Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

Atorvastatin versus Placebo in ICU Patients with COVID-19: Ninety-day Results of the INSPIRATION-S Trial.

BACKGROUND: In the INSPIRATION-S trial, atorvastatin versus placebo was associated with a nonsignificant 16% reduction in 30-day composite of venous/arterial thrombosis or death in intensive care unit (ICU) patients with COVID-19. Thrombo-inflammatory response in coronavirus disease 2019 (COVID-19) may last beyond the first 30 days. METHODS: This article reports the effects of atorvastatin 20 mg daily versus placebo on 90-day clinical and functional outcomes from INSPIRATION-S, a double-blind multicenter randomized trial of adult ICU patients with COVID-19. The main outcome for this prespecified study was a composite of adjudicated venous/arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. Functional status was assessed with the Post-COVID-19 Functional Scale. RESULTS: In the primary analysis, 587 patients were included (age: 57 [Q1-Q3: 45-68] years; 44% women). By 90-day follow-up, the main outcome occurred in 96 (33.1%) patients assigned to atorvastatin and 113 (38.0%) assigned to placebo (hazard ratio [HR]: 0.80, 95% confidence interval [CI]: 0.60-1.05, p = 0.11). Atorvastatin in patients who presented within 7 days of symptom onset was associated with reduced 90-day hazard for the main outcome (HR: 0.60, 95% CI: 0.42-0.86, p interaction = 0.02). Atorvastatin use was associated with improved 90-day functional status, although the upper bound CI crossed 1.0 (ORordinal: 0.64, 95% CI: 0.41-1.01, p = 0.05). CONCLUSION: Atorvastatin 20 mg compared with placebo did not significantly reduce the 90-day composite of death, treatment with ECMO, or venous/arterial thrombosis. However, the point estimates do not exclude a potential clinically meaningful treatment effect, especially among patients who presented within 7 days of symptom onset (NCT04486508).

The early start of hemoperfusion decreases the mortality rate among severe COVID-19 patients: A preliminary study.

BACKGROUND: Coronavirus disease-2019 (COVID-19)-related organ failure is partly related to a sepsis-like syndrome and extreme pro-inflammatory cytokine release, named cytokine storm. Therapeutic strategies that prevent the production of or remove the pro-inflammatory cytokines could potentially be an effective therapy in critically afflicted COVID-19 patients. METHODS: In this clinical trial study, from April until June 2020, 68 COVID-19 patients (35 vs. 33 controls) with severe critical symptoms, and PaO2 /FiO2 (P/F) ratio less than 200 mmHg either received a single standard therapy or a combination of standard treatment for COVID-19 combined with hemoperfusion (hemofilter, HA330 D Javfron) for 4 h, in 3 consecutive days. The length of hospital stay and mechanical ventilation, the resolution of radiologic abnormalities, and the mortality rate were defined as the primary outcomes. RESULTS: Demographic characteristics, the acute physiology, and chronic health evaluation score of both groups were similar (p > 0.05). Importantly, we noticed a significant mortality rate reduction in the perfused group compared with controls (37.1% vs. 63.6%, p = 0.02), this positive effect was stronger among those with a P/F ratio higher than 75 (mortality rate of 84.7% for P/F ratio < 75 vs. 15.4% for P/F ratio ≥ 75, p = 0.02). CONCLUSIONS: The results imply that early start of hemoperfusion could be more effective and significantly reduce the mortality rate among COVID-19 patients with critical diseases.

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

BACKGROUND: Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. METHODS: This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. RESULTS: Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). CONCLUSION: Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

Incidence of symptomatic venous thromboembolism following hospitalization for coronavirus disease 2019: Prospective results from a multi-center study.

BACKGROUND: Thrombosis and pulmonary embolism appear to be major causes of mortality in hospitalized coronavirus disease 2019 (COVID-19) patients. However, few studies have focused on the incidence of venous thromboembolism (VTE) after hospitalization for COVID-19. METHODS: In this multi-center study, we followed 1529 COVID-19 patients for at least 45 days after hospital discharge, who underwent routine telephone follow-up. In case of signs or symptoms of pulmonary embolism (PE) or deep vein thrombosis (DVT), they were invited for an in-hospital visit with a pulmonologist. The primary outcome was symptomatic VTE within 45 days of hospital discharge. RESULTS: Of 1529 COVID-19 patients discharged from hospital, a total of 228 (14.9%) reported potential signs or symptoms of PE or DVT and were seen for an in-hospital visit. Of these, 13 and 12 received Doppler ultrasounds or pulmonary CT angiography, respectively, of whom only one patient was diagnosed with symptomatic PE. Of 51 (3.3%) patients who died after discharge, two deaths were attributed to VTE corresponding to a 45-day cumulative rate of symptomatic VTE of 0.2% (95%CI 0.1%-0.6%; n = 3). There was no evidence of acute respiratory distress syndrome (ARDS) in these patients. Other deaths after hospital discharge included myocardial infarction (n = 13), heart failure (n = 9), and stroke (n = 9). CONCLUSIONS: We did not observe a high rate of symptomatic VTE in COVID-19 patients after hospital discharge. Routine extended thromboprophylaxis after hospitalization for COVID-19 may not have a net clinical benefit. Randomized trials may be warranted.

Clinical Utility of Red Cell Distribution Width in Patients with Pleural Effusion.

BACKGROUND: The red cell distribution width (RDW) value has been recently recognized as a valuable biomarker in clinical practice. The RDW value has not been evaluated so far in patients with pleural effusion. Thus, this study aimed to investigate whether RDW could distinguish between exudative and transudative pleural effusions. MATERIALS AND METHODS: We measured protein and lactate dehydrogenase levels on both pleural fluids and serum samples from 223 cases and classified them as transudates or exudates based on the classic Light's criteria. We collected blood cell count elements such as RDW from the medical records. We also investigated the correlation between RDW and the nature of pleural effusion. RESULTS: In 55.2% of the patients, pleural fluid was exudative. Although we found no significant association between RDW and the nature of the pleural fluid, we detected a significantly higher amount of RDW (14.9 ≤) in patients with exudative pleural effusion compared to transudate (66.7% vs. 33.3%; P= 0.01). In this category, neoplastic conditions were mostly observed in the patients (76.3%), followed by pulmonary thromboembolism (21.1%) and systemic lupus erythematous (2.6%). CONCLUSION: The findings could not reveal any noticeable correlation between RDW and the Light criteria. However, it appears that elevated RDW levels give insights into the valuable nature of RDW in different conditions such as neoplastic diseases.

Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: Rationale and design of the INSPIRATION/INSPIRATION-S studies.

BACKGROUND: Microvascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown. METHODS: The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies test two independent hypotheses within a randomized controlled trial with 2 × 2 factorial design. Hospitalized critically-ill patients with reverse transcription polymerase chain reaction confirmed COVID-19 will be randomized to intermediate-dose versus standard dose prophylactic anticoagulation. The 600 patients undergoing this randomization will be screened and if meeting the eligibility criteria, will undergo an additional double-blind stratified randomization to atorvastatin 20 mg daily versus matching placebo. The primary endpoint, for both hypotheses will be tested for superiority and includes a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Key secondary endpoints include all-cause mortality, adjudicated VTE, and ventilator-free days. Key safety endpoints include major bleeding according to the Bleeding Academic Research Consortium definition and severe thrombocytopenia (platelet count <20,000/fL) for the anticoagulation hypothesis. In a prespecified secondary analysis for non-inferiority, the study will test for the non-inferiority of intermediate intensity versus standard dose anticoagulation for major bleeding, considering a non-inferiority margin of 1.8 based on odds ratio. Key safety endpoints for the statin hypothesis include rise in liver enzymes >3 times upper normal limit and clinically-diagnosed myopathy. The primary analyses will be performed in the modified intention-to-treat population. Results will be tested in exploratory analyses across key subgroups and in the intention-to-treat and per-protocol cohorts. CONCLUSIONS: INSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19.

Von Willebrand factor-cleaving protease activity in thrombotic microangiopathy: first report from iran.

BACKGROUND: Thrombotic microangiopathy (TMA) is a rare but devastating small vessels disorder that is characterized by intravascular platelet thrombi, thrombocytopenia, and various degrees of organ ischemia and anemia, which is due to erythrocyte fragmentation in microcirculation. OBJECTIVES: The Aim of this study was to determine the von Willebrand factor-cleaving protease (ADAMTS13) activity during the acute phase of TMA. We also investigated inhibiting antibodies against ADAMTS13 in these patients. PATIENTS AND METHODS: In a collaborative work with Mario-Negro institute of pharmacological research in Bergamo-Italy, we registered the clinical and laboratory data, collected the serum samples, and transferred the samples to the laboratories. Serum samples were taken before the start of plasmapheresis or at least 15 days after the final exchange. RESULTS: We recruited 40 patients (14 males and 26 females) with the mean age of 46.12 ± 17.26 years. The mean activity of ADAMTS13 was 34.58% ± 21.83%. Two patients had inhibitory antibodies against ADAMTS13 with profound deficiency of ADAMTS13 activity (< 6%). Infectious diseases were the most common underlying condition, followed by systemic lupus erythematous. CONCLUSIONS: Majority of patients had an underlying condition and had various ADAMTS13 activity. The presence of inhibiting antibodies and accompanied complete deficiency of ADAMTS13 activity is an indicator of severity.

Epidemiological and clinical characteristics of inflammatory bowel disease in patients from northwestern iran.

BACKGROUND: There are few reports from Iran about the epidemiology and clinical features of inflammatory bowel disease (IBD). This study aims to determine the epidemiologic profile and clinical features of IBD in Northwest Iran referral centers. METHODS: In a cross-sectional setting, we evaluated 200 patients with definitive diagnoses of IBD who referred to Tabriz educational hospitals during the period of 2005 to 2007. Demographic characteristics as well as patients' clinical profiles were evaluated. Disease activity and severity were determined by the Crohn's Disease Activity Index and Truelove and Witt's classification of ulcerative colitis (UC). The related probable demographic factors were tested. RESULTS: Of the 200 IBD patients, 183 (91.5%) were diagnosed with UC and 17 (8.5%) with Crohn's disease (CD). There was a positive first degree relative of IBD in 10.9% of UC and 11.8% of CD patients. Abdominal pain was the primary presenting symptom in 25.7% of UC patients and in 58.8% of those with CD. Among UC patients, left-sided colitis was the main feature (52.5%); while in patients with CD, colon involvement was predominant (52.9%). There was no significant contributor for activity or severity of disease noted among demographic factors. CONCLUSION: The occurrence of UC was much higher than CD. The onset of IBD occurred in younger ages with a predominance in males. Left-sided colitis in UC and colon involvement in CD was common. Mostly, the pattern of IBD was mild to moderate with good response to pharmacotherapy. Disease activity and severity were unaffected by demographic features.

Effects of low dose zinc supplementation on biochemical markers in non-alcoholic cirrhosis: a randomized clinical trial.

BACKGROUND: The present study aimed to evaluate the effects of low dose zinc (Zn) supplementation on biochemical markers and underlying disease status in non-alcoholic cirrhotic patients. METHODS: We enrolled 60 cirrhotic patients in a double-blind, placebo-controlled, randomized clinical trial. All patients in the interventional group (n = 30) received long-term, low dose Zn supplementation (50 mg elemental Zn sulfate daily). The control group (n = 30) received placebo (starch). Child-Pugh scores and biochemical markers were assessed for both interventional and control groups at the first day and the end of the 90th day of the interventional period. A per-protocol analysis was performed after excluding all participants who did not receive or complete the randomized intervention. The mean differences of quantitative variables between and within groups were evaluated by independent samples t-test and paired-samples t-test, respectively. SPSS version 13.00 was used for statistical analysis. RESULTS: In the initial evaluation, 16 (53.30%) patients from the interventional group had a Child-Pugh score of 5-8 and 14 (46. 70%) had a score of 9-12. In the control group 18 (60.00%) had a Child-Pugh score of 5-8 and 12 (40.00%) scored 9-12. After three months the mean Child-Pugh score in the interventional group showed a significant improvement (from 6.56 ± 0.21 to 5.72 ± 0.22, P = 0.001) whereas in the control group despite no significant decline, the mean Child-Pugh score increased slightly (from 6.25 ± 0.27 to 6.67 ± 0.31, P = 0.14). Zn supplementation significantly decreased copper (Cu; P = 0.01) and creatinine (Cr; P < 0.0001) levels. CONCLUSION: In this study, we determined that low dose Zn supplementation could prevent deterioration of clinical status of cirrhosis and prevent excess Cu accumulation in non-alcoholic cirrhotic patients. Zn supplementation produces metabolic effects and trends towards improvements in liver function, hepatic encephalopathy, and nutritional status. Registration ID in IRCT: IRCT201106122017N4.

Bone density and bone metabolism in patients with inflammatory bowel disease.

BACKGROUND/AIMS: Patients with inflammatory bowel disease (IBD) are at high risk for low bone mineral density (BMD). This study aimed to evaluate BMD in IBD patients and its relationship with bone metabolism in a group of Iranian patients. PATIENTS AND METHODS: A cross-sectional study was conducted on patients with IBD to assess BMD status and serum biochemical factors. After getting the demographic data from 200 patients, they were screened using dual-energy X-ray absorptiometry of the lumbar spine (L2-L4) and femoral neck for BMD status. Serum levels of calcium, phosphate, alkaline phosphatase (ALP), and 25-hydroxyvitamin D (25-OH vitamin D) were measured to assess the bone metabolism status. RESULTS: Two hundred patients with IBD were enrolled in the study. One hundred and eighty three (91.5%) patients were identified as having ulcerative colitis (UC) and 17 (8.5%) as having Crohn's disease (CD). Based on the lumbar and femoral neck bone mass densitometry, 148 (74.4%) patients had low BMD at either lumbar spine or femoral neck. Of these, 100 patients (50.3%) were osteopenic and 48 patients (24.1%) were osteoporotic. A 58.6% and 61% of patients with UC had low BMD in the lumbar and femoral neck, respectively. These results for those with CD were 76.5% and 70.6%, respectively. The mean of femoral neck and lumbar T-scores in patients with UC were -1.14 and -1.38, and in patients with CD were -1.24 and -1.47, respectively (P > 0.05). The mean (±SD) levels for calcium (Ca) in UC and CD were in the normal range. The mean (±SD) levels of ALP and 25-OH vitamin D in both the groups were in the normal range, and in comparison between groups (UC and CD), no significant differences were observed (P = 0.20 for ALP and P = 0.44 for 25-OH vitamin D). In the assessment of correlation between biochemical markers and BMD, an inverse correlation between lumbar T-score and ALP or 25-OH vitamin D only in patients with UC was observed. CONCLUSIONS: The high prevalence of low BMD in the Iranian population with IBD needs attention. The subclinical vitamin D deficiency may contribute to bone loss in IBD patients, which is more pronounced in patients with UC in this study because of the small population of patients with CD.

Shrapnel splinter in the common bile duct.

Obstructive jaundice is infrequently caused by a foreign body. We report a 42-year-old man who presented with obstructive jaundice by an impacted shrapnel splinter in the common bile duct (CBD) 23 years after a combat injury. To our knowledge, this is the first case report of this type in Iranian literature, although there are a few reports of combat related injuries in other countries. This diagnosis should be considered in the assessment of any patient with jaundice and abdominal pain who has experienced a previous combat injury.