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JAMA Mar 2024Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Aspirin may reduce severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and lower the incidence of end-stage liver disease and hepatocellular carcinoma, in patients with MASLD. However, the effect of aspirin on MASLD is unknown.
OBJECTIVE
To test whether low-dose aspirin reduces liver fat content, compared with placebo, in adults with MASLD.
DESIGN, SETTING, AND PARTICIPANTS
This 6-month, phase 2, randomized, double-blind, placebo-controlled clinical trial was conducted at a single hospital in Boston, Massachusetts. Participants were aged 18 to 70 years with established MASLD without cirrhosis. Enrollment occurred between August 20, 2019, and July 19, 2022, with final follow-up on February 23, 2023.
INTERVENTIONS
Participants were randomized (1:1) to receive either once-daily aspirin, 81 mg (n = 40) or identical placebo pills (n = 40) for 6 months.
MAIN OUTCOMES AND MEASURES
The primary end point was mean absolute change in hepatic fat content, measured by proton magnetic resonance spectroscopy (MRS) at 6-month follow-up. The 4 key secondary outcomes included mean percentage change in hepatic fat content by MRS, the proportion achieving at least 30% reduction in hepatic fat, and the mean absolute and relative reductions in hepatic fat content, measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF). Analyses adjusted for the baseline value of the corresponding outcome. Minimal clinically important differences for study outcomes were not prespecified.
RESULTS
Among 80 randomized participants (mean age, 48 years; 44 [55%] women; mean hepatic fat content, 35% [indicating moderate steatosis]), 71 (89%) completed 6-month follow-up. The mean absolute change in hepatic fat content by MRS was -6.6% with aspirin vs 3.6% with placebo (difference, -10.2% [95% CI, -27.7% to -2.6%]; P = .009). Compared with placebo, aspirin treatment significantly reduced relative hepatic fat content (-8.8 vs 30.0 percentage points; mean difference, -38.8 percentage points [95% CI, -66.7 to -10.8]; P = .007), increased the proportion of patients with 30% or greater relative reduction in hepatic fat (42.5% vs 12.5%; mean difference, 30.0% [95% CI, 11.6% to 48.4%]; P = .006), reduced absolute hepatic fat content by MRI-PDFF (-2.7% vs 0.9%; mean difference, -3.7% [95% CI, -6.1% to -1.2%]; P = .004]), and reduced relative hepatic fat content by MRI-PDFF (-11.7 vs 15.7 percentage points; mean difference, -27.3 percentage points [95% CI, -45.2 to -9.4]; P = .003). Thirteen participants (32.5%) in each group experienced an adverse event, most commonly upper respiratory tract infections (10.0% in each group) or arthralgias (5.0% for aspirin vs 7.5% for placebo). One participant randomized to aspirin (2.5%) experienced drug-related heartburn.
CONCLUSIONS AND RELEVANCE
In this preliminary randomized clinical trial of patients with MASLD, 6 months of daily low-dose aspirin significantly reduced hepatic fat quantity compared with placebo. Further study in a larger sample size is necessary to confirm these findings.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04031729.
Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Young Adult; Anti-Inflammatory Agents; Aspirin; Carcinoma, Hepatocellular; Double-Blind Method; End Stage Liver Disease; Fatty Liver; Follow-Up Studies; Liver; Liver Cirrhosis; Liver Neoplasms; Proton Magnetic Resonance Spectroscopy
PubMed: 38502074
DOI: 10.1001/jama.2024.1215 -
Circulation Feb 2024Bleeding rates on dual antiplatelet therapy (DAPT) within 1 month after percutaneous coronary intervention (PCI) remain high in clinical practice, particularly in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Bleeding rates on dual antiplatelet therapy (DAPT) within 1 month after percutaneous coronary intervention (PCI) remain high in clinical practice, particularly in patients with acute coronary syndrome or high bleeding risk. Aspirin-free strategy might result in lower bleeding early after PCI without increasing cardiovascular events, but its efficacy and safety have not yet been proven in randomized trials.
METHODS
We randomly assigned 6002 patients with acute coronary syndrome or high bleeding risk just before PCI either to prasugrel (3.75 mg/day) monotherapy or to DAPT with aspirin (81-100 mg/day) and prasugrel (3.75 mg/day) after loading of 20 mg of prasugrel in both groups. The coprimary end points were major bleeding (Bleeding Academic Research Consortium 3 or 5) for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke) for noninferiority with a relative 50% margin.
RESULTS
The full analysis set population consisted of 5966 patients (no-aspirin group, 2984 patients; DAPT group, 2982 patients; age, 71.6±11.7 years; men, 76.6%; acute coronary syndrome, 75.0%). Within 7 days before randomization, aspirin alone, aspirin with P2Y12 inhibitor, oral anticoagulants, and intravenous heparin infusion were given in 21.3%, 6.4%, 8.9%, and 24.5%, respectively. Adherence to the protocol-specified antiplatelet therapy was 88% in both groups at 1 month. At 1 month, the no-aspirin group was not superior to the DAPT group for the coprimary bleeding end point (4.47% and 4.71%; hazard ratio, 0.95 [95% CI, 0.75-1.20]; =0.66). The no-aspirin group was noninferior to the DAPT group for the coprimary cardiovascular end point (4.12% and 3.69%; hazard ratio, 1.12 [95% CI, 0.87-1.45]; =0.01). There was no difference in net adverse clinical outcomes and each component of coprimary cardiovascular end point. There was an excess of any unplanned coronary revascularization (1.05% and 0.57%; hazard ratio, 1.83 [95%CI, 1.01-3.30]) and subacute definite or probable stent thrombosis (0.58% and 0.17%; hazard ratio, 3.40 [95% CI, 1.26-9.23]) in the no-aspirin group compared with the DAPT group.
CONCLUSIONS
The aspirin-free strategy using low-dose prasugrel compared with the DAPT strategy failed to attest superiority for major bleeding within 1 month after PCI but was noninferior for cardiovascular events within 1 month after PCI. However, the aspirin-free strategy was associated with a signal suggesting an excess of coronary events.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT04609111.
Topics: Male; Humans; Middle Aged; Aged; Aged, 80 and over; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Acute Coronary Syndrome; Percutaneous Coronary Intervention; Drug Therapy, Combination; Aspirin; Hemorrhage; Stents; Thrombosis; Treatment Outcome; Nitrates
PubMed: 37994553
DOI: 10.1161/CIRCULATIONAHA.123.066720 -
Lancet (London, England) May 2024Following percutaneous coronary intervention with stent placement to treat acute coronary syndromes, international clinical guidelines generally recommend dual... (Randomized Controlled Trial)
Randomized Controlled Trial
Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT): a randomised, placebo-controlled, double-blind clinical trial.
BACKGROUND
Following percutaneous coronary intervention with stent placement to treat acute coronary syndromes, international clinical guidelines generally recommend dual antiplatelet therapy with aspirin plus a P2Y receptor inhibitor for 12 months to prevent myocardial infarction and stent thrombosis. However, data on single antiplatelet therapy with a potent P2Y inhibitor earlier than 12 months after percutaneous coronary intervention for patients with an acute coronary syndrome are scarce. The aim of this trial was to assess whether the use of ticagrelor alone, compared with ticagrelor plus aspirin, could reduce the incidence of clinically relevant bleeding events without an accompanying increase in major adverse cardiovascular or cerebrovascular events (MACCE).
METHODS
In this randomised, placebo-controlled, double-blind clinical trial, patients aged 18 years or older with an acute coronary syndrome who completed the IVUS-ACS study and who had no major ischaemic or bleeding events after 1-month treatment with dual antiplatelet therapy were randomly assigned to receive oral ticagrelor (90 mg twice daily) plus oral aspirin (100 mg once daily) or oral ticagrelor (90 mg twice daily) plus a matching oral placebo, beginning 1 month and ending at 12 months after percutaneous coronary intervention (11 months in total). Recruitment took place at 58 centres in China, Italy, Pakistan, and the UK. Patients were required to remain event-free for 1 month on dual antiplatelet therapy following percutaneous coronary intervention with contemporary drug-eluting stents. Randomisation was done using a web-based system, stratified by acute coronary syndrome type, diabetes, IVUS-ACS randomisation, and site, using dynamic minimisation. The primary superiority endpoint was clinically relevant bleeding (Bleeding Academic Research Consortium [known as BARC] types 2, 3, or 5). The primary non-inferiority endpoint was MACCE (defined as the composite of cardiac death, myocardial infarction, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularisation), with an expected event rate of 6·2% in the ticagrelor plus aspirin group and an absolute non-inferiority margin of 2·5 percentage points between 1 month and 12 months after percutaneous coronary intervention. The two co-primary endpoints were tested sequentially; the primary superiority endpoint had to be met for hypothesis testing of the MACCE outcome to proceed. All principal analyses were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03971500, and is completed.
FINDINGS
Between Sept 21, 2019, and Oct 27, 2022, 3400 (97·0%) of the 3505 participants in the IVUS-ACS study were randomly assigned (1700 patients to ticagrelor plus aspirin and 1700 patients to ticagrelor plus placebo). 12-month follow-up was completed by 3399 (>99·9%) patients. Between month 1 and month 12 after percutaneous coronary intervention, clinically relevant bleeding occurred in 35 patients (2·1%) in the ticagrelor plus placebo group and in 78 patients (4·6%) in the ticagrelor plus aspirin group (hazard ratio [HR] 0·45 [95% CI 0·30 to 0·66]; p<0·0001). MACCE occurred in 61 patients (3·6%) in the ticagrelor plus placebo group and in 63 patients (3·7%) in the ticagrelor plus aspirin group (absolute difference -0·1% [95% CI -1·4% to 1·2%]; HR 0·98 [95% CI 0·69 to 1·39]; p<0·0001, p=0·89).
INTERPRETATION
In patients with an acute coronary syndrome who had percutaneous coronary intervention with contemporary drug-eluting stents and remained event-free for 1 month on dual antiplatelet therapy, treatment with ticagrelor alone between month 1 and month 12 after the intervention resulted in a lower rate of clinically relevant bleeding and a similar rate of MACCE compared with ticagrelor plus aspirin. Along with the results from previous studies, these findings show that most patients in this population can benefit from superior clinical outcomes with aspirin discontinuation and maintenance on ticagrelor monotherapy after 1 month of dual antiplatelet therapy.
FUNDING
The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and the Jiangsu Provincial & Nanjing Municipal Clinical Trial Project.
TRANSLATION
For the Mandarin translation of the abstract see Supplementary Materials section.
Topics: Humans; Ticagrelor; Aspirin; Percutaneous Coronary Intervention; Acute Coronary Syndrome; Double-Blind Method; Male; Female; Middle Aged; Platelet Aggregation Inhibitors; Aged; Drug Therapy, Combination; Hemorrhage; Purinergic P2Y Receptor Antagonists; Dual Anti-Platelet Therapy; Treatment Outcome
PubMed: 38599220
DOI: 10.1016/S0140-6736(24)00473-2 -
European Heart Journal. Cardiovascular... May 2024
Topics: Humans; Aspirin; Drug Hypersensitivity
PubMed: 38268418
DOI: 10.1093/ehjcvp/pvae008 -
JAMA Neurology May 2024Dual antiplatelet therapy has been demonstrated to be superior to single antiplatelet in reducing recurrent stroke among patients with transient ischemic attack or minor... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Dual antiplatelet therapy has been demonstrated to be superior to single antiplatelet in reducing recurrent stroke among patients with transient ischemic attack or minor stroke, but robust evidence for its effect in patients with mild to moderate ischemic stroke is lacking.
OBJECTIVE
To evaluate whether dual antiplatelet therapy is superior to single antiplatelet among patients with mild to moderate ischemic stroke.
DESIGN, SETTING, AND PARTICIPANTS
This was a multicenter, open-label, blinded end point, randomized clinical trial conducted at 66 hospitals in China from December 20, 2016, through August 9, 2022. The date of final follow-up was October 30, 2022. The analysis was reported on March 12, 2023. Of 3065 patients with ischemic stroke, 3000 patients with acute mild to moderate stroke within 48 hours of symptom onset were enrolled, after excluding 65 patients who did not meet eligibility criteria or had no randomization outcome.
INTERVENTIONS
Within 48 hours after symptom onset, patients were randomly assigned to receive clopidogrel plus aspirin (n = 1541) or aspirin alone (n = 1459) in a 1:1 ratio.
MAIN OUTCOMES AND MEASURES
The primary end point was early neurologic deterioration at 7 days, defined as an increase of 2 or more points in National Institutes of Health Stroke Scale (NIHSS) score, but not as a result of cerebral hemorrhage, compared with baseline. The superiority of clopidogrel plus aspirin to aspirin alone was assessed based on a modified intention-to-treat population, which included all randomized participants with at least 1 efficacy evaluation regardless of treatment allocation. Bleeding events were safety end points.
RESULTS
Of the 3000 randomized patients, 1942 (64.6%) were men, the mean (SD) age was 65.9 (10.6) years, median (IQR) NIHSS score at admission was 5 (4-6), and 1830 (61.0%) had a stroke of undetermined cause. A total of 2915 patients were included in the modified intention-to-treat analysis. Early neurologic deterioration occurred in 72 of 1502 (4.8%) in the dual antiplatelet therapy group vs 95 of 1413 (6.7%) in the aspirin alone group (risk difference -1.9%; 95% CI, -3.6 to -0.2; P = .03). Similar bleeding events were found between 2 groups.
CONCLUSIONS AND RELEVANCE
Among Chinese patients with acute mild to moderate ischemic stroke, clopidogrel plus aspirin was superior to aspirin alone with regard to reducing early neurologic deterioration at 7 days with similar safety profile. These findings indicate that dual antiplatelet therapy may be a superior choice to aspirin alone in treating patients with acute mild to moderate stroke.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02869009.
Topics: Humans; Clopidogrel; Aspirin; Male; Female; Middle Aged; Aged; Platelet Aggregation Inhibitors; Drug Therapy, Combination; Ischemic Stroke; Stroke
PubMed: 38466274
DOI: 10.1001/jamaneurol.2024.0146 -
JAMA Neurology Jun 2024Evidence supports using antiplatelet therapy in patients with acute ischemic stroke. However, neurological deterioration remains common under the currently recommended... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Evidence supports using antiplatelet therapy in patients with acute ischemic stroke. However, neurological deterioration remains common under the currently recommended antiplatelet regimen, leading to poor clinical outcomes.
OBJECTIVE
To determine whether intravenous tirofiban administered within 24 hours of stroke onset prevents early neurological deterioration in patients with acute noncardioembolic stroke compared with oral aspirin.
DESIGN, SETTING, AND PARTICIPANTS
This investigator-initiated, multicenter, open-label, randomized clinical trial with blinded end-point assessment was conducted at 10 comprehensive stroke centers in China between September 2020 and March 2023. Eligible patients were aged 18 to 80 years with acute noncardioembolic stroke within 24 hours of onset and had a National Institutes of Health Stroke Scale (NIHSS) score of 4 to 20.
INTERVENTION
Patients were assigned randomly (1:1) to receive intravenous tirofiban or oral aspirin for 72 hours using a central, web-based, computer-generated randomization schedule; all patients then received oral aspirin.
MAIN OUTCOME
The primary efficacy outcome was early neurological deterioration (increase in NIHSS score ≥4 points) within 72 hours after randomization. The primary safety outcome was symptomatic intracerebral hemorrhage within 72 hours after randomization.
RESULTS
A total of 425 patients were included in the intravenous tirofiban (n = 213) or oral aspirin (n = 212) groups. Median (IQR) age was 64.0 years (56.0-71.0); 124 patients (29.2%) were female, and 301 (70.8%) were male. Early neurological deterioration occurred in 9 patients (4.2%) in the tirofiban group and 28 patients (13.2%) in the aspirin group (adjusted relative risk, 0.32; 95% CI, 0.16-0.65; P = .002). No patients in the tirofiban group experienced intracerebral hemorrhage. At 90-day follow-up, 3 patients (1.3%) in the tirofiban group and 3 (1.5%) in the aspirin group died (adjusted RR, 1.15; 95% CI, 0.27-8.54; P = .63), and the median (IQR) modified Rankin scale scores were 1.0 (0-1.25) and 1.0 (0-2), respectively (adjusted odds ratio, 1.28; 95% CI, 0.90-1.83; P = .17).
CONCLUSIONS AND RELEVANCE
In patients with noncardioembolic stroke who were seen within 24 hours of symptom onset, tirofiban decreased the risk of early neurological deterioration but did not increase the risk of symptomatic intracerebral hemorrhage or systematic bleeding.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04491695.
Topics: Humans; Tirofiban; Male; Female; Middle Aged; Aged; Ischemic Stroke; Platelet Aggregation Inhibitors; Aspirin; Adult; Treatment Outcome; Aged, 80 and over
PubMed: 38648030
DOI: 10.1001/jamaneurol.2024.0868 -
The Canadian Journal of Cardiology Aug 2023Pericardial effusion is the most common manifestation of pericardial diseases during pregnancy. This effusion is benign, mild, or moderate, well tolerated, with... (Review)
Review
Pericardial effusion is the most common manifestation of pericardial diseases during pregnancy. This effusion is benign, mild, or moderate, well tolerated, with spontaneous resolution after delivery; no specific treatment is required. Acute pericarditis is the second most common condition, usually requiring medical therapy during pregnancy. Cardiac tamponade and constrictive pericarditis are rare in pregnancy. Pre-pregnancy counselling is essential in women of childbearing age with recurrent pericarditis to plan pregnancy in a phase of disease quiescence and to review therapy. High-dose aspirin or nonselective nonsteroidal anti-inflammatory drugs, such as ibuprofen and indomethacin, can be used up to the 20th week of gestation. Low-dose prednisone (2.5-10 mg/d) can be administered throughout pregnancy. All of these medications, apart from high-dose aspirin, may be used during lactation. Colchicine is compatible with pregnancy and breastfeeding, and it can be continued throughout pregnancy to prevent recurrences. Appropriate follow-up with a multidisciplinary team with experience in the field is recommended throughout pregnancy to ensure good maternal and fetal outcomes.
Topics: Pregnancy; Humans; Female; Pericarditis; Pericarditis, Constrictive; Pericardial Effusion; Aspirin; Anti-Inflammatory Agents, Non-Steroidal; Cardiac Tamponade
PubMed: 37086835
DOI: 10.1016/j.cjca.2023.04.010 -
Hepatology Communications Oct 2023The hepatoprotective effects of aspirin have been observed in individuals with viral hepatitis; however, its impact on the general population remains uncertain....
BACKGROUND
The hepatoprotective effects of aspirin have been observed in individuals with viral hepatitis; however, its impact on the general population remains uncertain. Understanding the association between aspirin use and the development of liver diseases is crucial for optimizing preventive strategies.
METHODS
We identified individuals with aspirin use in the UK Biobank and the Penn Medicine Biobank, as well as propensity-score-matched controls. Outcome measures included new liver disease development, diagnosed by MRI or "International Classification of Diseases and Related Health Problems" coding, and incidences of gastrointestinal bleeding and ulcers.
RESULTS
In the UK Biobank cohort, regular aspirin use was associated with an 11.2% reduction in the risk of developing new liver diseases during the average 11.84 ± 2.01-year follow-up period (HR=0.888, 95% CI = 0.819-0.963; p = 4.1 × 10-3). Notably, the risk of metabolic dysfunction-associated steatotic liver disease (ICD-10 K76.0) and MRI-diagnosed steatosis was significantly lower among aspirin users (HR = 0.882-0.911), whereas no increased risk of gastrointestinal bleeding or ulcers was observed. These findings were replicated in the Penn Medicine Biobank cohort, in which the protective effect of aspirin appeared to be dependent on the duration of intake. The greatest risk reduction for new liver disease development was observed after at least 1 year of aspirin use (HR = 0.569, 95% CI = 0.425-0.762; p = 1.6 × 10-4). Intriguingly, when considering general risk factors, only men exhibited a lower risk of MRI-confirmed or ICD-coded steatosis with aspirin use (HRs = 0.806-0.906), while no significant protective effect of aspirin was observed in females.
CONCLUSION
This cohort study demonstrated that regular aspirin use was associated with a reduced risk of liver disease in men without an elevated risk of gastrointestinal bleeding or ulcers. Further investigation is warranted to elucidate potential sex-related differences in the effects of aspirin and to inform tailored preventive strategies for liver diseases.
Topics: Female; Male; Humans; Incidence; Cohort Studies; Ulcer; Liver Diseases; Fatty Liver; Gastrointestinal Hemorrhage; Aspirin
PubMed: 37708453
DOI: 10.1097/HC9.0000000000000268 -
The Journal of Pharmacology and... Aug 2023At 125, aspirin still represents the cornerstone of anti-platelet therapy for the acute treatment and long-term prevention of atherothrombosis. The development of a... (Review)
Review
At 125, aspirin still represents the cornerstone of anti-platelet therapy for the acute treatment and long-term prevention of atherothrombosis. The development of a selective regimen of low-dose aspirin for the inhibition of platelet thromboxane production was key to maximizing its antithrombotic efficacy and minimizing its gastrointestinal toxicity. Based on about 50 observational studies, published over the past 30 years, aspirin and other cyclooxygenase inhibitors have been associated with a reduced risk of colorectal cancer, and possibly other digestive tract cancers. The apparent chemopreventive effect of aspirin has been confirmed in post-hoc analyses of randomized cardiovascular trials and their meta-analyses. Moreover, prevention of sporadic colorectal adenoma recurrence was demonstrated by randomized controlled trials of low-dose aspirin and selective cyclooxygenase-2 inhibitors. A single placebo-controlled randomized trial of aspirin has shown long-term colorectal cancer prevention in patients with the Lynch syndrome. The sequential involvement of thromboxane-dependent platelet activation and cyclooxygenase-2-driven inflammatory response in the early stages of colorectal carcinogenesis may explain these clinical benefits. The aim of this mini-review is to analyze the existing evidence for a chemopreventive effect of aspirin and other cyclooxygenase inhibitors and discuss the missing pieces of this mechanistic and clinical puzzle. SIGNIFICANCE STATEMENT: Low-dose aspirin and other cyclooxygenase inhibitors have been associated with a reduced risk of colorectal cancer, and possibly other digestive tract cancers. The sequential involvement of thromboxane-dependent platelet activation and cyclooxygenase-2-driven inflammatory response in the early stages of colorectal carcinogenesis may explain these clinical benefits. The aim of this mini-review is to analyze the evidence for a chemopreventive effect of aspirin and other cyclooxygenase inhibitors and discuss the missing pieces of this mechanistic and clinical puzzle.
Topics: Humans; Cyclooxygenase 2; Aspirin; Cyclooxygenase 2 Inhibitors; Colorectal Neoplasms; Gastrointestinal Neoplasms; Thromboxanes; Carcinogenesis; Cyclooxygenase 1; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic
PubMed: 37280092
DOI: 10.1124/jpet.122.001631 -
The New England Journal of Medicine Apr 2024
Review
Topics: Humans; Gastrointestinal Hemorrhage; Male; Middle Aged; Aneurysm, Ruptured; Intracranial Aneurysm; Prosthesis Implantation; Stents; Aspirin; Clopidogrel; Platelet Aggregation Inhibitors; Shock, Hemorrhagic; Diverticulum; Jejunum
PubMed: 38647094
DOI: 10.1056/NEJMicm2312626