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1.
Viruses ; 14(2)2022 01 18.
Article in English | MEDLINE | ID: covidwho-1625015

ABSTRACT

BACKGROUND: Venous thromboembolism (VTE)-including deep vein thrombosis, pulmonary embolism, and cerebral venous sinus thrombosis (CVST)-may occur early after vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We sought to describe the site, clinical characteristics, and outcomes of VTE after vaccination against SARS-CoV-2. METHODS: In a prospective study using the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) platform, patients with VTE 4-30 days after vaccination against SARS-CoV-2 (1 February 2021 through 30 April 2021) were included. VTE patients recruited from the same centers into RIETE in the same months in 2018-2019 were selected as the reference group. All-cause mortality and major bleeding were the main study outcomes. RESULTS: As of 30 April 2020, 102 patients with post-vaccination VTEs had been identified (28 after adenovirus-based vaccination [ChAdOx1 nCov-19; AstraZeneca] and 74 after mRNA-based vaccination [mRNA-1273; Moderna, and BNT162b2; Pfizer]). Compared with 911 historical controls, patients with VTE after adenovirus-based vaccination more frequently had CVST (10.7% vs. 0.4%, p < 0.001) or thrombosis at multiple sites (17.9% vs. 1.3%, p < 0.001), more frequently had thrombocytopenia (40.7% vs. 14.7%, p < 0.001), and had higher 14-day mortality (14.3% vs. 0.7%; odds ratio [OR]: 25.1; 95% confidence interval [CI]: 6.7-94.9) and major bleeding rates (10.3% vs. 1.0%, OR: 12.03, 95% CI: 3.07-47.13). The site of thrombosis, accompanying thrombocytopenia, and 14-day mortality rates were not significantly different for patients with VTE after mRNA-based vaccination, compared with historical controls. CONCLUSIONS: Compared with historical controls, VTE after adenovirus-based vaccination against SARS-CoV-2 is accompanied by thrombocytopenia, occurs in unusual sites, and is associated with worse clinical outcomes.


Subject(s)
/adverse effects , COVID-19/prevention & control , Registries , Vaccination/adverse effects , Venous Thromboembolism/etiology , /administration & dosage , Aged , Aged, 80 and over , /administration & dosage , Female , Humans , Male , Middle Aged , Outcome Assessment, Health Care , Prospective Studies , Risk Factors , Thrombocytopenia/etiology , Time Factors , Vaccination/mortality
2.
Semin Thromb Hemost ; 2021 Dec 13.
Article in English | MEDLINE | ID: covidwho-1569320

ABSTRACT

The clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) who develop pulmonary embolism (PE) in the full spectrum of patient care settings need to be elucidated. The aim of this study was to compare the clinical characteristics, treatment, and 90-day outcomes in patients diagnosed with PE while recovering from COVID-19 in the outpatient setting versus those who were diagnosed with PE while being hospitalized with COVID-19. Data from the international Registro Informatizado de Enfermedad TromboEmbólica (RIETE) registry were used. The major study outcomes were all-cause death, major bleeding, and venous thromboembolism (VTE) recurrences during the first 90 days after PE. From March 2020 to March 2021, 737 patients with COVID-19 experienced acute PE. Of these, 340 (46%) were recovering from COVID-19 as outpatients (267 patients who had been treated at home for COVID-19 and 73 discharged after being hospitalized with COVID-19). Compared with inpatients with COVID-19, those recovering in the outpatient setting upon PE were less likely to be men (odds ratio [OR]: 0.54; 95% confidence interval [CI]: 0.40-0.72) and less likely to have hypertension (OR: 0.55; 95% CI: 0.41-0.74) or diabetes (OR: 0.51; 95% CI: 0.33-0.76). At 90-day follow-up, eight patients (none recovering from COVID-19 as outpatient vs. 2.4% of inpatients with COVID-19) developed recurrent VTE, 34 (1.9 vs. 7.9%) had major bleeding, and 128 (10 vs. 24%) died. On multivariable analysis, inpatients with COVID-19 were at a higher risk of major bleeding (adjusted hazard ratio [HR]: 6.80; 95% CI: 1.52-30.4) or death (adjusted HR: 2.24; 95% CI: 1.40-3.58). In conclusion, using a large multinational registry of patients with COVID-19 who experienced PE, thromboembolic episodes occurring in those recovering from COVID-19 as outpatients were associated with less ominous outcomes than inpatients with COVID-19.

3.
Viruses ; 13(11)2021 11 15.
Article in English | MEDLINE | ID: covidwho-1524170

ABSTRACT

INTRODUCTION: Hospitalized patients with COVID-19 are at increased risk for venous thromboembolism (VTE), but also for bleeding. We previously derived a prognostic score including four variables (elevated D-dimer, elevated ferritin, critical illness, and therapeutic-dose anticoagulation) that identified those at increased risk for major bleeding. METHODS: We aimed to validate the score in a subsequent cohort of hospitalized patients with COVID-19 receiving standard-, intermediate- or therapeutic doses of VTE prophylaxis. We evaluated its capacity to predict major bleeding, non-major bleeding, and bleeding-related death. RESULTS: The cohort included 972 patients from 29 hospitals, of whom 280 (29%) received standard-; 412 (42%) intermediate-, 157 (16%) therapeutic doses of VTE prophylaxis and 123 (13%) other drugs. Median duration of prophylaxis was 14.7 ± 10.3 days. Major bleeding occurred in 65 patients (6.7%) and non-major bleeding in 67 (6.9%). Thirty patients with major bleeding (46%) died within the first 30 days after bleeding. The prognostic score identified 203 patients (21%) at very low risk, 285 (29%) at low risk, 263 (27%) intermediate-risk and 221 (23%) at high risk for bleeding. Major bleeding occurred in 1.0%, 2.1%, 8.7% and 15.4% of the patients, respectively. Non-major bleeding occurred in 0.5%, 3.5%, 9.5% and 14.2%, respectively. The c-statistics was: 0.74 (95% confidence intervals [CI]: 0.68-0.79) for major bleeding, 0.73 (95% CI: 0.67-0.78) for non-major bleeding and 0.82 (95% CI: 0.76-0.87) for bleeding-related death. CONCLUSIONS: In hospitalized patients with COVID-19, we validated that a prognostic score including 4 easily available items may identify those at increased risk for bleeding.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/complications , Ferritins/blood , Fibrin Fibrinogen Degradation Products/analysis , Hemorrhage/etiology , Cohort Studies , Critical Illness , Female , Hemorrhage/epidemiology , Hospitalization , Humans , Male , Prognosis , Risk Factors , Venous Thromboembolism/complications , Venous Thromboembolism/prevention & control
4.
Viruses ; 13(11)2021 10 22.
Article in English | MEDLINE | ID: covidwho-1481019

ABSTRACT

Patients with coronavirus disease 2019 (COVID-19) have a higher risk of venous thromboembolic disease (VTE) than patients with other infectious or inflammatory diseases, both as macrothrombosis (pulmonar embolism and deep vein thrombosis) or microthrombosis. However, the use of anticoagulation in this scenario remains controversial. This is a project that used DELPHI methodology to answer PICO questions related to anticoagulation in patients with COVID-19. The objective was to reach a consensus among multidisciplinary VTE experts providing answers to those PICO questions. Seven PICO questions regarding patients with COVID-19 responded with a broad consensus: 1. It is recommended to avoid pharmacological thromboprophylaxis in most COVID-19 patients not requiring hospital admission; 2. In most hospitalized patients for COVID-19 who are receiving oral anticoagulants before admission, it is recommended to replace them by low molecular weight heparin (LMWH) at therapeutic doses; 3. Thromboprophylaxis with LMWH at standard doses is suggested for COVID-19 patients admitted to a conventional hospital ward; 4. Standard-doses thromboprophylaxis with LMWH is recommended for COVID-19 patients requiring admission to Intensive Care Unit; 5. It is recommended not to determine D-Dimer levels routinely in COVID-19 hospitalized patients to select those in whom VTE should be suspected, or as a part of the diagnostic algorithm to rule out or confirm a VTE event; 6. It is recommended to discontinue pharmacological thromboprophylaxis at discharge in most patients hospitalized for COVID-19; 7. It is recommended to withdraw anticoagulant treatment after 3 months in most patients with a VTE event associated with COVID-19. The combination of PICO questions and DELPHI methodology provides a consensus on different recommendations for anticoagulation management in patients with COVID-19.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/complications , Heparin, Low-Molecular-Weight/therapeutic use , Venous Thromboembolism/drug therapy , Venous Thromboembolism/prevention & control , Anticoagulants/administration & dosage , Delphi Technique , Duration of Therapy , Heparin, Low-Molecular-Weight/administration & dosage , Humans , Venous Thromboembolism/complications , Venous Thromboembolism/diagnosis
6.
J Am Coll Cardiol ; 78(16): 1635-1654, 2021 10 19.
Article in English | MEDLINE | ID: covidwho-1454219

ABSTRACT

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management.


Subject(s)
COVID-19/drug therapy , COVID-19/prevention & control , Fatty Acids, Omega-3/therapeutic use , Fibric Acids/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Niacin/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Esters/pharmacology , Esters/therapeutic use , Fatty Acids, Omega-3/pharmacology , Fibric Acids/pharmacology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Lipid Regulating Agents/pharmacology , Lipid Regulating Agents/therapeutic use , Niacin/pharmacology , Randomized Controlled Trials as Topic , Sulfhydryl Compounds/pharmacology , Sulfhydryl Compounds/therapeutic use
7.
Chest ; 159(6): 2513, 2021 06.
Article in English | MEDLINE | ID: covidwho-1290754
9.
Thromb Haemost ; 122(1): 131-141, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1258614

ABSTRACT

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.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/drug therapy , Enoxaparin/administration & dosage , SARS-CoV-2 , Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , COVID-19/complications , COVID-19/mortality , Cohort Studies , Critical Care , Dose-Response Relationship, Drug , Enoxaparin/adverse effects , Extracorporeal Membrane Oxygenation , Female , Hemorrhage/chemically induced , Humans , Intensive Care Units , Iran/epidemiology , Kaplan-Meier Estimate , Male , Middle Aged , Pandemics , Thrombosis/etiology , Thrombosis/mortality
10.
JAMA ; 325(16): 1620-1630, 2021 04 27.
Article in English | MEDLINE | ID: covidwho-1239957

ABSTRACT

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.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/complications , Enoxaparin/administration & dosage , Extracorporeal Membrane Oxygenation , Oxygen Inhalation Therapy/methods , Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , COVID-19/mortality , Drug Administration Schedule , Enoxaparin/adverse effects , Female , Hemorrhage/chemically induced , Hospitalization , Humans , Intensive Care Units , Iran , Length of Stay/statistics & numerical data , Male , Middle Aged , Odds Ratio , Outcome Assessment, Health Care , Pulmonary Embolism/epidemiology , Thrombocytopenia/chemically induced , Thrombosis/etiology , Thrombosis/mortality , Treatment Outcome , Venous Thrombosis/epidemiology , Venous Thrombosis/mortality
11.
J Thromb Haemost ; 19(8): 1981-1989, 2021 08.
Article in English | MEDLINE | ID: covidwho-1238451

ABSTRACT

INTRODUCTION: Some local protocols suggest using intermediate or therapeutic doses of anticoagulants for thromboprophylaxis in hospitalized patients with coronavirus disease 2019 (COVID-19). However, the incidence of bleeding, predictors of major bleeding, or the association between bleeding and mortality remain largely unknown. METHODS: We performed a cohort study of patients hospitalized for COVID-19 that received intermediate or therapeutic doses of anticoagulants from March 25 to July 22, 2020, to identify those at increased risk for major bleeding. We used bivariate and multivariable logistic regression to explore the risk factors associated with major bleeding. RESULTS: During the study period, 1965 patients were enrolled. Of them, 1347 (69%) received intermediate- and 618 (31%) therapeutic-dose anticoagulation, with a median duration of 12 days in both groups. During the hospital stay, 112 patients (5.7%) developed major bleeding and 132 (6.7%) had non-major bleeding. The 30-day all-cause mortality rate for major bleeding was 45% (95% confidence interval [CI]: 36%-54%) and for non-major bleeding 32% (95% CI: 24%-40%). Multivariable analysis showed increased risk for in-hospital major bleeding associated with D-dimer levels >10 times the upper normal range (hazard ratio [HR], 2.23; 95% CI, 1.38-3.59), ferritin levels >500 ng/ml (HR, 2.01; 95% CI, 1.02-3.95), critical illness (HR, 1.91; 95% CI, 1.14-3.18), and therapeutic-intensity anticoagulation (HR, 1.43; 95% CI, 1.01-1.97). CONCLUSIONS: Among patients hospitalized with COVID-19 receiving intermediate- or therapeutic-intensity anticoagulation, a major bleeding event occurred in 5.7%. Use of therapeutic-intensity anticoagulation, critical illness, and elevated D-dimer or ferritin levels at admission were associated with increased risk for major bleeding.


Subject(s)
COVID-19 , Venous Thromboembolism , Anticoagulants/adverse effects , Cohort Studies , Humans , Retrospective Studies , SARS-CoV-2
12.
J Am Coll Cardiol ; 77(15): 1903-1921, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1235916

ABSTRACT

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.


Subject(s)
COVID-19/drug therapy , Fibrinolytic Agents/therapeutic use , Thromboembolism/prevention & control , COVID-19/complications , Humans , Randomized Controlled Trials as Topic , Thromboembolism/virology
13.
JAMA ; 325(16): 1620-1630, 2021 04 27.
Article in English | MEDLINE | ID: covidwho-1139203

ABSTRACT

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.


Subject(s)
Anticoagulants/administration & dosage , COVID-19/complications , Enoxaparin/administration & dosage , Extracorporeal Membrane Oxygenation , Oxygen Inhalation Therapy/methods , Thrombosis/prevention & control , Aged , Anticoagulants/adverse effects , COVID-19/mortality , Drug Administration Schedule , Enoxaparin/adverse effects , Female , Hemorrhage/chemically induced , Hospitalization , Humans , Intensive Care Units , Iran , Length of Stay/statistics & numerical data , Male , Middle Aged , Odds Ratio , Outcome Assessment, Health Care , Pulmonary Embolism/epidemiology , Thrombocytopenia/chemically induced , Thrombosis/etiology , Thrombosis/mortality , Treatment Outcome , Venous Thrombosis/epidemiology , Venous Thrombosis/mortality
14.
Thrombosis Update ; : 100029, 2020.
Article in English | ScienceDirect | ID: covidwho-989353

ABSTRACT

Background Hospitalized patients with COVID-19 and raised D-dimer levels have high rates of venous thromboembolism (VTE). Methods We used data from hospitalized patients with COVID-19 that were tested for pulmonary embolism (PE) or deep vein thrombosis (DVT) because of raised D-dimer levels. We aimed to identify patients at increased risk for VTE. Results From March 25 to July 5th 2020, 1,306 hospitalized patients with COVID-19 and raised D-dimer levels underwent testing for VTE in 12 centers. In all, 171 of 714 (24%) had PE, and 161 of 810 (20%) had DVT. The median time elapsed from admission to VTE testing was 12 days, and the median time from D-dimer measurement to testing 2 days. Most patients with VTE were men (62%), mean age was 62±15 years, 45% were in an intensive care unit. Overall, 681 patients (52%) received VTE prophylaxis with standard doses, 241 (18%) with intermediate doses and 100 (7.7%) with therapeutic doses of anticoagulants. On multivariable analysis, patients with D-dimer levels >20 times the upper normal range (19% of the whole cohort) were at increased risk for VTE (odds ratio [OR]: 3.24;95%CI: 2.18-4.83), as were those with a platelet count <100,000/μL (OR: 4.17;95%CI: 1.72-10.0). Conclusions Hospitalized patients with COVID-19 and D-dimer levels >20 times the upper normal range were at an increased risk for VTE. This may help to identify what patients could likely benefit from the use of higher than recommended doses of anticoagulants for VTE prophylaxis.

15.
Chest ; 159(3): 1182-1196, 2021 03.
Article in English | MEDLINE | ID: covidwho-950086

ABSTRACT

BACKGROUND: Individual studies have reported widely variable rates for VTE and bleeding among hospitalized patients with coronavirus disease 2019 (COVID-19). RESEARCH QUESTION: What is the incidence of VTE and bleeding among hospitalized patients with COVID-19? METHODS: In this systematic review and meta-analysis, 15 standard sources and COVID-19-specific sources were searched between January 1, 2020, and July 31, 2020, with no restriction according to language. Incidence estimates were pooled by using random effects meta-analyses. Heterogeneity was evaluated by using the I2 statistic, and publication bias was assessed by using the Begg and Egger tests. RESULTS: The pooled incidence was 17.0% (95% CI, 13.4-20.9) for VTE, 12.1% (95% CI, 8.4-16.4) for DVT, 7.1% (95% CI, 5.3-9.1) for pulmonary embolism (PE), 7.8% (95% CI, 2.6-15.3) for bleeding, and 3.9% (95% CI, 1.2-7.9) for major bleeding. In subgroup meta-analyses, the incidence of VTE was higher when assessed according to screening (33.1% vs 9.8% by clinical diagnosis), among patients in the ICU (27.9% vs 7.1% in the ward), in prospective studies (25.5% vs 12.4% in retrospective studies), and with the inclusion of catheter-associated thrombosis/isolated distal DVTs and isolated subsegmental PEs. The highest pooled incidence estimate of bleeding was reported for patients receiving intermediate- or full-dose anticoagulation (21.4%) and the lowest in the only prospective study that assessed bleeding events (2.7%). INTERPRETATION: Among hospitalized patients with COVID-19, the overall estimated pooled incidence of VTE was 17.0%, with higher rates with routine screening, inclusion of distal DVT, and subsegmental PE, in critically ill patients and in prospective studies. Bleeding events were observed in 7.8% of patients and were sensitive to use of escalated doses of anticoagulants and nature of data collection. Additional studies are required to ascertain the significance of various thrombotic events and to identify strategies to improve patient outcomes. TRIAL REGISTRY: PROSPERO; No.: CRD42020198864; URL: https://www.crd.york.ac.uk/prospero/.


Subject(s)
COVID-19 , Hemorrhage , Pulmonary Embolism , Venous Thromboembolism , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , COVID-19/blood , COVID-19/complications , COVID-19/epidemiology , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Humans , Incidence , Pulmonary Embolism/drug therapy , Pulmonary Embolism/epidemiology , Pulmonary Embolism/etiology , SARS-CoV-2 , Venous Thromboembolism/drug therapy , Venous Thromboembolism/epidemiology , Venous Thromboembolism/etiology
16.
Semin Thromb Hemost ; 47(4): 351-361, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-885548

ABSTRACT

Venous thromboembolism (VTE) is common in patients with coronavirus disease-2019 (COVID-19). However, limited data exist on patient characteristics, treatments, and outcomes. To describe the clinical characteristics, treatment patterns, and short-term outcomes of patients diagnosed with VTE during hospitalization for COVID-19. This is a prospective multinational study of patients with incident VTE during the course of hospitalization for COVID-19. Data were obtained from the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry. All-cause mortality, VTE recurrences, and major bleeding during the first 10 days were separately investigated for patients in hospital wards versus those in intensive care units (ICUs). As of May 03, 2020, a total number of 455 patients were diagnosed with VTE (83% pulmonary embolism, 17% isolated deep vein thrombosis) during their hospital stay; 71% were male, the median age was 65 (interquartile range, 55-74) years. Most patients (68%) were hospitalized in medical wards, and 145 in ICUs. Three hundred and seventeen (88%; 95% confidence interval [CI]: 84-91%) patients were receiving thromboprophylaxis at the time of VTE diagnosis. Most patients (88%) received therapeutic low-molecular-weight heparin, and 15 (3.6%) received reperfusion therapies. Among 420 patients with complete 10-day follow-up, 51 (12%; 95% CI: 9.3-15%) died, no patient recurred, and 12 (2.9%; 95% CI: 1.6-4.8%) experienced major bleeding. The 10-day mortality rate was 9.1% (95% CI: 6.1-13%) among patients in hospital wards and 19% (95% CI: 13-26%) among those in ICUs. This study provides characteristics and early outcomes of patients diagnosed with acute VTE during hospitalization for COVID-19. Additional studies are needed to identify the optimal strategies to prevent VTE and to mitigate adverse outcomes associated.


Subject(s)
COVID-19 , Heparin, Low-Molecular-Weight/administration & dosage , Hospital Mortality , Registries , Venous Thromboembolism , Adult , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/diagnosis , COVID-19/mortality , COVID-19/therapy , Female , Follow-Up Studies , Hemorrhage/etiology , Hemorrhage/mortality , Hemorrhage/therapy , Humans , Male , Middle Aged , Prospective Studies , SARS-CoV-2 , Venous Thromboembolism/diagnosis , Venous Thromboembolism/etiology , Venous Thromboembolism/mortality , Venous Thromboembolism/therapy
17.
Thromb Res ; 196: 382-394, 2020 12.
Article in English | MEDLINE | ID: covidwho-791550

ABSTRACT

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.


Subject(s)
Anticoagulants/administration & dosage , Atorvastatin/administration & dosage , COVID-19/drug therapy , Enoxaparin/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Thrombosis/prevention & control , Venous Thromboembolism/prevention & control , Anticoagulants/adverse effects , Atorvastatin/adverse effects , COVID-19/complications , COVID-19/diagnosis , Critical Illness , Double-Blind Method , Enoxaparin/adverse effects , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Iran , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Thrombosis/diagnosis , Thrombosis/etiology , Time Factors , Treatment Outcome , Venous Thromboembolism/diagnosis , Venous Thromboembolism/etiology
18.
J Am Coll Cardiol ; 75(23): 2950-2973, 2020 06 16.
Article in English | MEDLINE | ID: covidwho-547082

ABSTRACT

Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.


Subject(s)
Anticoagulants/pharmacology , Betacoronavirus/isolation & purification , Coronavirus Infections , Fibrinolytic Agents/pharmacology , Pandemics , Platelet Aggregation Inhibitors/pharmacology , Pneumonia, Viral , Thromboembolism , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Humans , Pneumonia, Viral/blood , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , SARS-CoV-2 , Thromboembolism/drug therapy , Thromboembolism/epidemiology , Thromboembolism/etiology , Thromboembolism/physiopathology , Treatment Outcome
19.
Thromb Haemost ; 120(7): 1004-1024, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-418767

ABSTRACT

Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.


Subject(s)
Coronavirus Infections/immunology , Fibrinolytic Agents/therapeutic use , Inflammation/drug therapy , Pneumonia, Viral/immunology , Thrombosis/drug therapy , Animals , Anti-Inflammatory Agents/therapeutic use , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Glycosaminoglycans/therapeutic use , Hemostasis , Humans , Inflammation/complications , Inflammation/immunology , Pandemics , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Thrombosis/complications , Thrombosis/immunology
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