Increasing Doses of Anticoagulation Are Associated with Improved Survival in Hospitalized COVID-19 Patients

Background: Hypercoagulability may contribute to COVID-19 pathogenicity. Evidence comparing clinical outcomes among patients with COVID-19 receiving therapeutic compared to prophylactic dose anticoagulation is limited. We evaluated whether therapeutic anticoagulation (tAC) is associated with improved survival compared to prophylactic (pAC) and no anticoagulation (AC) in hospitalized COVID-19 patients. Methods: This was a retrospective, multi-center cohort study of consecutive COVID-19 patients admitted between March 13th, 2020 and May 5th, 2020 to eight hospitals within a large academic system in Southeast Michigan, USA. Participants were assigned to three groups based on whether they received no AC, pAC throughout most of their hospitalization, or at least 3 days of tAC. Major bleeding was defined as transfusion of five or more units of packed red blood cells within 48 hours regardless of hemoglobin level, hemoglobin < 7g/dL and any red blood cell transfusion or a diagnosis code for major bleeding during the hospitalization or radiological evidence of intracranial hemorrhage Results: A total of 3480 patients were included (mean age, 64.5 years [17.0]; 51.5% female; 52.1% black and 40.6% white). 18.5% (n=642) were treated in the intensive care unit (ICU). 60.9% received pAC (n=2121), 28.7% received at least 3 days of tAC (n=998), and 10.4% (n=361) did not receive AC. Propensity score (PS) weighted Kaplan-Meier plot demonstrated a statistical difference in the 25-day survival probability in the tAC group compared to the pAC group (57.5% vs 50.7%, Figure). In a PS weighted multivariate proportional hazards model adjusting for age, body mass index and ICU status, AC was associated with a reduced risk of death at both prophylactic (hazard ratio [HR] 0.35 [95% confidence interval {CI} 0.22-0.54]) and therapeutic doses (HR 0.14 [95% CI 0.05-0.23]) compared to no AC. Major bleeding occurred more frequently among tAC patients (81 [8.1%]) compared to those who received no AC (20 [5.5%]) or pAC (46 [2.2%]). Conclusions : Higher doses of AC are associated with lower mortality in hospitalized COVID-19 patients. The lowest hazard ratio was observed in ICU patients, but risk was also significantly lower in non-ICU hospitalized patients. Bleeding occurred more frequently with higher doses of anticoagulation. Ongoing randomized trials are warranted to prospectively evaluate efficacy and risk of tAC in patients with COVID-19. Figure Disclosures No relevant conflicts of interest to declare.

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Dementia Adjudication Triggers Associated With Increased Mortality for Older Australians: Evidence From ASPREE

Innovation in Aging ◽

10.1093/geroni/igaa057.523 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 161-161

Author(s):

Jane Banaszak-Holl ◽

Xiaoping Lin ◽

Jing Xie ◽

Stephanie Ward ◽

Henry Brodaty ◽

...

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

The Elderly ◽

Cox Proportional Hazards ◽

Service Planning ◽

Cox Proportional Hazards Model ◽

Cognitive Test ◽

Risk Of Death ◽

Hazards Model ◽

Using Data

Abstract Research Aims: This study seeks to understand whether those with dementia experience higher risk of death, using data from the ASPREE (ASPirin in Reducing Events in the Elderly) clinical trial study. Methods: ASPREE was a primary intervention trial of low-dose aspirin among healthy older people. The Australian cohort included 16,703 dementia-free participants aged 70 years and over at enrolment. Participants were triggered for dementia adjudication if cognitive test results were poorer than expected, self-reporting dementia diagnosis or memory problems, or dementia medications were detected. Incidental dementia was adjudicated by an international adjudication committee using the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV) criteria and results of a neuropsychological battery and functional measures with medical record substantiation. Statistical analyses used a cox proportional hazards model. Results: As previously reported, 1052 participants (5.5%) died during a median of 4.7 years of follow-up and 964 participants had a dementia trigger, of whom, 575 (60%) were adjucated as having dementia. Preliminary analyses has shown that the mortality rate was higher among participants with a dementia trigger, regardless of dementia adjudication outcome, than those without (15% vs 5%, Χ2 = 205, p <.001). Conclusion: This study will provide important analyses of differences in the hazard ratio for mortality and causes of death among people with and without cognitive impairment and has important implications on service planning.

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Modelling heterogeneity in survival data

Journal of Applied Probability ◽

10.1017/s0021900200042534 ◽

1991 ◽

Vol 28 (03) ◽

pp. 695-701 ◽

Cited By ~ 11

Author(s):

Philip Hougaard

Keyword(s):

Survival Data ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Mixture Distribution ◽

Survival Models ◽

Risk Of Death ◽

Hazards Model ◽

Occupational Mortality ◽

Heterogeneity Distribution ◽

Biased Estimates

Ordinary survival models implicitly assume that all individuals in a group have the same risk of death. It may, however, be relevant to consider the group as heterogeneous, i.e. a mixture of individuals with different risks. For example, after an operation each individual may have constant hazard of death. If risk factors are not included, the group shows decreasing hazard. This offers two fundamentally different interpretations of the same data. For instance, Weibull distributions with shape parameter less than 1 can be generated as mixtures of constant individual hazards. In a proportional hazards model, neglect of a subset of the important covariates leads to biased estimates of the other regression coefficients. Different choices of distributions for the unobserved covariates are discussed, including binary, gamma, inverse Gaussian and positive stable distributions, which show both qualitative and quantitative differences. For instance, the heterogeneity distribution can be either identifiable or unidentifiable. Both mathematical and interpretational consequences of the choice of distribution are considered. Heterogeneity can be evaluated by the variance of the logarithm of the mixture distribution. Examples include occupational mortality, myocardial infarction and diabetes.

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G CSF association with prolonged survival in HIV infected patients with disseminated Mycobacterium avium complex infection

International Journal of STD & AIDS ◽

10.1258/0956462981922476 ◽

1998 ◽

Vol 9 (7) ◽

pp. 394-399 ◽

Cited By ~ 11

Author(s):

Philip Keiser ◽

Steven Rademacher ◽

James Smith ◽

Daniel Skiest

Keyword(s):

Mycobacterium Avium ◽

Mycobacterium Avium Complex ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Cd4 Count ◽

Risk Of Death ◽

Hazards Model

Summary: Clarithromycin can ameliorate symptoms and improve survival in disseminated Mycobacterium avium complex DMAC infection. Optimal combina tions of this drug with other agents remain unknown. Granulocyte colony stimulating factor G CSF is a cytokine that can improve phagocytosis of M. avium complex in vitro . We aim to determine if G CSF administration is associated with improved survival in patients with DMAC in a retrospective, cohort study. Case records from 1991 to 1995 of 91 patients with DMAC at Parkland Memorial Hospital were reviewed for date of initial DMAC diagnosis, baseline CD4 count, race, sex, antiretroviral use, G CSF use, therapy for DMAC clarithromycin, ethambutol, ciprofloxacin and rifabutin and date of death. Of 91 cases identified, 25 were treated with G CSF and 66 never received this drug. Baseline characteristics were similar in each group including CD4 count 40 cells mm 3 vs 33 cells mm 3, P =0.68 , clarithromycin use 18 patients vs 52 patients, P =0.90 , and antiretroviral use 20 patients vs 42 patients, P =0.21 . Subjects treated with G CSF lived longer than those who did not receive this drug 355 days vs 211 days, P 0.01 . In the subgroup treated with clarithromycin, G CSF was also associated with increased survival 377 days vs 252 days, P 0.01 . Cox proportional hazards model showed a decreased risk of death in patients treated with G CSF RH=0.22, P 0.01 , clarithromycin RH=0.13, P 0.01 and ethambutol RH=0.51, P =0.02 . Ciprofloxacin and rifabutin use did not influence survival. These data support the use of clarithromycin and ethambutol in the treatment of DMAC. Addition of G CSF to a regimen of clarithromycin and ethambutol may increase survival in DMAC and should be studied prospectively.

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Prognostic indicators of secondary progression in a paediatric-onset multiple sclerosis cohort in Kuwait

Multiple Sclerosis Journal ◽

10.1177/1352458515608960 ◽

2015 ◽

Vol 22 (8) ◽

pp. 1086-1093 ◽

Cited By ~ 4

Author(s):

Saeed Akhtar ◽

Raed Alroughani ◽

Samar F Ahmed ◽

Jasem Y Al-Hashel

Keyword(s):

Multiple Sclerosis ◽

Confidence Interval ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Cox Proportional Hazards Model ◽

Adjusted Hazard Ratio ◽

Secondary Progressive ◽

Hazards Model

Background: The frequency of paediatric-onset multiple sclerosis (POMS) and the precise risk of secondary progression of disease are largely unknown in the Middle East. This cross-sectional cohort study assessed the risk and examined prognostic factors for time to onset of secondary progressive multiple sclerosis (SPMS) in a cohort of POMS patients. Methods: The Kuwait National MS Registry database was used to identify a cohort of POMS cases (diagnosed at age <18 years) from 1994 to 2013. Data were abstracted from patients’ records. A Cox proportional hazards model was used to evaluate the prognostic significance of the variables considered. Results: Of 808 multiple sclerosis (MS) patients, 127 (15.7%) were POMS cases. The median age (years) at disease onset was 16.0 (range 6.5–17.9). Of 127 POMS cases, 20 (15.8%) developed SPMS. A multivariable Cox proportional hazards model showed that at MS onset, brainstem involvement (adjusted hazard ratio 5.71; 95% confidence interval 1.53–21.30; P=0.010), and POMS patient age at MS onset (adjusted hazard ratio 1.38; 95% confidence interval 1.01–1.88; P=0.042) were significantly associated with the increased risk of a secondary progressive disease course. Conclusions: This study showed that POMS patients with brainstem/cerebellar presentation and a relatively higher age at MS onset had disposition for SPMS and warrant an aggressive therapeutic approach.

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Early Hb Response to ESA Treatment May Be An Indicator of Better Survival Prognosis

Blood ◽

10.1182/blood.v112.11.4587.4587 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4587-4587

Author(s):

Jesse A Berlin ◽

Peter Bowers ◽

Sudhakar Rao ◽

Suresh Aravind ◽

Steven Sun ◽

...

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

Performance Status ◽

Epoetin Alfa ◽

Survival Prognosis ◽

Risk Of Death ◽

Hazards Model ◽

Kaplan Meier ◽

Increased Risk ◽

Baseline Covariates

Abstract Chemotherapy induced anemia patients who respond to ESA treatment have hemoglobin increases within 4–8 weeks. Patients with inadequate Hb response after several weeks treatment often have their ESA dose escalated.. We conducted an exploratory analysis to test the hypothesis that safety outcomes in randomized studies of epoetin alfa might differ depending on the Hb response after 4–8 weeks of treatment. Methods: The analysis compared the survival across subsets of epoetin-alfa treated patients. Specifically, a landmark analysis was used, which defines a hemoglobin responder at a pre-specified point in time (in this case 4 & 8 weeks post treatment), and then examines survival subsequent to that point in time.Patients were categorized as “Hb responder” when their Hb increased by >0.5 g/dL; “Hb stable” when Hb change within ≤ 0.5g/dL; “Hb non-responder” when the Hb decreased >0.5 g/dL, compared to the value prior to epoetin-alfa treatment. Survival was estimated using the Kaplan-Meier method and comparisons were made between the responders and non-responders versus the stable group. Cox’s proportional hazards model was used to adjust for the following baseline covariates: hemoglobin prior to treatment, baseline performance status, and advanced disease at baseline. All analyses were stratified by study to account for any differences in the study populations and study conduct. Results: These exploratory findings suggest the possibility that patients identified as non-responders to ESAs after 4 or 8 weeks of ESA treatment may be at increased risk of death, and that this effect is most pronounced in the studies that treated patients beyond the correction of anemia. Although these analyses were adjusted for several key baseline covariates, it is unclear whether these effects result from treatment, or whether patients who fail to respond to epoetin alfa are inherently at increased risk of death (e.g., due underlying malignancy), regardless of their treatment status.

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Clinical Evaluation of the European LeukemiaNet Criteria for Resistance/Intolerance to Hydroxyurea In Essential Thrombocythemia

Blood ◽

10.1182/blood.v116.21.4086.4086 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4086-4086

Author(s):

Carles Besses ◽

Alberto Alvarez-Larrán ◽

Montserrat Gómez ◽

Anna Angona ◽

Paula Amat ◽

...

Keyword(s):

Platelet Count ◽

Essential Thrombocythemia ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Leg Ulcers ◽

Risk Of Death

Abstract Abstract 4086 Definition of resistance/intolerance to hydroxyurea (HU) in essential thrombocythemia (ET) has been proposed by the European LeukemiaNet (ELN) however its clinical utilility has not been validated yet. We have retrospectively evaluated such criteria in 166 ET patients treated with HU for a median of 4.5 years. Response to HU treatment was categorized using the ELN criteria. The ELN definitions of resistance/intolerance to HU required the fulfillment of at least one of the following criteria: platelet count greater than 600 × 109/L after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight over 80 kg); platelet count greater than 400 × 109/L and leukocytes less than 2.5 × 109/L or hemoglobin (Hb) less than 100 g/L at any dose of HU; presence of leg ulcers or other unacceptable mucocutaneous manifestations at any dose of HU; HU-related fever. Survival and time-to-event curves were estimated using the Kaplan-Meier method.Variab les attaining a significant level at the univariate analysis were included in a Cox proportional hazards model. Overall, 134 patients achieved a complete clinicohematologic response (CR) and 25 a partial response. Thirty-three patients met at least one of the ELN criteria defining resistance (n=15) or intolerance (n=21) to HU. Fifteen cases developed anemia with thrombocytosis. Other definitions of resistance were less useful. When compared with the others, resistant patients were more likely to display hyperproliferative features at ET diagnosis, such as higher levels of leukocytes (p= 0.05), platelets (p=0.004) and serum LDH (p=0.02). Eleven patients developed leg ulcers leading to a permanent discontinuation of the drug in 8 cases. No distinctive clinical profile could be ascribed to patients exhibiting leg ulcers, with the exception of a high prevalence of cardiovascular risk factors. Other unacceptable mucocutaneous manifestations occurred in 9 patients. Hematologic and mucocutaneous complications were unrelated, with only two patients presenting both types of toxicities. With a median follow-up from ET diagnosis of 7 years (range: 0.5–23), 38 patients (23%) had died, resulting in a survival probability of 65% at 10 years from HU start. The risk of death from any cause was increased by 6.2-fold (95%CI: 2.3–16.7, P<0.001) in patients who met any of the ELN criteria of resistance to HU. Anemia was in all instances the first finding qualifying for resistance to HU, with the median subsequent survival of patients with anemia being only 2.4 years (range, 0.01–4.9). A remarkable incidence of myelofibrosis was observed in patients fulfilling the ELN criteria for resistance, since this complication was recorded in 7 of 15 such cases (p>0.001). In conclusion, the best discriminating ELN criterion of resistance to HU is based on the detection of anemia. Moreover, such criterion is particularly useful since it also identifies a subset of ET patients with a poor prognosis. Disclosures: No relevant conflicts of interest to declare.

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A Non‐Proportional Hazards Model with Hazard Ratio Functions Free from Covariate Values

International Statistical Review ◽

10.1111/insr.12364 ◽

2020 ◽

Vol 88 (3) ◽

pp. 715-727

Author(s):

Anthony Y. C. Kuk

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

Hazard Ratio ◽

Hazards Model

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Survival of Red Maasai, Dorper and crossbred lambs in the sub-humid tropics

Animal Science ◽

10.1017/s1357729800053261 ◽

2003 ◽

Vol 76 (1) ◽

pp. 3-17 ◽

Cited By ~ 13

Author(s):

R. Nguti ◽

P. Janssen ◽

G.J. Rowlands ◽

J.O. Audho ◽

R.L. Baker

Keyword(s):

Body Weight ◽

Standard Error ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Survival Rates ◽

Risk Of Death ◽

Intestinal Nematode ◽

Hazards Model ◽

Faecal Egg Count ◽

Time Varying Covariates

AbstractThe survival rates of Dorper, Red Maasai and crossbred lambs born over a period of 6 years at Diani Estate, Coast Province, Kenya were compared using the Cox mixed proportional hazards model with a random (frailty) term for sire. Of the 1785 lambs born, proportionately 0·44 died before they were 1 year old. Almost half of these deaths occurred before weaning; a third were associated with mis-mothering and a fifth with gastro-intestinal nematode parasite (endoparasite) infections. Half of the deaths post weaning were associated with endoparasite infections, predominantly Haemonchus contortus. The Red Maasai lambs had a lower risk of death than the Dorper lambs with a relative hazard of 0·27 pre-weaning and 0·25 post weaning. Other crosses and back crosses had relative hazards in between these values and 1; there was no evidence of heterosis. Survival rates were different among years and appeared to be associated to some degree with variations in rainfall. There were highly significant effects of both birth weight and weaning weight on survival. Body weight, together with packed red cell volume and faecal egg count, were also introduced into the proportional hazard model as time-varying covariates. All three variables had major influences on survival. The risk of death over the following month in animals individually treated with an anthelmintic drug pre weaning was reduced by 0·61 compared with those not treated. The sire frailty variance estimate was similar to its standard error pre-weaning but larger post weaning. When adjusted for lamb body weight the sire variance post weaning increased to three times its standard error.

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Predictors of Survival After Surgical Treatment of Spinal Metastasis

Neurosurgery ◽

10.1227/neu.0b013e318207780c ◽

2011 ◽

Vol 68 (3) ◽

pp. 674-681 ◽

Cited By ~ 64

Author(s):

Robert T Arrigo ◽

Paul Kalanithi ◽

Ivan Cheng ◽

Todd Alamin ◽

Eugene J Carragee ◽

...

Keyword(s):

Charlson Comorbidity Index ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Spinal Metastasis ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Cox Proportional Hazards Model ◽

Ambulatory Status ◽

Hazards Model ◽

Comorbidity Index

Abstract BACKGROUND: Surgery for spinal metastasis is a palliative treatment aimed at improving patient quality of life by alleviating pain and reversing or delaying neurologic dysfunction, but with a mean survival time of less than 1 year and significant complication rates, appropriate patient selection is crucial. OBJECTIVE: To identify the most significant prognostic variables of survival after surgery for spinal metastasis. METHODS: Chart review was performed on 200 surgically treated spinal metastasis patients at Stanford Hospital between 1999 and 2009. Survival analysis was performed and variables entered into a Cox proportional hazards model to determine their significance. RESULTS: Median overall survival was 8.0 months, with a 30-day mortality rate of 3.0% and a 30-day complication rate of 34.0%. A Cox proportional hazards model showed radiosensitivity of the tumor (hazard ratio: 2.557, P < .001), preoperative ambulatory status (hazard ratio: 2.355, P = .0001), and Charlson Comorbidity Index (hazard ratio: 2.955, P < .01) to be significant predictors of survival. Breast cancer had the best prognosis (median survival, 27.1 months), whereas gastrointestinal tumors had the worst (median survival, 2.66 months). CONCLUSION: We identified the Charlson Comorbidity Index score as one of the strongest predictors of survival after surgery for spinal metastasis. We confirmed previous findings that radiosensitivity of the tumor and ambulatory status are significant predictors of survival.

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The Impact of Different Prophylactic Anticoagulation Doses on the Outcomes of Patients with COVID-19

Blood ◽

10.1182/blood-2020-142594 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-17

Author(s):

Rodolfo Jiménez-Soto ◽

Mercedes Aguilar-Soto ◽

Roberta Demichelis

Keyword(s):

Mechanical Ventilation ◽

Major Bleeding ◽

Lower Risk ◽

Conflicts Of Interest ◽

Risk Of Death ◽

Prophylactic Anticoagulation ◽

Therapeutic Doses ◽

The Impact ◽

Higher Doses ◽

D Dimer

Introduction As the COVID-19 pandemic spread throughout the world, it was seen that patients who presented with critical disease had a higher incidence of thrombotic complications, associated with a poor prognosis. Currently prophylactic anticoagulation is recommended for all patients with COVID-19 who require hospitalization as part of the supportive management. However, since a higher incidence of thrombosis despite prophylactic anticoagulation has been reported, some recommendations indicate that an increase to intermediate or therapeutic dosing should be considered. The full spectrum of complications and outcomes related to this strategy are still unknown. Methods We conducted a cross-sectional study using the COVID-19 registry of the ARMII study group, based in Centro Medico ABC, a private hospital in Mexico City. We included all patients admitted from March 12 to July 31, 2020, who received prophylactic anticoagulation at standard (enoxaparin 40mg QD), intermediate (0.5 mg/kg QD or 40 mg BID), or therapeutic doses (1mg/kg BID), a decision taken by the attending physician based on clinical and laboratory criteria. Patients with previous or presenting with thrombosis were excluded. We compared the three groups to identify baseline characteristics and conducted multivariable logistic regressions to measure the association of anticoagulation profiles and adverse outcomes. Results Out of total 322 patients, we identified 81 (25%) who received standard dose, 164 (51%) who received intermediate and 77 (24%) on therapeutic doses. Age and sex were distribuited similarly among groups; patients with intermediate and therapeutic doses were more overweight and obese, but this was not significant (p=0.052). On admission, patients who received intermediate and therapeutic doses had lower oximetry registry when compared with standard doses (89%, 88% and 92% respectively, p=0.008). Three severity scales, NEWS, MULBSTA and CALL, were higher in patients with intermediate and therapeutic doses (p=0.01, p=0.02 and p=0.005, respectively). Regarding laboratory values, patients on therapeutic doses had higher leucocytes on admission (median 6 x 109L, 6 and 8, p=0.05) but lower lymphocyte absolute counts (median 1240 cells/mm3, 935 and 920, p<0.001). Patients who were given higher doses of anticoagulation had higher levels of C-reactive protein, DHL, and ferritin (p<0.001) and higher levels of IL-6 (p=0.02). Levels of D-dimer were also higher in this group (p<0.001). Patients with therapeutic doses of anticoagulation were more likely to present major bleeding when compared to intermediate or standard prophylactic doses (9% vs 1% vs 0%, p=0.0006) and clinically relevant bleeding (12% vs 2% vs 5%, p=0.01). (Table 1) The incidence of pulmonary embolism (PE) in the entire cohort was 5%, while the incidence of major bleeding was 2.5%. There were no differences between the different doses of anticoagulation; no patients presented deep venous thrombosis. During follow-up, a total of 21 patients died, representing 6.5% of the study population. Independent factors that predicted death included age, CRP and D-dimer levels on admission, history of hypertension and requirement of mechanical invasive ventilation. When adjusting for these confounders, therapeutic anticoagulation was associated with a lower risk of death (OR 0.079 95% CI 0.008-0.76). When restricting the analysis for patients who required mechanical ventilation, anticoagulation was also associated with a lower risk of death (OR 0.031 95% CI 0.002-0.54) but not for intermediate doses (OR 0.10 95% CI 0.01-1.06). (Figure 1) Conclusions Anticoagulation might not play a causal role in the risk of requiring mechanical ventilation, but the decision to increase doses might reflect patients who present with more severe disease. In our cohort, the majority of the patients were receiving intermediate prophylactic doses and the incidence of PE is lower than in worldwide reports. Therapeutic doses of anticoagulation were not associated with a lower risk of PE, but were associated with lower risk of death. However, therapeutic doses were also associated with a higher risk of major and clinically significant bleeding. Randomized-controlled clinical trials are needed to understand the role of higher doses of prophylactic anticoagulation in COVID-19. Disclosures No relevant conflicts of interest to declare.

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