Sepsis & Critical Care
Rivers EGDT Trial
2001 ยท NEJM ยท Sepsis
Does early goal-directed therapy improve survival in septic shock?
N=263 with severe sepsis or septic shock in the ED. Protocol-based EGDT (CVP, MAP, ScvO₂ targets + fluids, vasopressors, dobutamine, transfusion) reduced in-hospital mortality from 46.5% to 30.5% (NNT=6). Conclusion: Revolutionized sepsis care. Later trials (ProCESS/ARISE/ProMISe) showed the specific protocol wasn't needed, but early aggressive resuscitation was the key takeaway.
Landmark Positive -changed sepsis management
Surviving Sepsis Campaign Guidelines
2018 ยท Crit Care Med / Intensive Care Med ยท Sepsis
What are evidence-based recommendations for sepsis and septic shock management?
Bundle-based approach: 1-hour bundle with antibiotics within 1 hour, 30 mL/kg crystalloid for hypoperfusion, norepinephrine first-line vasopressor, re-measure lactate at 2 hours, source control. Conclusion: Established the 1-hour sepsis bundle as standard of care. Early antibiotics and aggressive resuscitation are the cornerstones.
Guideline
SOAP II Trial
2010 ยท NEJM ยท Sepsis / Vasopressors
Is norepinephrine superior to dopamine as first-line vasopressor in shock?
N=1,679 with shock (septic, cardiogenic, hypovolemic). No difference in 28-day mortality, but dopamine caused significantly more arrhythmias (24.1% vs 12.4%). Conclusion: Norepinephrine is the first-line vasopressor for septic shock. Dopamine should be avoided due to arrhythmia risk.
Norepinephrine preferred
SMART Trial
2018 ยท NEJM ยท Sepsis / Fluids
Are balanced crystalloids superior to normal saline in critically ill adults?
N=15,802 critically ill adults in medical ICU. Balanced crystalloids (LR or PlasmaLyte) reduced major adverse kidney events at 30 days vs normal saline (14.3% vs 15.4%) with a trend toward mortality benefit. Conclusion: LR or PlasmaLyte is preferred over NS as the default resuscitation fluid. NS causes hyperchloremic acidosis and AKI.
Balanced crystalloids preferred in ICU
APROCCHSS Trial
2018 ยท NEJM ยท Sepsis
Do hydrocortisone + fludrocortisone reduce 90-day mortality in septic shock?
N=1,241 with septic shock. Hydrocortisone 200 mg/day plus fludrocortisone 50 mcg/day reduced 90-day mortality (43% vs 49%) and increased vasopressor-free days. Conclusion: Adding fludrocortisone is the key difference from ADRENAL. Surviving Sepsis Campaign recommends steroids in refractory shock.
Positive
PRORATA Trial
2010 ยท Lancet ยท Sepsis / Antibiotics
Does procalcitonin-guided antibiotic discontinuation reduce use without harm?
N=621 ICU patients with suspected bacterial infection. PCT-guided antibiotic duration reduced antibiotic days (14.3 vs 17.1) with no increase in mortality or length of stay. Conclusion: Procalcitonin-guided protocols allow earlier antibiotic discontinuation and support antimicrobial stewardship in the ICU.
Positive -supports PCT-guided de-escalation
NICE-SUGAR Trial
2009 ยท NEJM ยท Critical Care
Does intensive glucose control improve ICU outcomes?
N=6,104 ICU patients expected to stay ≥3 days. Intensive glucose control (81โ108 mg/dL) increased 90-day mortality vs conventional control (≤180 mg/dL), 27.5% vs 24.9%. Severe hypoglycemia was 13x higher (6.8% vs 0.5%). Conclusion: Ended the era of tight glucose control in the ICU. Target 140โ180 mg/dL is now standard.
Negative -tight control harms ICU patients
ProCESS Trial
2014 ยท NEJM ยท Sepsis
Is protocolized EGDT superior to usual care?
N=1,341 with septic shock across 31 US EDs. Protocol-based EGDT vs protocol-based standard therapy vs usual care showed no difference in 60-day mortality across all 3 groups (~19%). Conclusion: Along with ARISE and ProMISe, showed the specific EGDT protocol (CVP, ScvO₂, dobutamine, transfusion targets) was unnecessary. Early recognition + antibiotics + fluids is what matters.
Neutral -protocol not needed
ADRENAL Trial
2018 ยท NEJM ยท Sepsis
Does hydrocortisone reduce 90-day mortality in septic shock?
N=3,658 with septic shock on vasopressors and mechanical ventilation. Hydrocortisone 200 mg/day infusion showed no difference in 90-day mortality but achieved faster shock reversal and shorter ICU stay. Conclusion: Paired with APROCCHSS (2018). Both support steroids for refractory septic shock per Surviving Sepsis guidelines, benefit is hemodynamic, not mortality.
Neutral (faster reversal, no survival benefit)
CORTICUS Trial
2008 ยท NEJM ยท Sepsis
Does hydrocortisone improve survival in septic shock?
N=499 with septic shock (less severe than Annane 2002). Hydrocortisone 50 mg q6h for 5 days then taper showed no mortality benefit. Faster shock reversal but more hyperglycemia and superinfections. Conclusion: Steroids hasten vasopressor weaning but don't clearly save lives. Consider only for refractory shock despite adequate fluids and vasopressors.
Neutral -faster shock reversal, no survival benefit
VASST Trial
2008 ยท NEJM ยท Sepsis / Vasopressors
Does adding vasopressin to norepinephrine reduce mortality in septic shock?
N=778 with septic shock on norepinephrine. Adding vasopressin (0.01โ0.03 units/min) showed no difference in 28-day mortality overall. Trend toward benefit in less severe shock (NE <15 mcg/min). May reduce atrial fibrillation incidence. Conclusion: Vasopressin is a catecholamine-sparing second vasopressor, not a mortality reducer. Used at 0.03 units/min to spare norepinephrine dose.
Neutral -vasopressin as catecholamine-sparing agent
CITRIS-ALI Trial
2019 ยท JAMA ยท Sepsis
Does IV vitamin C reduce organ failure in sepsis-induced ARDS?
N=167 with sepsis-induced ARDS. IV vitamin C 200 mg/kg/day for 4 days showed no difference in SOFA score (primary endpoint). A secondary mortality signal was seen (29.8% vs 46.3%) but was not the primary outcome. Conclusion: IV vitamin C is not standard of care for sepsis. The VITAMINS trial (2020) also showed no benefit.
Neutral primary / signal secondary
ALBIOS Trial
2014 ยท NEJM ยท Sepsis
Does albumin supplementation (target โฅ30 g/L) reduce 28-day mortality in sepsis?
N=1,818 with severe sepsis or septic shock. 20% albumin plus crystalloid vs crystalloid alone showed no reduction in 28-day or 90-day mortality and no benefit on organ failure scores. Conclusion: Albumin is not recommended for routine volume resuscitation in sepsis.
Negative
PROWESS-SHOCK Trial
2012 ยท NEJM ยท Sepsis
Does drotrecogin alfa (activated protein C) reduce mortality in septic shock?
N=1,696 with septic shock. Drotrecogin alfa (Xigris) showed no difference in 28-day mortality vs placebo (26.4% vs 24.2%). Drug was withdrawn from the market worldwide. Conclusion: Activated protein C has no role in sepsis management. The drug was pulled in 2011 after failing to replicate the original PROWESS results.
Negative -drug withdrawn
Sepsis-3
2016 ยท JAMA ยท Sepsis
Redefined sepsis using SOFA criteria. Replaced SIRS-based definition.
Sepsis redefined as life-threatening organ dysfunction from dysregulated host response (SOFA ≥2). Septic shock = sepsis + vasopressors + lactate >2. Eliminated "severe sepsis" as a category. qSOFA introduced for bedside screening (≥2 of: SBP ≤100, RR ≥22, altered mentation). Conclusion: Shifted focus from inflammation (SIRS) to organ dysfunction as the defining feature of sepsis.
Guideline
Surviving Sepsis Campaign 2021
2021 ยท Critical Care Medicine ยท Sepsis
Updated sepsis guidelines with key changes to resuscitation strategy?
Key changes: balanced crystalloids preferred over NS, start vasopressors early if MAP <65 during resuscitation (don't wait for fluids to finish), target MAP 65, albumin not recommended for initial resuscitation, corticosteroids for refractory shock. Conclusion: Major shift toward dynamic assessment over protocolized care. Emphasis on early vasopressor initiation.
Guideline
ANDROMEDA-SHOCK
2019 ยท JAMA ยท Sepsis
Peripheral perfusion vs lactate-guided resuscitation in septic shock?
N=424 with septic shock. CRT-guided resuscitation (capillary refill <3s target) showed a trend toward lower 28-day mortality vs lactate-guided (34.9% vs 43.4%), though not statistically significant. Conclusion: Capillary refill time is a valid bedside resuscitation target alongside lactate. Led to the larger ANDROMEDA-SHOCK-2 trial.
Neutral
CENSER Trial
2019 ยท Annals of EM ยท Sepsis
Does early norepinephrine improve outcomes in septic shock?
N=310 ED patients with septic shock. Early norepinephrine (within 1 hour) plus fluids achieved shock control in 76% vs 48% with fluids alone. Conclusion: Don't wait to finish fluid resuscitation before starting vasopressors. Early norepinephrine is safe and effective.
Positive
ATHOS-3
2017 ยท NEJM ยท Critical Care / Sepsis
Does angiotensin II improve blood pressure in vasodilatory shock on high-dose vasopressors?
N=344 with vasodilatory shock on high-dose vasopressors. Angiotensin II achieved MAP response in 70% vs 23% with placebo. Conclusion: Angiotensin II is a rescue vasopressor option for refractory distributive shock unresponsive to norepinephrine and vasopressin.
Positive
SAFE Study
2004 ยท NEJM ยท Critical Care
Is albumin superior to normal saline for ICU fluid resuscitation?
N=6,997 ICU patients. 4% albumin vs normal saline for fluid resuscitation showed no difference in 28-day mortality overall. Albumin was harmful in the traumatic brain injury subgroup. Conclusion: Albumin is not superior to crystalloids for most ICU patients. Avoid in TBI.
Neutral
VISEP
2008 ยท NEJM ยท Critical Care
What are the effects of intensive insulin and HES in severe sepsis?
N=600 with severe sepsis. HES increased AKI and need for RRT vs Ringer's lactate. Intensive insulin increased hypoglycemia without benefit. Conclusion: HES is harmful in sepsis, causes renal failure. Avoid all starches in the critically ill.
Negative
6S Trial
2012 ยท NEJM ยท Critical Care
Is HES inferior to Ringer's acetate for fluid resuscitation in severe sepsis?
N=798 with severe sepsis. HES 130/0.42 increased 90-day mortality (51% vs 43%) and need for renal replacement therapy vs Ringer's acetate. Conclusion: Along with VISEP and CHEST, this trial ended HES use in the critically ill. Crystalloids are the standard.
Negative
SUP-ICU Trial
2018 ยท NEJM ยท Critical Care
Does routine stress ulcer prophylaxis benefit ICU patients?
N=3,298 ICU patients at risk for GI bleeding. Pantoprazole 40 mg daily vs placebo showed no difference in 90-day mortality or clinically important GI bleeding. Conclusion: Not all ICU patients need stress ulcer prophylaxis. Reserve for high-risk patients (ventilated >48h, coagulopathy, prior GI bleed).
Neutral
ARDS & Ventilation
ARDSnet ARMA Trial
2000 ยท NEJM ยท ARDS / Ventilation
Does low tidal volume ventilation (6 mL/kg IBW) reduce mortality in ARDS?
N=861 with ARDS on mechanical ventilation. Low tidal volume (6 mL/kg IBW, Pplat ≤30 cmH₂O) reduced 28-day mortality from 39.8% to 31% vs 12 mL/kg, with more ventilator-free days. Conclusion: Foundation of lung-protective ventilation. All ARDS patients should receive 6 mL/kg IBW tidal volumes with plateau pressure ≤30.
Positive -practice changing
PROSEVA Trial
2013 ยท NEJM ยท ARDS
Does prone positioning reduce 28-day mortality in severe ARDS?
N=466 with severe ARDS (P/F <150) on lung-protective ventilation. Prone positioning ≥16 hours/day cut 28-day mortality in half (16% vs 32.8%) with no increase in complications. Conclusion: Proning ≥16h/day is standard of care for severe ARDS. Must be established on lung-protective ventilation first.
Positive -practice changing
FACTT Trial
2006 ยท NEJM ยท ARDS
Does conservative vs liberal fluid strategy improve outcomes in ARDS?
N=1,000 with ARDS. Conservative fluid management produced more ventilator-free days (14.6 vs 12.1) and less need for RRT, though no mortality difference. Conclusion: Supports the "dry lung" strategy in ARDS. Target neutral to negative fluid balance after initial resuscitation is complete.
Conservative strategy preferred
ACURASYS Trial
2010 ยท NEJM ยท ARDS
Does early cisatracurium infusion improve outcomes in moderate-severe ARDS?
N=340 with moderate-severe ARDS (P/F <150). 48-hour cisatracurium infusion reduced 90-day mortality (31.6% vs 40.7%), improved oxygenation at 48h, and reduced barotrauma. Conclusion: Supported early NMB in severe ARDS, but later superseded by ROSE (2019) which showed no benefit when lighter background sedation is used.
Positive
EOLIA Trial
2018 ยท NEJM ยท ARDS
Does early VV-ECMO reduce 60-day mortality in very severe ARDS?
N=249 with very severe ARDS (P/F <80). 60-day mortality was 35% vs 46% but did not reach significance. 35% of the control arm crossed over to ECMO. Bayesian re-analysis showed 88% probability of benefit. Conclusion: ECMO should be considered for refractory severe ARDS at ECMO-capable centers despite the negative primary endpoint. High crossover rate diluted the treatment effect.
Negative (trend to benefit)
ROSE Trial
2019 ยท NEJM ยท ARDS
Does early cisatracurium improve outcomes in ARDS when lighter sedation is standard?
N=1,006 with moderate-severe ARDS. Early continuous cisatracurium showed no difference in 90-day mortality vs usual care with lighter sedation (42.5% vs 42.8%), with more cardiovascular adverse events. Conclusion: Supersedes ACURASYS when deep sedation is not used. NMB may still be considered for ventilator dyssynchrony or refractory hypoxemia.
Negative -NMB not routinely recommended
OSCILLATE Trial
2013 ยท NEJM ยท ARDS
Does HFOV improve outcomes in moderate-severe ARDS?
N=548 with moderate-severe ARDS. Trial stopped early, in-hospital mortality was higher with HFOV (47% vs 35%). Conclusion: HFOV is not recommended for ARDS. Paired with OSCAR trial (also no benefit). Conventional lung-protective ventilation remains the gold standard.
Negative -HFOV harmful
DEXA-ARDS
2020 ยท Lancet Resp Med ยท ARDS
Does dexamethasone improve outcomes in moderate-severe ARDS?
N=277 with moderate-severe ARDS (P/F ≤200). Dexamethasone 20 mg ร5 days then 10 mg ร5 days increased ventilator-free days (4.8 vs 2.6) and reduced 60-day mortality (21% vs 36%). Conclusion: Supports early dexamethasone in established moderate-severe ARDS.
Positive
LUNG SAFE
2016 ยท JAMA ยท ARDS
How well is ARDS recognized and managed worldwide?
N=29,144 ICU patients across 50 countries. 10% of ICU admissions had ARDS, but 40% were not recognized by clinicians. Lung-protective ventilation was used in only 35% of cases. Conclusion: ARDS is massively underdiagnosed and undertreated worldwide. Always consider it in hypoxemic patients.
Landmark
Airway & Sedation
ABC Trial (Awakening & Breathing Coordination)
2008 ยท Lancet ยท Airway & Ventilator Management / Sedation
Does pairing spontaneous awakening trials with spontaneous breathing trials improve outcomes?
N=336 mechanically ventilated ICU patients. Daily SAT paired with SBT increased ventilator-free days (14.7 vs 11.6), shortened ICU stay, and reduced 1-year mortality by 32%. Conclusion: Established daily SAT + SBT pairing as standard of care. Foundation of the ABCDEF bundle.
Positive -ABCDEF bundle foundation
MENDS Trial
2007 ยท JAMA ยท Sedation
Does dexmedetomidine reduce delirium vs lorazepam in mechanically ventilated patients?
N=106 mechanically ventilated ICU patients requiring sedation. Dexmedetomidine produced more delirium/coma-free days than lorazepam with no mortality difference. Conclusion: Paired with SEDCOM, both support dexmedetomidine over benzodiazepines for ICU sedation to reduce delirium.
Dexmedetomidine preferred
SEDCOM Trial
2009 ยท JAMA ยท Sedation
Does dexmedetomidine reduce delirium vs midazolam in mechanically ventilated patients?
N=375 mechanically ventilated ICU patients needing sedation >24h. Dexmedetomidine reduced delirium prevalence (54% vs 76.6%) and shortened time to extubation vs midazolam. Conclusion: With MENDS, established dexmedetomidine as the preferred sedative to reduce delirium in ventilated ICU patients.
Dexmedetomidine preferred
MIND-USA Trial
2018 ยท NEJM ยท Sedation / Delirium
Do haloperidol or ziprasidone reduce delirium duration in critically ill patients?
N=566 critically ill adults with delirium. IV haloperidol, IV ziprasidone, and placebo showed no difference in delirium/coma-free days, 90-day mortality, or ventilator-free days. Conclusion: Antipsychotics should not be routinely used for ICU delirium. Focus on the ABCDEF bundle and non-pharmacologic measures instead.
Negative -antipsychotics don't treat ICU delirium
PADIS Guidelines
2018 ยท Critical Care Medicine ยท Critical Care
What are best practices for pain, agitation, delirium, immobility, and sleep in ICU?
Analgesia-first approach, target light sedation (RASS 0 to –2), daily SAT + SBT, avoid benzodiazepines, early mobility, and sleep hygiene. Conclusion: Foundation of modern ICU sedation practice. The ABCDEF bundle integrates all these recommendations into a daily workflow.
Guideline
ACS, Acute Management
ISIS-2 Trial
1988 ยท Lancet ยท ACS / MI
Does aspirin and/or streptokinase reduce mortality in acute MI?
N=17,187 with suspected acute MI. Aspirin alone reduced 5-week vascular mortality by 23%, streptokinase alone by 25%, and the combination by 42%. Conclusion: Established aspirin as life-saving in acute MI. One of the most influential trials in cardiology history.
Landmark Positive
PLATO Trial
2009 ยท NEJM ยท Cardiology / ACS
Is ticagrelor superior to clopidogrel in ACS?
N=18,624 hospitalized with ACS (STEMI or NSTEMI). Ticagrelor 90 mg BID reduced CV death, MI, and stroke vs clopidogrel 75 mg daily with no increase in major bleeding. All-cause mortality also reduced. Conclusion: Ticagrelor is the preferred P2Y12 inhibitor in ACS. Reversible binding with faster onset/offset than clopidogrel, and avoids CYP2C19 resistance issues.
Positive, ticagrelor preferred P2Y12
TRITON-TIMI 38 Trial
2007 ยท NEJM ยท Cardiology / ACS
Is prasugrel superior to clopidogrel in ACS patients undergoing PCI?
N=13,608 ACS patients scheduled for PCI. Prasugrel reduced CV death, MI, stroke, and stent thrombosis vs clopidogrel, but increased major and fatal bleeding. Conclusion: More potent but riskier. Contraindicated in prior stroke/TIA (net harm), age ≥75 (no net benefit), and weight <60 kg. Use ticagrelor instead in these patients.
Positive with caution, more bleeding
ESSENCE Trial
1997 ยท NEJM ยท Cardiology / ACS
Is enoxaparin (LMWH) superior to unfractionated heparin in unstable angina / NSTEMI?
N=3,171 with unstable angina or non-Q-wave MI. Enoxaparin 1 mg/kg SC BID reduced death, MI, and recurrent angina at 14 and 30 days vs UFH IV drip, with no increase in major bleeding. Conclusion: Established LMWH as preferred over UFH in NSTEMI. Enoxaparin offers predictable dosing without aPTT monitoring. UFH still preferred if PCI planned within 24h (easier to reverse).
Positive, enoxaparin superior to UFH in UA/NSTEMI
TIMACS Trial
2009 ยท NEJM ยท Cardiology / ACS
Does early (<24h) vs delayed (>36h) intervention improve outcomes in NSTEMI?
N=3,031 with NSTEMI. No overall difference, but in high-risk patients (GRACE >140), early intervention within 24h significantly reduced death/MI/stroke (13.9% vs 21.0%). Low-risk patients could safely wait. Conclusion: GRACE >140 should trigger an early invasive strategy within 24h. Low-risk patients can safely undergo delayed catheterization.
Positive in high-risk (GRACE >140)
HEART Pathway Trial
2015 ยท Circulation ยท Cardiology / ACS
Can HEART score safely identify low-risk chest pain for early ED discharge?
N=282 ED patients with acute chest pain. HEART score 0โ3 plus negative serial troponins safely reduced cardiac testing by 12% and shortened hospital stay. 30-day MACE in the low-risk group was <2%. Conclusion: HEART 0โ3 with negative troponins = safe for discharge with outpatient follow-up. Now widely adopted in EDs for chest pain risk stratification.
Positive, safe early discharge
STREAM
2013 ยท NEJM ยท Cardiology
Is a pharmaco-invasive strategy noninferior to primary PCI for early STEMI?
N=1,892 STEMI patients presenting within 3h who could not get primary PCI within 1h. Tenecteplase followed by transfer for angiography within 6โ24h was noninferior to primary PCI. Conclusion: When PCI is delayed >120 min, lyse first then transfer. Pharmaco-invasive strategy is valid for STEMI at non-PCI centers.
Neutral
Stable CAD & Revascularization
COURAGE Trial
2007 ยท NEJM ยท Stable CAD
Does PCI beat optimal medical therapy in stable CAD?
N=2,287 with stable CAD and objective ischemia. PCI plus optimal medical therapy showed no difference in death or MI vs medical therapy alone at 4.6 years. PCI provided better early angina relief only. Conclusion: Medical therapy is first-line for stable angina. PCI is reserved for refractory symptoms, not for outcome benefit.
Neutral, PCI did not beat medical therapy
FREEDOM Trial
2012 ยท NEJM ยท Revascularization
CABG vs PCI in diabetic patients with multivessel CAD?
N=1,900 diabetic patients with multivessel CAD. CABG significantly reduced death and MI at 5 years vs PCI with drug-eluting stents (18.7% vs 26.6%), though stroke was higher with CABG (5.2% vs 2.4%). Conclusion: Diabetic patients with multivessel disease should be referred for CABG unless high surgical risk.
Positive, CABG wins in diabetics
SYNTAX Trial
2009 ยท NEJM / Lancet ยท Revascularization
PCI vs CABG for complex multivessel or left-main CAD?
N=1,800 with three-vessel or left-main CAD. CABG was superior for complex disease (high SYNTAX score ≥33). PCI was comparable for low-complexity lesions. Conclusion: Introduced the SYNTAX score for Heart Team decision-making. High complexity = CABG, low complexity = PCI acceptable.
CABG wins for complex disease
CV Secondary Prevention (Lipids, Anti-inflammatory, Post-MI)
4S Trial (Scandinavian Simvastatin Survival Study)
1994 ยท Lancet ยท Cardiology / Lipids
Does simvastatin reduce mortality in patients with CHD?
N=4,444 with CHD and elevated cholesterol. Simvastatin over 5.4 years reduced all-cause mortality by 30%, coronary death by 42%, and major coronary events by 34%. Conclusion: First trial to prove statins reduce mortality. Changed lipid management forever and launched the statin era.
Landmark Positive, statins save lives
PROVE ITโTIMI 22 Trial
2004 ยท NEJM ยท ACS / Lipids
Is intensive statin therapy better than standard therapy after ACS?
N=4,162 hospitalized for ACS. Atorvastatin 80 mg (intensive) reduced death, MI, unstable angina, revascularization, and stroke by 16% vs pravastatin 40 mg (standard). Conclusion: Established that "lower is better" for LDL after ACS. Foundation for high-intensity statin guidelines in all ACS patients.
Positive, high-intensity statin after ACS
SAVE Trial
1992 ยท NEJM ยท Cardiology
Does captopril improve outcomes post-MI with LV dysfunction?
N=2,231 post-MI patients with EF ≤40%. Captopril reduced mortality by 19% and heart failure by 37% vs placebo. Conclusion: Established ACE inhibitors post-MI for LV dysfunction. Start ACEi in all post-MI patients with reduced EF.
Positive, ACEi post-MI
LoDoCo2 Trial
2020 ยท NEJM ยท Cardiology / Secondary Prevention
Does low-dose colchicine reduce CV events in chronic coronary disease?
N=5,522 with chronic coronary disease (> 6 months stable), on aspirin + statin. Colchicine 0.5 mg daily reduced the composite of CV death, MI, ischemic stroke, or ischemia-driven revascularization by 31% (6.8% vs 9.6%, HR 0.69) over 28.6 months. NNT ~36. Conclusion: Pivotal trial for colchicine in chronic ASCVD. Led to FDA approval of Lodoco (June 2023), the first anti-inflammatory drug approved for CV risk reduction. Layered on top of aspirin + statin.
Landmark Positive, secondary prevention
COLCOT Trial
2019 ยท NEJM ยท Cardiology / Post-MI
Does colchicine started within 30 days of MI reduce recurrent CV events?
N=4,745 with MI in the prior 30 days. Colchicine 0.5 mg daily reduced the primary composite (CV death, cardiac arrest, MI, stroke, urgent revascularization) by 23% (5.5% vs 7.1%, HR 0.77) at 22.6 months. Stroke reduced by 74%. Slightly more pneumonia with colchicine. Conclusion: First major trial showing colchicine benefit post-MI. With LoDoCo2, formed the evidence base for FDA approval of low-dose colchicine for CV secondary prevention.
Positive, 23% RRR in post-MI MACE
CLEAR SYNERGY (OASIS-9)
2024 ยท NEJM ยท Cardiology / Post-MI
Does colchicine (and spironolactone) reduce CV events started at the time of PCI for MI?
N=7,062 with recent STEMI or NSTEMI undergoing PCI. Factorial design (colchicine vs placebo, spironolactone vs placebo). Over 3 years, colchicine did NOT reduce the composite of CV death, MI, stroke, or ischemia-driven revascularization (9.1% vs 9.3%, HR 0.99). More diarrhea with colchicine. Conclusion: The largest colchicine-in-ACS trial was neutral. Suggests benefit is restricted to the chronic stable phase (as in LoDoCo2), not the immediate post-ACS window. Favor starting colchicine in chronic follow-up rather than acutely.
Neutral, tempers acute-phase enthusiasm
Heart Failure
SOLVD Treatment Trial
1991 ยท NEJM ยท Heart Failure
Does enalapril reduce mortality in HFrEF?
N=2,569 with EF ≤35% and NYHA IIโIV symptoms. Enalapril reduced all-cause mortality by 16% and HF hospitalization by 26%. Conclusion: Established ACE inhibitors as foundational therapy in HFrEF. One of the four pillars of GDMT.
Landmark Positive -ACEi standard for HFrEF
PARADIGM-HF Trial
2014 ยท NEJM ยท Heart Failure
Is sacubitril/valsartan superior to enalapril in HFrEF?
N=8,442 NYHA IIโIV, EF ≤40% on standard GDMT. Sacubitril/valsartan (Entresto) reduced CV death or HF hospitalization by 20% and all-cause mortality by 16% vs enalapril. Stopped early. Conclusion: ARNI replaced ACEi/ARB as pillar #1 of HFrEF GDMT. Requires 36h ACEi washout before starting.
Landmark Positive -ARNI replaced ACEi
RALES Trial
1999 ยท NEJM ยท Heart Failure
Does spironolactone reduce mortality in severe HFrEF?
N=1,663 NYHA IIIโIV, EF ≤35%, already on ACEi + loop diuretic. Spironolactone 25โ50 mg reduced all-cause mortality by 30% and HF hospitalization by 35%. Stopped early for benefit. Conclusion: Established MRAs as pillar #3 of HFrEF GDMT. Watch for hyperkalemia (K >5.0) and renal function.
Landmark Positive -MRA became HFrEF pillar
MADIT-II Trial
2002 ยท NEJM ยท Heart Failure / Arrhythmia
Does prophylactic ICD reduce mortality post-MI with low EF?
N=1,232 with prior MI and EF ≤30%. Prophylactic ICD reduced all-cause mortality by 31% (14.2% vs 19.8%), driven by reduction in arrhythmic death. Conclusion: Established the ICD indication: prior MI + EF ≤35% (after 40 days post-MI, 90 days post-revascularization).
Positive -ICD for primary prevention
CONSENSUS Trial
1987 ยท NEJM ยท Heart Failure
Does enalapril improve survival in severe heart failure?
N=253 NYHA IV heart failure. Enalapril reduced mortality by 40% at 6 months. Conclusion: First trial showing ACE inhibitors save lives in heart failure. Launched the neurohormonal era of HF therapy.
Positive
COPERNICUS
2001 ยท NEJM ยท Heart Failure
Does carvedilol improve survival in severe HFrEF?
N=2,289 NYHA IV, EF <25%. Carvedilol reduced mortality by 35%. Conclusion: Proved beta-blockers are safe and effective even in severe/decompensated HF once the patient is euvolemic.
Positive
CIBIS-II
1999 ยท Lancet ยท Heart Failure
Does bisoprolol reduce mortality in HFrEF?
N=2,647 NYHA IIIโIV, EF ≤35%. Bisoprolol reduced all-cause mortality by 34%. Conclusion: Along with MERIT-HF and COPERNICUS, proved the beta-blocker class effect in HFrEF. Only carvedilol, metoprolol succinate, and bisoprolol are evidence-based.
Positive
MERIT-HF
1999 ยท Lancet ยท Heart Failure
Does metoprolol succinate improve outcomes in HFrEF?
N=3,991 NYHA IIโIV, EF ≤40%. Metoprolol succinate (CR/XL) reduced all-cause mortality by 34%. Stopped early for benefit. Conclusion: Established beta-blockers as standard HFrEF therapy. One of three landmark BB trials (with CIBIS-II and COPERNICUS).
Positive
DAPA-HF
2019 ยท NEJM ยท Heart Failure
Does dapagliflozin improve outcomes in HFrEF regardless of diabetes status?
N=4,744 with EF ≤40% (with or without diabetes). Dapagliflozin reduced CV death and HF hospitalization by 26%. Conclusion: First SGLT2i trial in HF regardless of diabetes status. Made SGLT2 inhibitors the 4th pillar of HFrEF GDMT.
Positive
EMPEROR-Reduced
2020 ยท NEJM ยท Heart Failure
Does empagliflozin improve outcomes in HFrEF?
N=3,730 with EF ≤40%. Empagliflozin reduced CV death and HF hospitalization by 25%. Conclusion: Confirmed the SGLT2i class effect in HFrEF alongside DAPA-HF. Both dapagliflozin and empagliflozin are guideline-recommended.
Positive
DIGIT-HF
2025 ยท NEJM ยท Heart Failure
Does digitoxin added to GDMT improve outcomes in advanced HFrEF?
Positive
EMPHASIS-HF
2011 ยท NEJM ยท Heart Failure
Does eplerenone improve outcomes in mild HFrEF?
N=2,737 NYHA II, EF ≤30%. Eplerenone reduced CV death and HF hospitalization by 37%. Conclusion: Extended the MRA benefit beyond severe HF (RALES) to mild HFrEF. MRAs are a pillar for all symptomatic HFrEF.
Positive
DELIVER
2022 ยท NEJM ยท Heart Failure
Does dapagliflozin improve outcomes in HFpEF?
N=6,263 with EF >40%. Dapagliflozin reduced CV death and HF hospitalization by 18%. Conclusion: Confirmed SGLT2i benefit across the entire EF spectrum, works in both HFrEF and HFpEF.
Positive
EMPEROR-Preserved
2021 ยท NEJM ยท Heart Failure
Does empagliflozin improve outcomes in HFpEF?
N=5,988 with EF >40%. Empagliflozin reduced HF hospitalization by 29%. Conclusion: First drug to show benefit in HFpEF, a game-changer for a population with historically no effective therapies.
Positive
A-HeFT
2004 ยท NEJM ยท Heart Failure
Does hydralazine-nitrate improve outcomes in Black patients with HF?
N=1,050 self-identified Black patients with NYHA IIIโIV HF. BiDil (hydralazine + isosorbide dinitrate) reduced mortality by 43%. Stopped early for benefit. Conclusion: Add hydralazine-nitrate for self-identified Black patients with HFrEF already on optimal GDMT.
Positive
DIG Trial
1997 ยท NEJM ยท Heart Failure
Does digoxin reduce mortality in HFrEF?
N=6,800 with EF ≤45%. Digoxin reduced HF hospitalizations but showed no mortality benefit. Conclusion: Digoxin helps symptoms but doesn't save lives. Reserved for refractory HF or rate control in AF when other agents fail.
Neutral
SHIFT Trial
2010 ยท Lancet ยท Heart Failure
Does ivabradine improve outcomes in HFrEF with elevated heart rate?
N=6,558 with EF ≤35%, HR ≥70 in sinus rhythm. Ivabradine reduced CV death and HF hospitalization by 18%. Conclusion: For HFrEF patients in sinus rhythm with HR ≥70 despite maximally tolerated beta-blocker.
Positive
VICTORIA
2020 ยท NEJM ยท Heart Failure
Does vericiguat reduce events in worsening HFrEF?
N=5,050 with worsening HFrEF. Vericiguat (soluble guanylate cyclase stimulator) reduced CV death and HF hospitalization by 10%, a modest but significant benefit. Conclusion: Add-on option for patients failing standard GDMT with recent HF hospitalization.
Positive
STRONG-HF
2022 ยท NEJM ยท Heart Failure
Does rapid GDMT titration after HF hospitalization improve outcomes?
N=1,078 discharged after acute HF. Rapid up-titration of GDMT within 2 weeks reduced HF readmission and death by 34% vs usual care. Conclusion: Don't wait, optimize GDMT fast after discharge. Aggressive early titration is safe and beneficial.
Positive
EMPULSE
2022 ยท Nature Medicine ยท Heart Failure
Does empagliflozin initiated during HF hospitalization improve outcomes?
N=530 hospitalized for acute HF. Empagliflozin started in-hospital improved a composite of death, HF events, and symptoms at 90 days. Conclusion: Start SGLT2i in-hospital during acute HF, don't wait for discharge.
Positive
TOPCAT
2014 ยท NEJM ยท Heart Failure
Does spironolactone improve outcomes in HFpEF?
N=3,445 with EF ≥45%. Primary endpoint was negative overall, but the Americas subgroup showed an 18% benefit. Conclusion: Regional differences (Russia/Georgia sites questioned) muddied results. Americas-only analysis suggests MRA may help HFpEF, but evidence is not definitive.
Neutral
CHARM-Preserved
2003 ยท Lancet ยท Heart Failure
Does candesartan improve outcomes in HFpEF?
N=3,023 with EF >40%. Candesartan showed a modest trend toward fewer HF hospitalizations but was not statistically significant. Conclusion: ARBs alone don't clearly help HFpEF. SGLT2 inhibitors (EMPEROR-Preserved, DELIVER) are the real game-changers for this population.
Neutral
TRANSFORM-HF
2022 ยท NEJM ยท Heart Failure
Is torsemide superior to furosemide in HF?
N=2,859 hospitalized for HF. Torsemide vs furosemide showed no difference in all-cause mortality at 12 months. Conclusion: Torsemide is not superior to furosemide for HF outcomes. Either loop diuretic is acceptable.
Neutral
STEP-HFpEF
2023 ยท NEJM ยท Heart Failure / Endocrinology
Does semaglutide improve outcomes in obese HFpEF?
N=529 with HFpEF, BMI ≥30, no diabetes. Semaglutide reduced body weight by 13.3% and improved symptoms, exercise capacity, and 6-minute walk distance. Conclusion: GLP-1 RA for obese HFpEF, treats the obesity driving the heart failure. Led to the larger SUMMIT trial.
Positive
SCD-HeFT
2005 ยท NEJM ยท Heart Failure / Cardiology
Does ICD implantation reduce mortality in moderate heart failure?
N=2,521 NYHA IIโIII, EF ≤35%. ICD reduced all-cause mortality by 23%. Amiodarone was no better than placebo. Conclusion: With MADIT-II, established primary prevention ICD criteria for HFrEF patients with EF ≤35%.
Positive
MADIT-CRT
2009 ยท NEJM ยท Heart Failure / Cardiology
Does CRT-D improve outcomes in mild HF?
N=1,820 NYHA IโII, EF ≤30%, QRS ≥130 ms. CRT-D reduced HF events by 34% vs ICD alone. Conclusion: CRT benefit requires LBBB and QRS ≥150 ms. Less benefit with non-LBBB morphology or narrower QRS.
Positive
RAFT
2010 ยท NEJM ยท Heart Failure / Cardiology
Does CRT-D reduce mortality vs ICD in moderate HF?
N=1,798 NYHA IIโIII, EF ≤30%, QRS ≥120 ms. CRT-D reduced all-cause mortality by 25% vs ICD alone. Conclusion: Confirmed mortality benefit of CRT in patients meeting criteria (EF ≤35%, LBBB, QRS ≥150 ms).
Positive
Cardiogenic Shock
SHOCK Trial
1999 ยท NEJM ยท Cardiogenic Shock
Does early revascularization reduce mortality in cardiogenic shock complicating MI?
N=302 with cardiogenic shock complicating acute MI. 30-day mortality was similar, but 6-month and 1-year mortality were significantly reduced with early revascularization (PCI or CABG). Conclusion: Established early PCI/catheterization as standard of care for cardiogenic shock complicating MI.
Early revascularization preferred
IABP-SHOCK II Trial
2012 ยท NEJM ยท Cardiogenic Shock
Does IABP reduce 30-day mortality in cardiogenic shock complicating MI?
N=600 with cardiogenic shock complicating acute MI undergoing revascularization. IABP showed no difference in 30-day mortality (39.7% vs 41.3%) and no benefit on any secondary endpoint. Conclusion: Led to downgrade of IABP in ESC/ACC guidelines. IABP is no longer routinely recommended in cardiogenic shock.
Negative -practice changing
Cardiology, Anticoagulation & AF
RE-LY
2009 ยท NEJM ยท Cardiology / Anticoagulation
Is dabigatran noninferior or superior to warfarin in AF?
N=18,113 with AF. Dabigatran 150 mg BID reduced stroke by 34% vs warfarin. The 110 mg dose had less bleeding. Conclusion: First DOAC approved for AF. Only DOAC with a specific reversal agent (idarucizumab).
Positive
ARISTOTLE
2011 ยท NEJM ยท Cardiology / Anticoagulation
Is apixaban superior to warfarin in atrial fibrillation?
N=18,201 with AF. Apixaban reduced stroke by 21%, major bleeding by 31%, and mortality by 11% vs warfarin. Conclusion: Best overall efficacy and safety profile among DOACs for AF. The go-to DOAC for most patients.
Positive
ROCKET AF
2011 ยท NEJM ยท Cardiology / Anticoagulation
Is rivaroxaban noninferior to warfarin for stroke prevention in AF?
N=14,264 high-risk AF patients. Rivaroxaban was noninferior to warfarin for stroke prevention with less intracranial bleeding. Conclusion: Once-daily DOAC option for AF. Must be taken with food for adequate absorption.
Positive
ENGAGE AF-TIMI 48
2013 ยท NEJM ยท Cardiology / Anticoagulation
Is edoxaban noninferior to warfarin for stroke prevention in AF?
N=21,105 with AF. Edoxaban 60 mg was noninferior to warfarin for stroke prevention with 20% less major bleeding. Conclusion: Fourth DOAC for AF. Once daily dosing. Dose reduce to 30 mg if CrCl 15โ50 or weight ≤60 kg.
Positive
EAST-AFNET 4
2020 ยท NEJM ยท Cardiology / Arrhythmia
Does early rhythm control improve outcomes in recently diagnosed AF?
N=2,789 with recently diagnosed AF. Early rhythm control reduced CV death, stroke, and HF hospitalization by 21% vs rate control. Conclusion: Changed the paradigm, early rhythm control (within 1 year of AF diagnosis) is better than waiting. Don't default to rate control.
Positive
RACE II
2010 ยท NEJM ยท Cardiology
Is lenient rate control noninferior to strict rate control in permanent AF?
N=614 with permanent AF. No difference in CV events between lenient (HR <110) and strict (<80) rate control. Conclusion: Lenient rate control is acceptable in permanent AF. Don't chase HR <80, a target of <110 is sufficient.
Neutral
PARTNER 3
2019 ยท NEJM ยท Cardiology
Is TAVR noninferior to surgery in low-risk severe aortic stenosis?
N=1,000 with severe aortic stenosis and low surgical risk. TAVR (SAPIEN 3) reduced death, stroke, and rehospitalization at 1 year (8.5% vs 15.1%) vs surgical valve replacement. Conclusion: TAVR expanded to low-risk patients. No longer just for inoperable or high-risk patients.
Positive
RE-VERSE AD
2017 ยท NEJM ยท Hematology / Anticoagulation
Does idarucizumab reverse dabigatran anticoagulation?
N=503 on dabigatran with serious bleeding or needing urgent surgery. Idarucizumab 5 g IV reversed anticoagulation within minutes in 98% of patients. Conclusion: Immediate complete reversal of dabigatran. Only works for dabigatran, not other DOACs.
Positive
ANNEXA-4
2019 ยท NEJM ยท Hematology / Anticoagulation
Does andexanet alfa reverse factor Xa inhibitor anticoagulation?
N=352 on apixaban or rivaroxaban with major bleeding. Andexanet alfa reduced anti-Xa activity by 92% and achieved good hemostasis in 82%. Conclusion: Reversal agent for apixaban and rivaroxaban in life-threatening bleeding. Expensive, some centers use 4-factor PCC as an alternative.
Positive
Hypertension
SPRINT Trial
2015 ยท NEJM ยท Hypertension
Does intensive BP control (<120) reduce CV events?
N=9,361 adults with high CV risk but without diabetes. Intensive SBP target <120 reduced MACE by 25% and all-cause mortality by 27%. Stopped early. More AKI and hypotension in intensive group. Conclusion: Changed BP targets for high-risk non-diabetic patients. Watch for AKI, syncope, and electrolyte abnormalities.
Positive -lower target saves lives
ALLHAT Trial
2002 ยท JAMA ยท Hypertension
Which antihypertensive class is best?
N=33,357 aged ≥55 with HTN. Chlorthalidone (thiazide) vs amlodipine (CCB) vs lisinopril (ACEi). No difference in fatal CHD/nonfatal MI. Chlorthalidone was superior for HF prevention. Conclusion: Largest antihypertensive trial ever. Reinforced thiazide-type diuretics as first-line, cheap, effective, and prevents heart failure.
Thiazide remains first-line
PATHWAY-2
2015 ยท Lancet ยท Cardiology / Hypertension
Is spironolactone the best add-on for resistant hypertension?
N=335 with resistant HTN on 3+ drugs. Spironolactone 25โ50 mg was superior to placebo, doxazosin, and bisoprolol, reducing SBP by 8.7 mmHg more than placebo. Conclusion: Spironolactone is the preferred 4th-line agent for resistant hypertension.
Positive
Pulmonology, COPD
Brochard et al. NIV in AECOPD
1995 ยท NEJM ยท AECOPD
Does NIV (BiPAP) reduce intubation and mortality in AECOPD with respiratory failure?
N=85 with AECOPD and acute respiratory failure. NIV (BiPAP) reduced intubation from 74% to 26%, reduced in-hospital mortality, and shortened ICU stay. Conclusion: Established NIV as standard of care for AECOPD with hypercapnic respiratory failure (pH <7.35, pCO₂ >45).
Positive -landmark trial
Austin et al. Oxygen Titration Trial
2010 ยท BMJ ยท AECOPD
Does titrated Oโ (SpOโ 88โ92%) reduce mortality vs high-flow Oโ in AECOPD?
N=405 with AECOPD treated by paramedics pre-hospital. Titrated O₂ targeting SpO₂ 88โ92% reduced mortality by 78% vs high-flow O₂ (8โ10 L/min), with less hypercapnia and respiratory acidosis. Conclusion: Drives the 88โ92% SpO₂ target in AECOPD. High-flow O₂ worsens hypercapnia via Haldane effect and V/Q mismatch.
Positive -practice changing
Plant et al. NIV on General Wards
2000 ยท Lancet ยท AECOPD
Is early NIV feasible and beneficial for AECOPD with mild-moderate acidosis on general wards?
N=236 with AECOPD and mild-moderate acidosis (pH 7.25โ7.35). NIV on general wards reduced intubation (15% vs 27%) and in-hospital mortality (10% vs 20%). Conclusion: Supports ward-based NIV for pH 7.25โ7.35. ICU-level NIV for pH <7.25 or deterioration on ward NIV.
Positive -NIV effective on wards
Anthonisen Criteria Trial
1987 ยท Ann Intern Med ยท AECOPD
Do antibiotics benefit patients with AECOPD?
N=173 with COPD and acute exacerbation. Antibiotics benefited Type 1 (all 3 cardinal symptoms) and Type 2 (2 of 3) exacerbations but not Type 3 (1 symptom). Conclusion: Cardinal symptoms: increased dyspnea, increased sputum volume, increased sputum purulence. Antibiotics indicated when ≥2 are present.
Positive (symptom-guided)
IMPACT Trial
2018 ยท NEJM ยท AECOPD
Does triple therapy (ICS/LABA/LAMA) reduce exacerbations vs dual therapy in symptomatic COPD?
N=10,355 with symptomatic COPD and ≥1 exacerbation in prior year. Triple therapy (FF/UMEC/VI) reduced moderate/severe exacerbations vs dual LABA/LAMA. Pneumonia risk increased with ICS. Conclusion: Supports ICS addition in exacerbation-prone patients, especially with elevated blood eosinophil counts.
Positive for high-risk patients
UPLIFT Trial
2008 ยท NEJM ยท AECOPD
Does tiotropium slow lung function decline and reduce exacerbations in COPD?
N=5,993 with COPD (GOLD IIโIV) over 4 years. Tiotropium 18 mcg daily reduced exacerbations and hospitalizations and improved quality of life, but did not significantly slow FEV₁ decline. Conclusion: Established LAMA as a cornerstone of COPD maintenance therapy. Does not reverse established airflow obstruction.
Positive for exacerbation prevention
Albert et al. Azithromycin COPD Trial
2011 ยท NEJM ยท AECOPD
Does daily azithromycin reduce COPD exacerbations?
N=1,142 COPD patients at risk for exacerbations. Azithromycin 250 mg daily for 1 year reduced exacerbation frequency (1.48 vs 1.83/year). Hearing loss risk identified. Conclusion: Maintenance azithromycin for exacerbation-prone COPD. Exclude patients with resting tachycardia or prolonged QTc. Not for acute treatment.
Positive (with caveats)
REDUCE Trial
2013 ยท JAMA ยท AECOPD
Is 5-day prednisone non-inferior to 14-day course for AECOPD?
N=314 hospitalized with AECOPD. Prednisone 40 mg/day for 5 days was noninferior to 14 days for re-exacerbation at 6 months, with fewer adverse effects. Conclusion: Established 5-day steroid course as standard for AECOPD. Prednisone 40 mg ร5 days is sufficient.
5 days = 14 days -use 5 days
Turner et al. MgSOโ in Acute Bronchospasm
1997 ยท Lancet ยท AECOPD
Does IV magnesium sulphate improve lung function in acute severe asthma/bronchospasm?
Acute severe asthma patients failing initial bronchodilators. IV MgSO₄ 1.2โ2 g over 20 min improved FEV₁ and reduced hospital admission rates. Conclusion: Primary evidence is in asthma. MgSO₄ is used in AECOPD as a third-line agent for refractory bronchospasm.
Positive (asthma); extrapolated to AECOPD
Soriano et al. AECOPD Triggers
1992 ยท Chest ยท AECOPD
What are the common infectious triggers of AECOPD?
Observational study of AECOPD episodes. Bacterial triggers in ~50%, viral in ~30%, both in ~10%, no pathogen in ~30%. Conclusion: Common bacteria: H. influenzae, S. pneumoniae, M. catarrhalis. Guides empiric antibiotic selection in AECOPD.
Observational
Pulmonology, ILD & Other
ASCEND
2014 ยท NEJM ยท Pulmonology
Does pirfenidone slow disease progression in IPF?
N=555 with IPF. Pirfenidone reduced FVC decline by 50% at 52 weeks. Conclusion: First antifibrotic approved for IPF. Slows progression but doesn't cure. One of two pillars of IPF therapy.
Positive
INPULSIS
2014 ยท NEJM ยท Pulmonology
Does nintedanib slow FVC decline in IPF?
N=1,066 with IPF. Nintedanib reduced annual FVC decline by ~50%. Conclusion: Second antifibrotic for IPF alongside pirfenidone. Main side effect is diarrhea.
Positive
MIST2
2011 ยท NEJM ยท Pulmonology
Does intrapleural tPA + DNase improve drainage in complicated parapneumonic effusion?
N=210 with complicated parapneumonic effusion/empyema. Intrapleural tPA + DNase improved fluid drainage and reduced surgery referral (4% vs 16%). Conclusion: tPA 10 mg + DNase 5 mg BID through chest tube for 3 days is the protocol for organized empyema.
Positive
PANTHER-IPF
2012 ยท NEJM ยท Pulmonology
Does triple immunosuppressive therapy improve outcomes in IPF?
N=238 with IPF. Prednisone + azathioprine + NAC increased mortality and hospitalizations vs placebo. Arm stopped early for harm. Conclusion: Do NOT use steroids or immunosuppression in IPF, it causes harm. Use antifibrotics (pirfenidone or nintedanib) instead.
Negative
NLST (National Lung Screening Trial)
2011 ยท NEJM ยท Oncology / Pulmonology
Does low-dose CT screening reduce lung cancer mortality?
N=53,454 high-risk adults (≥30 pack-years, age 55โ74). Annual low-dose CT reduced lung cancer mortality by 20% vs chest X-ray. Conclusion: Established LDCT screening for lung cancer. Current criteria: age 50โ80, ≥20 pack-years, smoked within 15 years.
Positive
Post-Cardiac Arrest
TTM-2 Trial
2021 ยท NEJM ยท Post-Cardiac Arrest
Does targeted hypothermia (33ยฐC) reduce mortality vs targeted normothermia (37.5ยฐC) post-arrest?
N=1,861 with out-of-hospital cardiac arrest and coma. No difference in 6-month mortality (50% vs 48%) or neurological outcome between 33ยฐC and normothermia. Conclusion: Supersedes TTM-1 (2013). Fever prevention ≤37.7ยฐC is the current standard. Active cooling to 33ยฐC is no longer required.
Normothermia non-inferior -major practice change
Kilgannon et al. Hyperoxia Post-Arrest
2010 ยท JAMA ยท Post-Cardiac Arrest
Is arterial hyperoxia associated with worse outcomes after cardiac arrest?
N=6,326 post-cardiac arrest ICU patients (observational). In-hospital mortality was higher with hyperoxia (PaO₂ >300) vs normoxia, 63% vs 45%. Conclusion: Target SpO₂ 94โ98% post-ROSC. Titrate FiO₂ down, do not leave on 100% O₂.
Avoid hyperoxia post-arrest
Status Epilepticus
RAMPART Trial
2012 ยท NEJM ยท Status Epilepticus
Is IM midazolam non-inferior to IV lorazepam for prehospital status epilepticus?
N=893 with prehospital status epilepticus. IM midazolam 10 mg was noninferior to IV lorazepam 4 mg, with more patients seizure-free on ED arrival (73% vs 63%) due to faster administration. Conclusion: IM route is faster when no IV access. Supports IM/IN midazolam as first-line in the community setting.
IM midazolam preferred prehospital
ESETT Trial
2019 ยท NEJM ยท Status Epilepticus
Which second-line agent is most effective for benzodiazepine-refractory status epilepticus?
N=384 with established status epilepticus after benzodiazepines. Levetiracetam 4,500 mg, fosphenytoin 20 mg PE/kg, and valproate 40 mg/kg were all equally effective (~46% seizure cessation). Conclusion: All three are acceptable second-line agents. Choice should be guided by comorbidities and side effect profile.
Neutral -all equivalent
Neurology, Stroke
NINDS tPA Trial
1995 ยท NEJM ยท Neurology
Does IV alteplase improve outcomes in acute ischemic stroke?
N=624 with acute ischemic stroke within 3 hours. IV alteplase 0.9 mg/kg resulted in 30% more patients with minimal or no disability at 3 months. ICH rate 6.4% vs 0.6%. Conclusion: Established the 3-hour window for IV tPA. Later ECASS-III extended to 4.5 hours. Time is brain.
Landmark Positive -tPA changed stroke care
MR CLEAN Trial
2015 ยท NEJM ยท Neurology
Does thrombectomy improve outcomes in large vessel occlusion stroke?
N=500 with acute ischemic stroke and proximal anterior circulation occlusion within 6 hours. Thrombectomy increased functional independence by 13.5% (NNT=7.4). Conclusion: First of five 2015 thrombectomy trials that established mechanical thrombectomy as standard of care for LVO stroke.
Landmark Positive -thrombectomy standard for LVO
ECASS III
2008 ยท NEJM ยท Neurology
Is IV tPA effective for acute ischemic stroke in the 3-4.5 hour window?
N=821 with acute ischemic stroke randomized to alteplase vs placebo within 3โ4.5h of symptom onset. Alteplase improved functional outcome at 90 days. Conclusion: Extended the IV tPA treatment window from 3 hours to 4.5 hours, now the standard time cutoff worldwide.
Positive
DAWN Trial
2018 ยท NEJM ยท Neurology
Does thrombectomy benefit LVO stroke patients 6-24h with clinical-imaging mismatch?
N=206 with LVO stroke 6โ24h and clinical-core mismatch (NIHSS โฅ10 with small infarct core). Thrombectomy dramatically improved functional independence (mRS 0โ2: 49% vs 13%). Conclusion: Extended the thrombectomy window from 6h to 24h for selected patients with mismatch on perfusion imaging.
Positive
DEFUSE-3
2018 ยท NEJM ยท Neurology
Does thrombectomy improve outcomes in LVO stroke 6-16h with perfusion mismatch?
N=182 with anterior LVO stroke 6โ16h and perfusion mismatch on CT/MRI. Thrombectomy significantly improved functional independence; trial stopped early for efficacy. Conclusion: Together with DAWN, established perfusion imaging-based selection for late-window thrombectomy up to 16 hours.
Positive
GI & Hepatology
TRIGGER Trial
2015 ยท Lancet ยท Upper GI Bleed
Does liberal vs restrictive transfusion affect outcomes in upper GI bleed?
N=936 with acute upper GI bleed. No difference in 28-day mortality between liberal (Hb 9) and restrictive (Hb 7) transfusion thresholds; trend toward worse outcomes with liberal strategy in liver disease. Conclusion: Restrictive transfusion (Hb โฅ7) is preferred in UGIB, fewer rebleeds, possibly via reduced portal pressure.
Restrictive strategy preferred
RFHE Trial (Rifaximin in Hepatic Encephalopathy)
2010 ยท NEJM ยท Hepatic Encephalopathy
Does rifaximin prevent recurrence of overt hepatic encephalopathy?
N=299 in hepatic encephalopathy remission (most on background lactulose). Rifaximin 550 mg BID reduced HE recurrence (22% vs 46%) and HE-related hospitalization. Conclusion: Rifaximin + lactulose is standard maintenance therapy for prevention of recurrent hepatic encephalopathy.
Positive
CONFIRM Trial
2024 ยท NEJM ยท Hepatology
Does terlipressin improve outcomes in hepatorenal syndrome?
N=300 with hepatorenal syndrome-AKI. Terlipressin + albumin improved HRS reversal (32% vs 17%), though with more respiratory adverse events. Conclusion: FDA-approved terlipressin for HRS-AKI. Monitor closely for respiratory failure during treatment.
Positive
PREDESCI
2019 ยท Lancet ยท Hepatology
Do beta-blockers prevent first decompensation in cirrhosis with portal HTN but no varices?
N=201 with cirrhosis and clinically significant portal hypertension but no varices. Beta-blockers reduced first decompensation events. Conclusion: Supports early beta-blocker use in compensated cirrhosis with elevated HVPG, even before varices develop.
Positive
PANTER
2010 ยท NEJM ยท Surgery / GI
Is a step-up approach superior to primary open necrosectomy for infected necrotizing pancreatitis?
N=88 with infected necrotizing pancreatitis. Step-up approach (percutaneous drain โ necrosectomy if fails) reduced major complications (40% vs 69%) and new-onset organ failure. Conclusion: Step-up approach is standard of care, drain first, operate only if drainage fails.
Positive
PONCHO
2015 ยท Lancet ยท Surgery / GI
Should cholecystectomy be performed during same admission for mild gallstone pancreatitis?
N=266 with mild gallstone pancreatitis. Same-admission cholecystectomy reduced readmission for biliary events (5% vs 17%). Conclusion: Perform cholecystectomy before discharge in mild gallstone pancreatitis to prevent recurrent biliary events.
Positive
Diabetes & Endocrine
DCCT Trial
1993 ยท NEJM ยท Diabetes
Does intensive glucose control reduce microvascular complications in T1DM?
N=1,441 with type 1 diabetes. Intensive insulin (A1c ~7%) reduced retinopathy by 76%, nephropathy by 50%, and neuropathy by 60% vs conventional therapy (A1c ~9%). Conclusion: Foundation for the A1c <7% target. Follow-up EDIC study showed early tight control benefits lasted decades ("metabolic memory").
Landmark Positive
UKPDS 34
1998 ยท Lancet ยท Diabetes
Does metformin improve outcomes in overweight T2DM?
N=1,704 overweight patients with newly diagnosed T2DM. Metformin reduced all-cause mortality by 36% and diabetes-related death by 42% vs conventional therapy, superior to sulfonylurea/insulin despite similar A1c. Conclusion: Established metformin as first-line therapy for T2DM with benefits beyond glucose lowering.
Landmark Positive -metformin first-line
EMPA-REG OUTCOME
2015 ยท NEJM ยท Diabetes / HF
Does empagliflozin reduce CV events in T2DM with CVD?
N=7,020 with T2DM and established CVD. Empagliflozin reduced MACE by 14%, CV death by 38%, HF hospitalization by 35%, and slowed eGFR decline by 39%. Conclusion: First SGLT2i CV outcome trial, launched the SGLT2i era for cardio-renal protection beyond glucose lowering.
Landmark Positive -SGLT2i revolution
DPP (Diabetes Prevention Program)
2002 ยท NEJM ยท Diabetes Prevention
Can lifestyle or metformin prevent T2DM?
N=3,234 overweight adults with impaired glucose tolerance. Intensive lifestyle (7% weight loss + 150 min/wk exercise) reduced T2DM incidence by 58%; metformin by 31%. Conclusion: Lifestyle intervention is the most effective strategy for diabetes prevention, superior to metformin alone.
Landmark Positive
LEADER Trial
2016 ยท NEJM ยท Diabetes / Cardiology
Does liraglutide reduce CV events in T2DM?
N=9,340 with T2DM at high CV risk. Liraglutide (GLP-1 RA) reduced MACE by 13% and CV death by 22%. Conclusion: Established GLP-1 RAs as cardioprotective in T2DM with CVD, now recommended alongside SGLT2i for atherosclerotic CVD.
Positive -GLP-1 RA cardioprotective
ADA Standards of Care 2026
2026 ยท Diabetes Care ยท DKA / Glucose
What are the recommended targets for inpatient glycemic management?
Targets: 140โ180 mg/dL (ICU), 100โ180 mg/dL (non-ICU). Initiate insulin at BG โฅ180 ร 2. 2026 updates: perioperative A1c <8% goal, CGM recommended at diagnosis, GLP-1 RA approved for T1DM with obesity. Conclusion: Comprehensive guideline for inpatient and outpatient diabetes care with new CKM framework.
Guideline
ADVANCE Trial
2008 ยท NEJM ยท Diabetes
Does intensive glucose control reduce events in T2DM?
N=11,140 with T2DM and high vascular risk. Intensive gliclazide-based therapy (target A1c โค6.5%) reduced nephropathy by 21% but showed no significant reduction in macrovascular events or mortality. Conclusion: Gentler intensive control is safe but only reduces renal events, A1c 6.5โ7% is the optimal target zone.
Mixed -microvascular but not macrovascular
ACCORD Trial
2008 ยท NEJM ยท Diabetes
Does very intensive A1c lowering reduce CV events in T2DM?
N=10,251 with T2DM and high CV risk. Intensive arm (target A1c <6%) stopped early due to 22% increase in all-cause mortality with more hypoglycemia and weight gain. Conclusion: Very tight A1c (<6.5%) is harmful in high-risk T2DM. Individualize targets: <7% for most, <8% for elderly/frail.
Negative -increased mortality
RABBIT 2
2007 ยท Diabetes Care ยท Endocrinology
Is basal-bolus insulin superior to sliding scale in hospitalized T2DM?
N=130 T2DM surgical patients. Basal-bolus insulin (glargine + glulisine) achieved better glucose control (BG <140: 66% vs 38%) with no increase in hypoglycemia vs sliding scale alone. Conclusion: Sliding scale alone is inferior, always use basal-bolus regimen for inpatient diabetes management.
Positive
SURMOUNT-1
2022 ยท NEJM ยท Endocrinology / Obesity
Does tirzepatide reduce body weight in obesity without diabetes?
N=2,539 adults with BMI โฅ30 (or โฅ27 with comorbidity) without diabetes. Tirzepatide reduced body weight by up to 22.5% at 72 weeks. Conclusion: Unprecedented weight loss with a non-surgical intervention, established tirzepatide as a leading obesity therapy.
Positive
SURPASS-2
2021 ยท NEJM ยท Endocrinology
Is tirzepatide superior to semaglutide in T2DM?
N=1,879 with T2DM. Tirzepatide (dual GIP/GLP-1 agonist) was superior to semaglutide with A1c reduction up to 2.5% and weight loss up to 12.4 kg. Conclusion: Tirzepatide is the most potent glucose-lowering and weight-loss agent available for T2DM.
Positive
Nephrology
DAPA-CKD
2020 ยท NEJM ยท Nephrology
Does dapagliflozin slow CKD progression regardless of diabetes status?
N=4,304 with eGFR 25โ75 and albuminuria. Dapagliflozin reduced sustained GFR decline/ESKD/renal death by 39%, with benefit regardless of diabetes status. Conclusion: SGLT2i is now standard of care for CKD with albuminuria, diabetic or not.
Positive
EMPA-KIDNEY
2022 ยท NEJM ยท Nephrology
Does empagliflozin improve kidney outcomes in broad CKD population?
N=6,609 with eGFR 20โ45 or 45โ90 with albuminuria. Empagliflozin reduced kidney progression and CV death by 28%. Conclusion: Confirmed SGLT2i class effect in CKD, benefits extend even to patients with low GFR.
Positive
FIDELIO-DKD
2020 ยท NEJM ยท Nephrology
Does finerenone improve kidney outcomes in diabetic kidney disease?
N=5,734 with T2DM and CKD on max RAAS blockade. Finerenone (non-steroidal MRA) reduced kidney failure and sustained GFR decline by 18%, with less hyperkalemia than spironolactone. Conclusion: Add finerenone on top of ACEi/ARB for diabetic kidney disease for additional renal protection.
Positive
FIGARO-DKD
2021 ยท NEJM ยท Nephrology
Does finerenone reduce cardiovascular events in T2DM with CKD?
N=7,437 with T2DM and CKD stages 1โ4. Finerenone reduced CV death/MI/stroke/HF hospitalization by 13%. Conclusion: With FIDELIO, established finerenone as a key agent for cardiorenal protection in diabetic CKD.
Positive
SHARP Trial (CKD)
2011 ยท Lancet ยท Nephrology
Does simvastatin + ezetimibe reduce CV events in CKD?
N=9,270 CKD patients (not on dialysis). Simvastatin/ezetimibe reduced major atherosclerotic events by 17%. No benefit seen in dialysis patients. Conclusion: Statins benefit CKD patients NOT yet on dialysis. Once on dialysis, do not start statins.
Positive
IDEAL Trial
2010 ยท NEJM ยท Nephrology
Does early dialysis initiation improve survival compared to late start?
N=828 CKD patients. Starting dialysis at eGFR 10โ14 (early) vs 5โ7 (late) showed no difference in mortality. Conclusion: No benefit to early dialysis start, initiate based on symptoms, not GFR number alone.
Neutral
TEMPO 3:3
2012 ยท NEJM ยท Nephrology
Does tolvaptan slow disease progression in ADPKD?
N=1,445 with early ADPKD. Tolvaptan slowed kidney growth and GFR decline over 3 years. Conclusion: Only disease-modifying therapy for ADPKD. Monitor LFTs for hepatotoxicity risk.
Positive
ONTARGET
2008 ยท NEJM ยท Nephrology / Cardiology
Does dual RAAS blockade with ACEi + ARB improve cardiovascular outcomes?
N=25,620 high CV risk patients. Telmisartan + ramipril combo increased renal adverse events (hyperkalemia, AKI) without CV benefit vs either agent alone. Conclusion: Do NOT combine ACEi + ARB, more harm, no benefit.
Negative
VA NEPHRON-D
2013 ยท NEJM ยท Nephrology
Does dual RAAS blockade improve outcomes in diabetic nephropathy?
N=1,448 with T2DM and proteinuria. Losartan + lisinopril stopped early, combo increased hyperkalemia and AKI without benefit. Conclusion: Do NOT combine ACEi + ARB for diabetic nephropathy.
Negative
CHOIR
2006 ยท NEJM ยท Nephrology
Does targeting higher Hgb with EPO improve outcomes in CKD?
N=1,432 CKD patients on epoetin. Targeting Hgb 13.5 vs 11.3 increased composite CV events. Conclusion: With TREAT, established that ESA target should be 10โ11.5 g/dL, not higher.
Negative
TREAT Trial
2009 ยท NEJM ยท Nephrology
Does targeting higher hemoglobin with darbepoetin improve outcomes in CKD anemia?
N=4,038 with T2DM, CKD, and anemia. Darbepoetin targeting Hgb 13 showed no benefit and increased stroke risk. Conclusion: Do not target Hgb >11โ12 with ESAs, higher targets cause more harm.
Negative
Nephrology, Contrast-Induced AKI
PRESERVE Trial
2018 ยท NEJM ยท Nephrology / CI-AKI
Do IV sodium bicarbonate or oral N-acetylcysteine prevent contrast-induced kidney injury?
N=4,993 high-risk patients with stage 3 or 4 CKD (plus diabetes for most) undergoing angiography. 2x2 factorial. Neither IV sodium bicarbonate (vs normal saline) nor oral NAC (vs placebo) reduced death, dialysis, or persistent Cr rise at 90 days. Conclusion: Definitive trial ending NAC and bicarbonate in CI-AKI prophylaxis. Current practice is IV isotonic saline only.
Negative, killed NAC and bicarbonate
AMACING Trial
2017 ยท Lancet ยท Nephrology / CI-AKI
Is no prophylaxis noninferior to IV saline for preventing contrast-induced AKI in moderate-risk CKD?
N=660 with eGFR 30 to 59 scheduled for elective contrast imaging (mostly IV). No prophylaxis vs IV 0.9% saline 1 mL/kg/hr. CI-AKI: 2.6% vs 2.7% (noninferior). No difference in dialysis, 35-day Cr, or mortality. Fluid-overload complications only in the saline arm. Conclusion: Supports the modern reframe that routine hydration in moderate-risk patients for IV contrast is unnecessary.
Noninferior, challenges routine hydration
ACT Trial
2011 ยท Circulation ยท Nephrology / CI-AKI
Does oral N-acetylcysteine prevent contrast-induced nephropathy?
N=2,308 undergoing coronary or peripheral angiography with at least one CI-AKI risk factor. Oral NAC 1,200 mg BID x 2 days vs placebo on IV saline background. CI-AKI: 12.7% vs 12.7%. No effect on 30-day death or dialysis. Conclusion: First large well-powered trial to disprove NAC benefit. Earlier "positive" studies likely confounded by NAC artifactually lowering serum Cr via assay interference.
Negative, NAC does not prevent CI-AKI
Rheumatology
RAVE Trial
2010 ยท NEJM ยท Rheumatology
Is rituximab noninferior to cyclophosphamide for ANCA vasculitis induction?
N=197 with GPA or MPA. Rituximab was noninferior to cyclophosphamide for remission induction and superior in relapsing disease. Conclusion: Rituximab is now first-line for ANCA vasculitis induction and maintenance therapy.
Positive
ORAL Surveillance
2022 ยท NEJM ยท Rheumatology
Is tofacitinib cardiovascularly safe in RA patients with CV risk?
N=4,362 RA patients >50yo with CV risk factors. Tofacitinib had higher rates of MACE and malignancy compared to TNF inhibitor. Conclusion: FDA black box warning on all JAK inhibitors, use only after TNFi failure.
Negative
CARES Trial
2018 ยท NEJM ยท Rheumatology
Is febuxostat cardiovascularly safe in gout patients with CV disease?
N=6,190 gout patients with CV disease. Febuxostat had higher CV and all-cause mortality compared to allopurinol. Conclusion: FDA black box warning on febuxostat. Use allopurinol first-line for gout.
Negative
Infectious Disease
START Trial (INSIGHT-START)
2015 ยท NEJM ยท HIV
Should ART start immediately regardless of CD4?
N=4,685 HIV-positive adults with CD4 >500. Immediate ART reduced serious AIDS events and death by 57%; stopped early for benefit. Conclusion: All HIV-positive patients should start ART immediately regardless of CD4 count.
Landmark Positive -treat all HIV immediately
HPTN 052 Trial
2011 ยท NEJM ยท HIV
Does early ART reduce HIV transmission?
N=1,763 serodiscordant couples (CD4 350โ550). Early ART reduced HIV transmission to partners by 96%. Conclusion: Foundation for U=U (Undetectable = Untransmittable), early treatment prevents transmission.
Landmark Positive -U=U foundation
ACTG 076 Trial
1994 ยท NEJM ยท HIV
Does zidovudine reduce vertical HIV transmission?
N=477 HIV-positive pregnant women and infants. Zidovudine during pregnancy, labor, and neonatal prophylaxis reduced vertical transmission by 67.5% (25.5% โ 8.3%). Conclusion: Foundation for modern PMTCT (prevention of mother-to-child transmission) protocols.
Landmark Positive -PMTCT became standard
POET Trial
2019 ยท NEJM ยท Infectious Disease
Can stable endocarditis switch from IV to oral antibiotics?
N=400 with stable left-sided endocarditis after โฅ10 days IV therapy. Oral switch was noninferior (12.1% vs 12.0% composite endpoint). Conclusion: Stable left-sided endocarditis can safely switch to oral antibiotics after initial IV course.
Positive -oral step-down safe
OVIVA Trial
2019 ยท NEJM ยท Infectious Disease
Are oral antibiotics noninferior to IV for bone/joint infections?
N=1,054 adults with bone and joint infections. Oral antibiotics were noninferior to IV (14.6% vs 14.1% treatment failure at 1 year). Conclusion: Oral antibiotics are sufficient for bone/joint infections, IV-to-oral switch is safe.
Positive -oral sufficient
ACORN Trial
2024 ยท JAMA ยท Infectious Disease / Nephrotoxicity
Does cefepime cause less AKI than pip-tazo when combined with vancomycin?
N=2,511 hospitalized adults receiving vancomycin. Pip-tazo + vancomycin had higher AKI (8.3% vs 4.4%) compared to cefepime + vancomycin. Conclusion: Prefer cefepime over pip-tazo when combining with vancomycin to reduce nephrotoxicity risk.
Positive -cefepime preferred with vanc
SMART Trial
2006 ยท NEJM ยท HIV
Can ART be safely interrupted based on CD4?
N=5,472 HIV-positive adults with CD4 >350 on ART. CD4-guided ART interruption increased opportunistic disease 2.6-fold and increased all-cause mortality. Conclusion: ART must be lifelong, treatment interruptions are dangerous.
Negative -never stop ART
MODIFY I/II
2017 ยท NEJM ยท Infectious Disease
Does bezlotoxumab prevent C. diff recurrence?
N=2,655 with C. difficile infection. Bezlotoxumab (anti-toxin B antibody) reduced recurrence from 27% to 17%. Conclusion: Single IV dose bezlotoxumab prevents C. diff recurrence in high-risk patients.
Positive
STOP-IT
2015 ยท NEJM ยท Infectious Disease / Surgery
Are short-course antibiotics sufficient for intra-abdominal infection with adequate source control?
N=518 with intra-abdominal infection and adequate source control. 4 days of antibiotics was noninferior to treatment until clinical resolution. Conclusion: 4 days is enough after adequate source control, stop antibiotics early.
Positive
COVID-19
RECOVERY Dexamethasone Trial
2021 ยท NEJM ยท COVID-19
Does dexamethasone reduce mortality in hospitalized COVID-19?
N=6,425 hospitalized with COVID-19. Dexamethasone 6 mg daily ร 10 days reduced 28-day mortality in patients on oxygen (23.3% vs 26.2%) and ventilated patients (29.3% vs 41.4%). No benefit without Oโ. Conclusion: First proven mortality benefit in COVID-19, dexamethasone became standard of care for hypoxic patients.
Landmark Positive
BNT162b2 Pfizer-BioNTech Vaccine Trial
2020 ยท NEJM ยท COVID-19
Is the BNT162b2 mRNA vaccine effective against COVID-19?
N=43,548 adults โฅ16 years. BNT162b2 mRNA vaccine (2 doses, 21 days apart) showed 95% efficacy against symptomatic COVID-19 and 100% efficacy against severe disease. Conclusion: First mRNA vaccine authorized for human use, ushered in the mRNA vaccine era.
Landmark Positive -95% efficacy
ACTT-1 Trial
2020 ยท NEJM ยท COVID-19
Does remdesivir improve recovery in hospitalized COVID-19?
N=1,062 hospitalized with COVID-19 and lower respiratory tract infection. Remdesivir shortened median recovery time from 15 to 10 days (31% faster) with a trend toward lower mortality. Conclusion: First antiviral with proven benefit in COVID-19 hospitalization.
Positive -shortens recovery
Oncology
IRIS Trial -Imatinib for CML
2006 ยท NEJM ยท Oncology
Is imatinib superior to interferon for CML?
N=1,106 with newly diagnosed chronic-phase CML. Imatinib achieved complete cytogenetic response in 76% vs 15% with interferon; estimated 5-year OS 89%. Conclusion: Imatinib turned CML from a fatal disease into a chronic manageable condition, paradigm for targeted therapy.
Landmark Positive -targeted therapy
HERA Trial -Trastuzumab for HER2+ Breast Cancer
2005 ยท NEJM ยท Oncology
Does trastuzumab improve outcomes in HER2+ breast cancer?
N=5,102 with HER2-positive early breast cancer. 1 year of adjuvant trastuzumab reduced recurrence by 46% and improved overall survival. Conclusion: Established 1 year of adjuvant trastuzumab as standard of care for HER2+ breast cancer.
Landmark Positive
KEYNOTE-024 Trial
2016 ยท NEJM ยท Oncology
Is pembrolizumab better than chemo in high PD-L1 NSCLC?
N=305 with untreated metastatic NSCLC and PD-L1 โฅ50%. Pembrolizumab improved PFS (10.3 vs 6.0 months), OS, and response rate (44.8% vs 27.8%). Conclusion: Pembrolizumab monotherapy became standard first-line for high PD-L1 NSCLC, the immunotherapy era.
Positive -immunotherapy era
CLEOPATRA Trial
2012 ยท NEJM ยท Oncology
Does adding pertuzumab to trastuzumab improve metastatic HER2+ breast cancer?
N=808 with HER2-positive metastatic breast cancer. Pertuzumab + trastuzumab + docetaxel improved median OS by 15.7 months (56.5 vs 40.8 months). Conclusion: Dual HER2 blockade became standard first-line for HER2+ metastatic breast cancer.
Positive -dual HER2 blockade
FLAURA Trial
2018 ยท NEJM ยท Oncology
Is osimertinib superior to first-gen EGFR TKIs?
N=556 with untreated EGFR-mutant advanced NSCLC. Osimertinib improved median PFS (18.9 vs 10.2 months) and OS (38.6 vs 31.8 months) vs standard EGFR TKI. Conclusion: Osimertinib is the preferred first-line EGFR TKI for advanced NSCLC.
Positive -osimertinib first-line
SHARP Trial -Sorafenib for HCC
2008 ยท NEJM ยท Oncology / Hepatology
Does sorafenib improve survival in advanced HCC?
N=602 with advanced HCC (Child-Pugh A). Sorafenib improved median OS (10.7 vs 7.9 months) and time to progression. Conclusion: First systemic therapy proven to improve survival in HCC, was standard of care until IMbrave150.
Positive -first systemic HCC therapy
IMbrave150 Trial
2020 ยท NEJM ยท Oncology / Hepatology
Is atezolizumab + bevacizumab superior to sorafenib in HCC?
N=501 with unresectable HCC, treatment-naive. Atezolizumab + bevacizumab improved 12-month OS (67.2% vs 54.6%) and median PFS (6.8 vs 4.3 months) vs sorafenib. Conclusion: New standard first-line for advanced HCC, immunotherapy + anti-VEGF replaced sorafenib.
Positive -new first-line for HCC
Hematology & Transfusion
TRICC Trial
1999 ยท NEJM ยท Transfusion / ICU
Restrictive vs liberal transfusion in critically ill patients?
N=838 euvolemic critically ill patients with Hgb <9. Restrictive strategy (transfuse if Hgb <7, maintain 7โ9) was noninferior to liberal (transfuse if <10, maintain 10โ12) with lower in-hospital mortality in less acutely ill patients. Conclusion: Established Hgb 7 g/dL trigger as standard in most ICU patients.
Positive -restrictive became standard
Villanueva Restrictive Transfusion Trial
2013 ยท NEJM ยท GI Bleeding
Restrictive vs liberal transfusion in acute upper GI bleeding?
N=921 with acute upper GI bleeding. Restrictive transfusion (Hgb <7) reduced 45-day mortality (5% vs 9%), rebleeding, and complications compared to liberal (Hgb <9). Conclusion: Restrictive transfusion actually improves GI bleed outcomes, transfuse at Hgb <7.
Positive -restrictive is BETTER in GI bleed
CLOT Trial
2003 ยท NEJM ยท Hematology
Is LMWH better than warfarin for cancer-associated VTE?
N=676 with cancer and acute VTE. Dalteparin (LMWH) ร 6 months reduced recurrent VTE by 52% (9% vs 17%) compared to dalteparin bridging then warfarin. Conclusion: LMWH became standard for cancer-associated VTE (now largely replaced by DOACs).
Positive -LMWH beat warfarin
EINSTEIN-DVT/PE
2010 ยท NEJM ยท Hematology / VTE
Is rivaroxaban effective for VTE treatment?
N=8,281 (DVT + PE combined). Rivaroxaban was noninferior to enoxaparin/warfarin with less major bleeding. Conclusion: Established rivaroxaban as oral-only VTE treatment without need for heparin bridging.
Positive
AMPLIFY
2013 ยท NEJM ยท Hematology / VTE
Is apixaban effective for VTE treatment?
N=5,395 with VTE. Apixaban was noninferior to enoxaparin/warfarin with 69% less major bleeding. Conclusion: Apixaban has the best bleeding profile among DOACs for VTE treatment.
Positive
PEITHO
2014 ยท NEJM ยท Pulmonary / VTE
Does thrombolysis improve outcomes in submassive PE?
N=1,006 with intermediate-risk PE (RV dysfunction + troponin). Tenecteplase reduced hemodynamic decompensation (1.6% vs 5%) but increased major bleeding (11.5% vs 2.4%). Conclusion: Do not routinely lyse submassive PE, reserve thrombolysis for hemodynamic deterioration.
Neutral
PROPPR
2015 ยท JAMA ยท Hematology / Trauma
What is the optimal massive transfusion ratio?
N=680 severely injured trauma patients. 1:1:1 (plasma:platelets:RBC) achieved better hemostasis and fewer deaths from exsanguination at 24h compared to 1:1:2. Conclusion: Supports balanced 1:1:1 ratio in massive transfusion protocols.
Positive
TRICS-III
2017 ยท NEJM ยท Hematology
Is restrictive transfusion safe in cardiac surgery?
N=5,243 undergoing cardiac surgery. Restrictive transfusion (Hgb <7.5) was noninferior to liberal (<9.5) for death/MI/stroke/renal failure. Conclusion: Even cardiac surgery patients do not need liberal transfusion thresholds.
Positive
HERCULES
2019 ยท NEJM ยท Hematology
Does caplacizumab improve outcomes in acquired TTP?
N=145 with acquired TTP. Caplacizumab (anti-vWF nanobody) + plasma exchange achieved faster platelet normalization and fewer TTP-related deaths and recurrences. Conclusion: Caplacizumab added to standard TTP treatment (PEX + steroids + rituximab).
Positive
MSH Trial (Multicenter Study of Hydroxyurea)
1995 ยท NEJM ยท Hematology
Does hydroxyurea reduce painful crises in sickle cell disease?
N=299 adults with severe SCD. Hydroxyurea reduced painful crises by 44%, ACS by 50%, and transfusions by 67%; stopped early for benefit. Conclusion: Established hydroxyurea as standard of care for sickle cell disease.
Positive
SUSTAIN Trial
2017 ยท NEJM ยท Hematology
Does crizanlizumab reduce vaso-occlusive crises in SCD?
N=198 with sickle cell disease. Crizanlizumab (anti-P-selectin antibody) reduced vaso-occlusive crises by 45% vs placebo. Conclusion: First targeted biologic therapy for sickle cell disease prevention.
Positive
VIALE-A
2020 ยท NEJM ยท Hematology / Oncology
Does venetoclax + azacitidine improve survival in older/unfit AML patients?
N=431 treatment-naive AML patients unfit for intensive chemo. Venetoclax + azacitidine improved OS (14.7 vs 9.6 months) and CR rate (66% vs 28%). Conclusion: Standard of care for older/unfit AML patients who cannot tolerate intensive induction chemotherapy.
Positive
IV Fluids & Resuscitation
SALT-ED Trial
2018 ยท NEJM ยท IV Fluids
Balanced crystalloids vs normal saline in non-critically ill adults?
N=13,347 non-critically ill adults receiving IV fluids in the ED. Balanced crystalloid (LR or Plasma-Lyte) had lower major adverse kidney events at 30 days (4.7% vs 5.6%) vs normal saline. Conclusion: Balanced crystalloids preferred over normal saline for IV fluid resuscitation.
Positive -balanced crystalloids preferred
🌟 2025 Practice-Changing Trials
Beta-Blocker Post-MI Meta-Analysis (5-Trial IPD)
2025 ยท NEJM ยท Cardiology
Do beta-blockers improve outcomes after MI with preserved EF?
N=17,801 from 5 trials (REBOOT, REDUCE-AMI, BETAMI, DANBLOCK, CAPITAL-RCT). Patients with recent MI and preserved EF (≥50%). No reduction in death, recurrent MI, or heart failure at 3.6 years. Conclusion: Definitively ends reflexive beta-blocker prescribing post-MI with preserved EF. Beta-blockers still benefit patients with reduced EF (40–49%).
No benefit,40-year paradigm retired
SUMMIT Trial
2025 ยท NEJM ยท Heart Failure / Endocrinology
Does tirzepatide improve outcomes in HFpEF with obesity?
N=731 with HFpEF (EF ≥50%), BMI ≥30, NYHA II–IV. Tirzepatide reduced CV death or worsening HF by 38% and cut worsening HF events by 46%. Improved quality of life scores. Conclusion: Dual GIP/GLP-1 agonism is disease-modifying for obese HFpEF, historically few effective treatments existed for this phenotype.
Positive,46% reduction in worsening HF
SOUL Trial
2025 ยท NEJM ยท Endocrinology / Cardiology
Does oral semaglutide reduce CV events in T2DM with ASCVD or CKD?
N=9,650 aged ≥50 with T2DM and established ASCVD, CKD, or both. Oral semaglutide 14 mg daily reduced major CV events (MACE) by 14% and nonfatal MI by 26% vs placebo. Conclusion: First oral GLP-1 RA to demonstrate CV superiority. Benefit seen regardless of background SGLT2i use. Provides an oral alternative to injectable semaglutide.
Positive, first oral GLP-1 RA with CV superiority
SURMOUNT-5
2025 ยท NEJM ยท Endocrinology
How does tirzepatide compare to semaglutide for obesity?
Adults with BMI ≥30 or overweight with comorbidities. First head-to-head comparison over 72 weeks. Tirzepatide achieved 20.2% weight loss vs 13.7% with semaglutide. Greater waist circumference reduction (18.4 vs 13.0 cm). Conclusion: Tirzepatide is consistently superior to semaglutide for weight loss. Dual incretin agonism (GIP + GLP-1) outperforms GLP-1 alone.
Positive, tirzepatide superior (-20% vs -14%)
ESSENCE Trial
2025 ยท NEJM ยท Gastroenterology / Hepatology
Does semaglutide resolve MASH and improve liver fibrosis?
N=1,197 with biopsy-confirmed MASH and fibrosis (F2–F3). Semaglutide 2.4 mg SC weekly achieved MASH resolution in 63% vs 34% placebo. Fibrosis improved in 37% vs 22%. Weight loss 10.5% vs 2.0%. Conclusion: First GLP-1 RA with Phase 3 data showing both histologic MASH resolution AND fibrosis improvement. Granted FDA Priority Review.
Positive,63% MASH resolution + fibrosis improvement
ANDROMEDA-SHOCK-2
2025 ยท JAMA ยท Critical Care / Sepsis
Does CRT-guided personalized resuscitation improve outcomes in septic shock?
N=1,467 with early septic shock across 86 centers in 19 countries. CRT-guided resuscitation led to less fluid (250 mL less at 6h), more vital-support-free days, and better composite outcomes vs usual care. 28-day mortality was similar. Conclusion: Capillary refill time is a valid bedside resuscitation target. Personalized fluid management reduces organ support without increasing mortality.
Positive, reduced organ support duration
CloCeBa Trial
2025 ยท Lancet ยท Infectious Disease
Is cefazolin non-inferior to cloxacillin for MSSA bacteremia?
N=315 with MSSA bacteremia at 21 hospitals. Cefazolin IV q8h was non-inferior to cloxacillin IV q4–6h (75% vs 74% clinical success at day 90). AKI dramatically lower with cefazolin (1% vs 12%). Serious adverse events nearly halved (15% vs 27%). Conclusion: First RCT confirming cefazolin as non-inferior with far better safety. Supports cefazolin as preferred first-line for MSSA bacteremia.
Positive, cefazolin non-inferior, far safer (AKI 1% vs 12%)
OCEAN Trial
2025 ยท NEJM ยท Cardiology
Is continued anticoagulation necessary after successful AF ablation?
N=1,284 with successful AF ablation ≥1 year prior and CHA₂DS₂-VASc ≥1. Rivaroxaban 15 mg vs aspirin over 3 years. Stroke/systemic embolism was extremely rare on both therapies. Rivaroxaban increased major bleeding (1.6% vs 0.6%) with no embolic benefit. Trial stopped early for futility. Conclusion: Challenges indefinite anticoagulation after successful AF ablation. Aspirin may be sufficient in low-event-rate post-ablation patients.
Neutral, rivaroxaban no better than aspirin post-ablation
DIGIT-HF
2025 ยท NEJM ยท Heart Failure
Does digitoxin added to GDMT improve outcomes in advanced HFrEF?
N=1,240 with advanced HFrEF (LVEF ≤40%, NYHA III–IV) already on background GDMT. Digitoxin reduced the composite of death and HF hospitalization by 18% over 3 years. Conclusion: Revives cardiac glycosides in the modern GDMT era. Digitoxin (not digoxin) has more predictable pharmacokinetics and requires no renal dose adjustment.
Positive,18% reduction in death + HF hospitalization
🌟 2026 Practice-Changing Trials & Guidelines
AHA/ACC Acute PE Guideline 2026
2026 ยท Circulation / JACC ยท Pulmonary / Critical Care
First comprehensive AHA/ACC PE guideline, new Category A–E classification system
First-ever AHA/ACC PE guideline with 129 recommendations from 10 societies. Replaces "massive/submassive/low-risk" with Categories A–E based on pathophysiological severity. DOACs preferred over warfarin. LMWH preferred over UFH. PERT activation for Category C–E. Systemic tPA reserved for Category E. Structured post-PE follow-up mandated. Conclusion: Paradigm shift in PE classification. New Category D captures "pre-arrest" patients previously grouped under submassive.
Guideline, paradigm shift in PE classification
HI-PEITHO
2026 ยท NEJM ยท Pulmonary / Critical Care
Does catheter-directed thrombolysis improve outcomes in intermediate-high-risk PE?
N=544 with intermediate-high-risk PE (RV dysfunction + elevated troponin) at 59 sites. Ultrasound-facilitated catheter-directed thrombolysis (low-dose alteplase 9–17 mg) reduced PE death, decompensation, and recurrence by 61% vs anticoagulation alone at 30 days. No increase in major bleeding. Conclusion: First RCT showing CDT benefit in intermediate-risk PE without the bleeding penalty of systemic tPA (PEITHO). Low-dose catheter-delivered alteplase is the key innovation.
Positive,61% reduction in decompensation, no increased bleeding
COBRRA Trial
2026 ยท NEJM ยท Hematology / Cardiology
Is apixaban safer than rivaroxaban for acute VTE?
N=2,760 with acute symptomatic PE or proximal DVT. First head-to-head comparison of apixaban vs rivaroxaban over 3 months. Apixaban cut clinically relevant bleeding by over 50% (3.3% vs 7.1%). Recurrent VTE was identical (1.0% vs 1.0%). Conclusion: Equal efficacy but far less bleeding with apixaban. The DOAC choice for VTE is no longer a coin flip, apixaban is preferred.
Positive,54% less bleeding, equal efficacy
CREST-2
2026 ยท NEJM ยท Cardiology / Vascular
Is carotid revascularization superior to intensive medical therapy for asymptomatic carotid stenosis?
N=2,485 with ≥70% asymptomatic carotid stenosis across 155 centers. Stenting significantly reduced 4-year stroke and death vs medical therapy alone (2.8% vs 6.0%). Endarterectomy did NOT reach significance (3.7% vs 5.3%). Conclusion: Carotid stenting is superior to medical therapy alone, but routine endarterectomy may not add benefit over intensive medical management in asymptomatic patients.
Positive for stenting, neutral for CEA
Surviving Sepsis Campaign 2026
2026 ยท Crit Care Med / Intensive Care Med ยท Critical Care
Updated evidence-based recommendations for sepsis and septic shock management
129 statements (46 new) by 130+ experts from 23 countries. Key changes: avoid anti-anaerobic antibiotics in low-risk; prehospital sepsis screening; peripheral vasopressors OK to start; hydrocortisone suggested for refractory shock; qSOFA replaced by NEWS/MEWS; post-sepsis follow-up mandated. Conclusion: Most significant SSC update since 2021. Antimicrobial stewardship emphasis is the biggest paradigm shift.
Guideline, antimicrobial stewardship + prehospital focus
TETON-2
2026 ยท NEJM ยท Pulmonary
Does inhaled treprostinil slow disease progression in idiopathic pulmonary fibrosis?
N=593 with IPF (75% already on background antifibrotic). Inhaled treprostinil slowed FVC decline by ~65% vs placebo over 52 weeks (–50 mL vs –136 mL). Clinical worsening reduced by 29%. Benefit was additive on top of nintedanib or pirfenidone. Conclusion: First new mechanism drug for IPF beyond the existing two antifibrotics. Establishes inhaled treprostinil as the third pillar of IPF therapy.
Positive, third pillar of IPF therapy
VISIONARY Trial (Sibeprenlimab)
2026 ยท NEJM ยท Nephrology
Does anti-APRIL therapy reduce proteinuria in IgA nephropathy?
N=510 (largest Phase 3 IgAN trial ever). Sibeprenlimab (anti-APRIL monoclonal antibody) reduced proteinuria by ~50% at 9 months vs a 2% increase with placebo. Over 51% relative reduction vs placebo. Granted FDA accelerated approval. Conclusion: First targeted, disease-modifying therapy for IgA nephropathy. Unlike steroids or SGLT2i, this directly blocks the APRIL pathway driving IgAN pathogenesis.
Positive,51% proteinuria reduction, FDA approved
ADA Standards of Care 2026
2026 ยท Diabetes Care ยท DKA / Glucose
Updated ADA standards: perioperative targets, CGM, GLP-1 RA for T1DM
Key 2026 changes: Perioperative glucose target 100–180 mg/dL (A1c <8% pre-surgery). CGM recommended at diagnosis of T1DM and T2DM on insulin. GLP-1 RA expanded to T1DM as adjunct. SGLT2i + finerenone combination for diabetic CKD. BP target <120 systolic for high CV risk. New section on cancer treatment-related hyperglycemia. Conclusion: Broadest update in years, perioperative standards and CGM recommendations are the most practice-changing.
Guideline