12:22 AM 14.9 % CRASH-3 Pathway 9.9 % 5.0 % No significant difference 0.0 % Tranexamic acid Placebo No significant difference in the rate of head injury-related death in hospital within 28 days of injury (18.5% vs. 19.8%; RR 0.94, 95% CI 0.86 to 1.02) Secondary outcomes Significant decrease in mild-to-moderate head injury-related death (5.8% vs. 7.5%; RR 0.78, 95% CI 0.64 to 0.95) Significant decrease in head injury-related death among patients with reactive pupils (11.5% vs. 13.2%; RR 0.87, 95% CI 0.77 to 0.98) No significant difference in severe head injury-related death (39.6% vs. 40.1%; RR 0.99, 99% CI 0.91 to 1.07) Safety outcomes No significant differences in risk of vascular occlusive events, seizures, and stroke. Conclusion In adult patients with TBI who were within 3 hours of injury, had a Glasgow Coma Scale score 12 or any intracranial bleeding on CT scan, and no major extracranial bleeding, tranexamic acid was not superior to placebo with respect to the rate of head injury-related death in hospital within 28 days of injury. Reference CRASH- trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019 Nov 9;394(10210):1713-1723. Open reference URL https://web.pathway.md/studies/rec6awzUz1qIKQ0yZ 2/2

6/28/23, 12:22 AM CREDENCE Pathway Feedback Search Clinical Topics Home Studies CREDENCE CREDENCE Disease Disease Chronic kidney disease Diabetes mellitus type 2 Trial question What is the role of canagliflozin in patients with T2DM and kidney disease? Study design Multi-center Double blinded RCT Population Characteristics of study participants 34.0% female N = 4401 66.0% male 4401 patients (1494 female, 2907 male) Inclusion criteria: patients with T2DM and kidney disease Key exclusion criteria: diabetic ketoacidosis, T1DM mellitus, renal transplant, chronic dialysis, uncontrolled hypertension, myocardial infarction, unstable angina, revascularization procedure Interventions N=2202 canagliflozin (100 mg PO once daily) N=2199 placebo (matching tablet) Primary outcome Incidence of ESRD, doubling of creatinine, renal death, or CV death 6.1 % / y 6.1 4.6 % / y 4.3 3 0 % / y https://web.pathway.md/studies/recNvS32Ff41qxbEc 1/2 6/28/23, 12:22 AM 3.0 % / y CREDENCE Pathway 1.5 % / y Significant decrease 0.0 % / y Canagliflozin Placebo Significant decrease in the incidence of ESRD, doubling of creatinine, renal death, or CV death (4.3% / y vs. 6.1% / y; HR 0.7, 95% CI 0.59 to 0.82) Secondary outcomes No significant difference in death from any cause (5.8% vs. 9.1%; HR 0.83, 95% CI 0.68 to 1.02) Significant decrease in CV death or hospitalization for HF (5.9% vs. 11.5%; HR 0.69, 95% CI 0.57 to 0.83) Significant decrease in CV death, MI or CVA (9.9% vs. 12.2%; HR 0.8, 95% CI 0.67 to 0.95) Safety outcomes No significant differences in serious adverse events, including lower-limb amputation and fracture. Conclusion In patients with T2DM and kidney disease, canagliflozin was superior to placebo with respect to the incidence of ESRD, doubling of creatinine, renal death, or CV death. Reference Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-2306. Open reference URL https://web.pathway.md/studies/recNvS32Ff41qxbEc 2/2

6/28/23, 12:22 AM CREST Pathway Feedback Search Clinical Topics Home Studies CREST CREST Disease Disease Carotid artery stenosis Transient ischemic attack Trial question What is the role of carotid artery stenting in patients with symptomatic or asymptomatic stenosis? Study design Multi-center Open label RCT Population Characteristics of study participants 35.0% female N = 2502 65.0% male 2502 patients (872 female, 1630 male) Inclusion criteria: patients with symptomatic or asymptomatic carotid stenosis Key exclusion criteria: previous stroke sufficiently severe to confound the assessment of end points, chronic AF, paroxysmal AF that had occurred within the preceding 6 months or that necessitated anticoagulation therapy, myocardial infarction within the previous 30 days, or unstable angina Interventions N=1271 carotid artery stenting (RX Acculink stent and, whenever feasible, the RX Accunet embolic-protection device plus antiplatelet therapy with aspirin and clopidogrel) N=1251 carotid endarterectomy (carotid endarterectomy plus antiplatelet therapy with aspirin) Primary outcome https://web.pathway.md/studies/recTBk7S0sZeLnglk 1/2 6/28/23, 12:22 AM CREST Pathway Stroke, myocardial infarction, or death from any cause during periprocedural period, or any ipsilateral stroke at 4 years 7.2 % 7.2 6.8 5.4 % 3.6 % 1.8 % No significant difference 0.0 % Carotid artery stenting Carotid endarterectomy No significant difference in stroke, myocardial infarction, or death from any cause during the periprocedural period, or any ipsilateral stroke at 4 years (7.2% vs. 6.8%; HR 1.11, 95% CI 0.81 to 1.51) Secondary outcomes Significant increase in stroke or death at 4 years (6.4% vs. 4.7%; HR 1.5, 95% CI 1.05 to 2.15) Significant decrease in myocardial infarction (1.1% vs. 2.3%; HR 0.5, 95% CI 0.26 to 0.94) Conclusion In patients with symptomatic or asymptomatic carotid stenosis, carotid artery stenting was not superior to carotid endarterectomy with respect to stroke, myocardial infarction, or death from any cause during the periprocedural period, or any ipsilateral stroke at 4 years. Reference Brott TG, Hobson RW nd, Howard G et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med. 2010 Jul 1;363(1):11-23. Open reference URL https://web.pathway.md/studies/recTBk7S0sZeLnglk 2/2

6/28/23, 12:22 AM CRHCP Pathway Feedback Search Clinical Topics Home Studies CRHCP CRHCP Disease Hypertension Trial question What is the role of non-physician community healthcare provider-led intensive BP intervention in adults with hypertension? Study design Multi-center Open label RCT Population 33995 patients Inclusion criteria: individuals aged 40 years with an untreated systolic BP 140 mmHg or a diastolic BP 90 mmHg Key exclusion criteria: age < 40 years; pregnancy; life expectancy < 3 years; malignant tumors Interventions N=163 non-physician community healthcare provider-led intervention (initiation and titration of antihypertensive medications to achieve a systolic BP goal < 130 mmHg and diastolic BP goal < 80 mmHg with supervision from primary care physicians) N=163 villages: usual care (villages: no intervention) Primary outcome Incidence of composite of myocardial infarction, stroke, heart failure requiring hospitalization, and cardiovascular disease death during the 36-month follow-up 2.4 % / y 2.4 1.8 % / y 1.62 1.2 % / y 0.6 % / y Significant decrease 0.0 % / y https://web.pathway.md/studies/reccnC0IaMU4AyIfO 1/2 6/28/23, 12:22 AM CRHCP Pathway Non-physician community healthcare provider-led intervention Villages: usual care Significant decrease in the incidence of composite of myocardial infarction, stroke, HF requiring hospitalization, and CVD death during the 36-month follow-up (1.62% / y vs. 2.4% / y; HR 0.67, 95% CI 0.61 to 0.73) Conclusion In individuals aged 40 years with an untreated systolic BP 140 mmHg or a diastolic BP 90 mmHg, non-physician community healthcare provider-led intervention was superior to villages: usual care with respect to the incidence of composite of myocardial infarction, stroke, HF requiring hospitalization, and CVD death during the 36-month follow-up. Reference Jiang He, Nanxiang Ouyang, Xiaofan Guo et al. Effectiveness of a non-physician community health-care provider-led intensive blood pressure intervention versus usual care on cardiovascular disease (CRHCP): an open-label, blinded-endpoint, cluster-randomised trial. Lancet. 2023 Mar 18;401(10380):928-938. Open reference URL https://web.pathway.md/studies/reccnC0IaMU4AyIfO 2/2

6/28/23, 12:23 AM CRISTAL Pathway Feedback Search Clinical Topics Home Studies CRISTAL CRISTAL Disease Disease Hip osteoarthritis Knee osteoarthritis Trial question Is aspirin monotherapy noninferior to enoxaparin in patients undergoing hip or knee arthroplasty for OA? Study design Multi-center Open label RCT Population Characteristics of study participants 56.6% female N = 9203 43.4% male 9203 patients (5511 female, 4200 male) Inclusion criteria: adult patients undergoing hip or knee arthroplasty for OA Key exclusion criteria: receipt of preoperative anticoagulation; medical contraindication to aspirin or enoxaparin; receipt of warfarin Interventions N=5416 aspirin (at a dose of 100 mg/day for 35 days after total hip arthroplasty and for 14 days after total knee arthroplasty) N=3787 enoxaparin (at a dose of 40 mg/day for 35 days after total hip arthroplasty and for 14 days after total knee arthroplasty) Primary outcome Symptomatic venous thromboembolism at day 90 3.5 % 3.45 https://web.pathway.md/studies/recJobn7ummhiY4wp 1/2 6/28/23, 12:23 AM CRISTAL Pathway 2.6 % 1.82 1.7 % Difference exceeding nonferiority margin 0.9 % 0.0 % Aspirin Enoxaparin Difference exceeding nonferiority margin in symptomatic VTE at day 90 (3.45% vs. 1.82%; AD 1.97%, 95% CI 0.54 to 3.41) Secondary outcomes No significant difference in death from any cause at 90 days (0.1% vs. 0.1%; AD 0.05%, 95% CI -0.05 to 0.15) No significant difference in major bleeding at 90 days (0.3% vs. 0.4%; ARD -0.05, 95% CI -0.35 to 0.25) No significant difference in drug adherence (85% vs. 86%; ARD -0.99, 99% CI -0.91 to 1.08) Conclusion In adult patients undergoing hip or knee arthroplasty for OA, aspirin was not noninferior to enoxaparin with respect to symptomatic VTE at day 90. Reference CRISTAL Study Group, Verinder S Sidhu, Thu-Lan Kelly et al. Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty: The CRISTAL Randomized Trial. JAMA. 2022 Aug 23;328(8):719-727. Open reference URL https://web.pathway.md/studies/recJobn7ummhiY4wp 2/2

6/28/23, 12:22 AM CRISTAL Pathway Feedback Search Clinical Topics Home Studies CRISTAL CRISTAL Trial question What is the effect of fluid resuscitation with colloids on mortality in critically ill patients presenting with hypovolemic shock? Study design Multi-center Open label RCT Population Characteristics of study participants 38.0% female N = 2857 62.0% male 2857 patients (1075 female, 1782 male) Inclusion criteria: patients admitted to the ICU with hypovolemic shock Key exclusion criteria: receipt of fluid therapy in the ICU, anesthesia-related hypotension, advanced chronic liver disease, chronic HF, acute anaphylactic reaction, inherited coagulation disorders, pregnancy, dehydrated, or brain death or organ donor Interventions N=1414 fluid resuscitation with colloids (gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) N=1443 fluid resuscitation with crystalloids (isotonic or hypertonic saline or Ringer lactate solution) Primary outcome Death at 28 days 27.0 % 27 25.4 20.3 % 13.5 % 6.8 % No significant difference 0.0 % https://web.pathway.md/studies/recywSdngWX4WnaqX 1/2 6/28/23, 12:22 AM CRISTAL Pathway Fluid resuscitation with colloids Fluid resuscitation with crystalloids No significant difference in death at 28 days (25.4% vs. 27%; RR 0.96, 96% CI 0.88 to 1.04) Secondary outcomes Significant decrease in death at 90 days (30.7% vs. 34.2%; RR 0.92, 95% CI 0.86 to 0.99) No significant difference in RRT (11% vs. 12.5%; RR 0.93, 95% CI 0.83 to 1.03) Conclusion In patients admitted to the ICU with hypovolemic shock, fluid resuscitation with colloids were not superior to fluid resuscitation with crystalloids with respect to death at 28 days. Reference Annane D, Siami S, Jaber S et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013 Nov 6;310(17):1809-17. Open reference URL https://web.pathway.md/studies/recywSdngWX4WnaqX 2/2

6/28/23, 12:28 AM Crizotinib in advanced ALK-positive lung cancer Pathway Feedback Search Clinical Topics Home Studies Crizotinib in advanced ALK-positive lung cancer Crizotinib in advanced ALK-positive lung cancer Disease Non-small cell lung cancer Trial question What is the role of crizotinib in patients with previously treated advanced non-small cell lung cancer with ALK gene rearrangement? Study design Multi-center Open label RCT Population Characteristics of study participants 56.0% female N = 347 44.0% male 347 patients (194 female, 153 male) Inclusion criteria: patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen Key exclusion criteria: age < 18 years, stable disease after one prior chemotherapy regimen, or still in the first-line treatment setting Interventions N=173 crizotinib (oral dose of 250 mg BID) N=174 chemotherapy (intravenous pemetrexed 500 mg/m of BSA or docetaxel 75 mg/m every 3 weeks) Primary outcome Median progression-free survival 7.7 months 7.7 https://web.pathway.md/studies/recfN4qybhtJ9b8sr 1/2 6/28/23, 12:28 AM Crizotinib in advanced ALK-positive lung cancer Pathway 5.8 months 3.9 months 3 1.9 months Significant increase 0.0 months Crizotinib Chemotherapy Significant increase in median progression-free survival (7.7 months vs. 3 months; HR 2.04, 95% CI 1.56 to 2.7) Secondary outcomes Significant increase in response (65% vs. 20%; RR 3.25, 95% CI 1.32 to 5.18) No significant difference in overall survival in an interim analysis (20.3 vs. 22.8; HR 0.98, 95% CI 0.65 to 1.47) Safety outcomes Significant differences in vision disorders (60% vs. 9%), diarrhea (60% vs. 19%), elevated aminotransferase (38% vs. 15%), dizziness (22% vs. 8%), dyspnea (13% vs. 19%), and alopecia (8% vs. 20%). Conclusion In patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen, crizotinib was superior to chemotherapy with respect to median progression-free survival. Reference Shaw AT, Kim DW, Nakagawa K et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013 Jun 20;368(25):2385-94. Open reference URL https://web.pathway.md/studies/recfN4qybhtJ9b8sr 2/2

6/28/23, 12:23 AM CSG Captopril Trial Pathway Feedback Search Clinical Topics Home Studies CSG Captopril Trial CSG Captopril Trial Disease Disease Disease Diabetes mellitus type 1 Diabetes mellitus type 2 Diabeti Trial question What is the role of captopril in patients with insulin-dependent diabetic nephropathy? Study design Multi-center Double blinded RCT Population Characteristics of study participants 47.0% female N = 409 53.0% male 409 patients (192 female, 217 male) Inclusion criteria: patients with insulin-dependent diabetic nephropathy Key exclusion criteria: pregnancy, white-cell count < 2500/mL , congestive HF (NYHA class III or worse), and a serum potassium concentration 6 mmol/L Interventions N=207 captopril (25 mg TID) N=202 placebo (matching tablet TID) Primary outcome Doubling of serum creatinine concentration 21.3 21.3 % 16.0 % 12 1 https://web.pathway.md/studies/recA5sckj2TMm2xph 1/2 6/28/23, 12:23 AM CSG Captopril Trial Pathway 12.1 10.7 % Significant increase 5.3 % NNH = 11 0.0 % Captopril Placebo Significant increase in doubling of serum creatinine concentration (12.1% vs. 21.3%; RR 48, 95% CI 16 to 69) Secondary outcomes Significant decrease in death, dialysis, or renal transplantation (11.1% vs. 21%; RR 0.5, 95% CI 0.3 to 0.82) Safety outcomes No significant difference in drug compliance at one year (92% vs. 95%). Conclusion In patients with insulin-dependent diabetic nephropathy, captopril was superior to placebo with respect to doubling of serum creatinine concentration. Reference Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993 Nov 11;329(20):1456-62. Open reference URL https://web.pathway.md/studies/recA5sckj2TMm2xph 2/2

6/28/23, 12:23 AM CULPRIT-SHOCK (1 year follow-up) Pathway Feedback Search Clinical Topics Home Studies CULPRIT SHOCK 1 year follow-up) CULPRIT SHOCK 1 year follow-up) Disease Disease Disease Cardiogenic shock Non-ST-elevation myocardial inf ST-elev Trial question What is the role of the PCI of the culprit lesion among patients with acute myocardial infarction and cardiogenic shock? Study design Multi-center Open label RCT Population Characteristics of study participants 23.7% female N = 706 76.3% male 706 patients (161 female, 524 male) Inclusion criteria: patients who had acute myocardial infarction that was complicated by cardiogenic shock Key exclusion criteria: resuscitation for > 30 minutes, no intrinsic heart action, an assumed severe deficit in cerebral function with fixed dilated pupils, a mechanical cause of cardiogenic shock, the onset of shock > 12 hours before randomization Interventions N=344 culprit-lesion-only PCI (treatment of the culprit lesion with all other lesions left untreated at the time of the initial procedure) N=342 multivessel PCI (treatment of the culprit lesion with all additional lesions, including chronic total occlusions) Primary outcome https://web.pathway.md/studies/recHJjwyzNsiep7CD 1/2 6/28/23, 12:23 AM CULPRIT-SHOCK (1 year follow-up) Pathway Death at 1 year follow-up 56.9 % 56.9 50 42.7 % 28.4 % 14.2 % No significant difference 0.0 % Culprit-lesion-only percutaneous coronary intervention Multivessel percutaneous coronary intervention No significant difference in death at 1 year follow-up (50% vs. 56.9%; RR 0.88, 95% CI 0.76 to 1.01) Secondary outcomes No significant difference in recurrent myocardial infarction at 1 year (1.7% vs. 2.1%; RR 0.85, 95% CI 0.29 to 2.5) No significant difference in death, recurrent infarction, or rehospitalization for HF at 1 year (55.2% vs. 59.5%; RR 0.87, 95% CI 0.93 to 1.06) Borderline significant decrease in death or recurrent infarction (50.9% vs. 58.4%; RR 0.87, 95% CI 0.76 to 1) Safety outcomes No significant differences in stroke, bleeding. Significant differences in rehospitalization for congestive HF (5.2% vs. 1.2%), repeat revascularization (32.3% vs. 9.4%). Conclusion In patients who had acute myocardial infarction that was complicated by cardiogenic shock, culprit-lesion-only PCI was not superior to multivessel PCI with respect to death at 1 year follow- up. Reference Holger Thiele, Ibrahim Akin, Marcus Sandri et al. One-Year Outcomes after PCI Strategies in Cardiogenic Shock. N Engl J Med. 2018 Nov 1;379(18):1699-1710. Open reference URL https://web.pathway.md/studies/recHJjwyzNsiep7CD 2/2

6/28/23, 12:23 AM CULPRIT-SHOCK Pathway Feedback Search Clinical Topics Home Studies CULPRIT SHOCK CULPRIT SHOCK Disease Disease Disease Cardiogenic shock Coronary artery disease Non-ST Trial question What is the role of PCI strategy of early revascularization of the culprit lesion only compared with immediate multivessel revascularization in patients with acute myocardial infarction and cardiogenic shock? Study design Multi-center Open label RCT Population Characteristics of study participants 23.7% female N = 706 76.3% male 706 patients (161 female, 524 male) Inclusion criteria: patients who had acute ST-segment elevation or non-ST-segment elevation myocardial infarction that was complicated by cardiogenic shock Key exclusion criteria: resuscitation for > 30 minutes, no intrinsic heart action, severe deficit in cerebral function with fixed dilated pupils, indication for primary urgent CABG, single-vessel coronary artery disease, mechanical cause of cardiogenic shock, shock with a noncardiogenic cause, massive PE Interventions N=344 culprit lesion-only percutaneous coronary revascularization (the use of standard interventional techniques, with the option of staged revascularization of nonculprit lesions) N=342 immediate multivessel culprit lesion-only percutaneous coronary revascularization (recanalizing chronic total occlusions during acute phase; recommended maximum dose of https://web.pathway.md/studies/recWNWTccNpcCyVp0 1/2 6/28/23, 12:23 AM CULPRIT-SHOCK Pathway contrast material was 300 ml) Primary outcome Death or renal-replacement therapy at 30 days 55.4 % 55.4 45.9 41.5 % 27.7 % Significant decrease 13.8 % NNT = 11 0.0 % Immediate multivessel culprit lesion-only percutaneous coronary revascularization Culprit lesion-only percutaneous coronary revascularization Significant decrease in death or renal-replacement therapy at 30 days (45.9% vs. 55.4%; RR 0.83, 95% CI 0.71 to 0.96) Secondary outcomes Significant decrease in death (43.3% vs. 51.6%; RR 0.84, 95% CI 0.72 to 0.98) Safety outcomes No significant difference in rates of bleeding and stroke. Conclusion In patients who had acute ST-segment elevation or non-ST-segment elevation myocardial infarction that was complicated by cardiogenic shock, culprit lesion-only percutaneous coronary revascularization was superior to immediate multivessel culprit lesion-only percutaneous coronary revascularization with respect to death or renal-replacement therapy at 30 days. Reference Thiele H, Akin I, Sandri M et al. PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock. N Engl J Med. 2017 Dec 21;377(25):2419-2432. Open reference URL https://web.pathway.md/studies/recWNWTccNpcCyVp0 2/2

6/28/23, 12:24 AM CURASMUR Pathway Feedback Search Clinical Topics Home Studies CURASMUR CURASMUR Trial question Is rocuronium noninferior to succinylcholine in patients undergoing endotracheal intubation in an out-of-hospital rapid sequence intubation? Study design Multi-center Single blinded RCT Population Characteristics of study participants 39.8% female N = 1248 60.2% male 1248 patients (490 female, 736 male) Inclusion criteria: adult patients needing out-of-hospital tracheal intubation Key exclusion criteria: younger than 18 years; pregnant women; contraindication to rocuronium, succinylcholine, or sugammadex; under guardianship; no health insurance Interventions N=624 rocuronium (intravenous bolus injection of 1.2 mg/kg of body weight) N=624 succinylcholine (intravenous bolus injection of 1 mg/kg of body weight) Primary outcome Successful first-attempt intubation 79.4 % 79.4 74.6 59.6 % 39.7 % Difference exceeding nonferiority margin 19.9 % 0.0 % Rocuronium Succinylcholine https://web.pathway.md/studies/recBFLDhc4a4AOhlK 1/2 6/28/23, 12:24 AM CURASMUR Pathway Difference exceeding nonferiority margin in successful first-attempt intubation (74.6% vs. 79.4%; ARD -4.8, 97.5% CI -9 to Infinity) Secondary outcomes No significant difference in Intubation Difficulty Scale score (4.2 vs. 4.1; AD 0.1, 95% CI -0.2 to 0.4) Significant increase in intubation failure under direct laryngoscopy (1.8% vs. 0.7%; AD 1.1%, 95% CI 0.3 to 2.3) No significant difference in death during prehospital care (1% vs. 0.5%; AD 0.5%, 95% CI -0.4 to 1.3) Safety outcomes No significant differences in hypoxemia, cardiac arrest, pulmonary aspiration. Significant difference in 1 severe complication (18.9% vs. 24.4%). Conclusion In adult patients needing out-of-hospital tracheal intubation, rocuronium was not noninferior to succinylcholine with respect to successful first-attempt intubation. Reference Bertrand Guihard, Charlotte Chollet-X mard, Philippe Lakhnati et al. Effect of Rocuronium vs Succinylcholine on Endotracheal Intubation Success Rate Among Patients Undergoing Out-of- Hospital Rapid Sequence Intubation: A Randomized Clinical Trial. JAMA. 2019 Dec 17;322(23):2303-2312. Open reference URL https://web.pathway.md/studies/recBFLDhc4a4AOhlK 2/2