**3.2 Patients hospitalised for COVID-19**

All patients hospitalised with COVID-19 should receive prophylactic dose antithrombotic therapy with low-molecular-weight heparin unless contraindicated (e.g. active bleeding or severe thrombocytopenia) [7, 26]. Low-molecular-weight (LMW) heparin is preferred, but unfractionated heparin may be used if LMW heparin is not available or if renal function is severely impaired (creatinine clearance <30 ml/min). Individuals with a history of heparin-induced thrombocytopenia (HIT) or active HIT should not receive low-molecular-weight heparin or unfractionated heparin; instead, Fondaparinux is advised. Aspirin is not indicated outside the usual standard

#### *COVID-19 and Thrombosis: Pathophysiological Mechanisms and Therapeutic Update DOI: http://dx.doi.org/10.5772/intechopen.102834*

indications [7, 26]. Patients chronically receiving anticoagulant or antiplatelet therapies for underlying conditions should continue these medications unless they have a bleeding or contraindication to them. In patients on chronic anticoagulant therapy, heparin is preferable to oral anticoagulants because of its shorter half-life, the possibility of intravenous or subcutaneous administration, and the reduced presence of drug interactions [26]. In addition, it has antithrombotic, anti-inflammatory and possibly antiviral properties [27].

In the case of suspected venous thromboembolic disease in patients with COVID-19, the recommendations proposed by the scientific societies for any patient with suspected and confirmed thrombotic disease should be followed [7, 26]. For most hospitalised patients with COVID-19, prophylactic dosing is supported. However, following the publication of several large and well-conducted randomised trials, the relative benefits of prophylactic, intermediate or therapeutic dosing continue to generate debate [28]. This is partly due to the increased risk of bleeding attributed to intermediate and therapeutic regimens [29].

Within inpatients, we differentiate those with moderate/non-critical illness from those with critical illness.

#### *3.2.1 Moderately ill or non-critically ill patients*

Patients with moderate/non-critical illness are those with clinical features that would normally result in admission to an inpatient ward without the need for advanced clinical support in intensive care unit (ICU). Examples include patients with mild to moderate dyspnoea or hypoxia [5, 21]. In recent months, several randomised clinical trials (ACTIV-4, REMAP-CAP and ATTACC, RAPID and HEP COVID) have shown that in non-critically ill hospitalised patients with COVID-19, heparin at therapeutic doses may be beneficial, with a high probability of reducing the need for organ support and progression to intubation and death [26, 30, 31]. Other trials, however (ACTION, BEMICOP), found no benefit in therapeutic versus prophylactic dosing [32, 33]. The multi-platform randomised clinical trial (ACTIV-4, REMAP-CAP and ATTACC) showed that in non-critically ill hospitalised patients with COVID-19, an initial strategy of therapeutic anticoagulation with heparin increased the likelihood of survival to hospital discharge with a reduced need for ICU-level organ support at 21 days compared with usual care thromboprophylaxis. Therapeutic dose anticoagulation was beneficial regardless of the patient's baseline D-dimer level. Therapeutic anticoagulation was administered according to local protocols for the treatment of acute venous thromboembolism for up to 14 days or until recovery. The need for organ support was defined as the need for high-flow nasal oxygen, invasive or non-invasive mechanical ventilation, vasopressor therapy or extracorporeal membrane oxygenation (ECMO) [30]. A subsequent randomised clinical trial (RAPID) demonstrated that the use of therapeutic heparin in moderately ill patients with COVID-19 and increased D-dimer levels (above the upper limit set by the local laboratory) were not associated with a significant reduction in the primary composite outcome of death, non-invasive or invasive mechanical ventilation, or ICU admission. However, it decreased the probability of death at 28 days and showed a low risk of haemorrhage [31]. Finally, in the randomised HEP-COVID clinical trial, therapeutic-dose LMWH in hospitalised COVID-19 patients with D-dimer levels at least four times the upper limit of normal reduced the outcome of thromboembolism and death at 30 days compared with standard heparin thromboprophylaxis, without increasing the risk of major bleeding [34]. The effectiveness

of anticoagulation appears to depend on the type of anticoagulant; for example, the Coronavirus Anticoagulation Trial (ACTION) used 15–20 mg rivaroxaban in 94% of patients assigned to therapeutic anticoagulation and found no benefit [32]. Finally, the randomised controlled clinical trial BEMICOP randomised adult patients with non-critical COVID and elevated D-dimer to receive heparin at therapeutic versus prophylactic doses for 10 days; however, the use of a short course of heparin at therapeutic doses did not improve the primary outcome (death, death in the intensive care unit), intensive care unit admission, need for mechanical ventilation support, the development of moderate/severe acute respiratory distress and venous or arterial thrombosis) over the subsequent 10 days compared with the use of heparin at a prophylactic dose [33].

In view of the discordance in different clinical trials, recent meta-analyses have attempted to clarify whether higher dosing (intermediate or therapeutic) could be of benefit over prophylactic dosing. Both groups of studies, the ones that included cohort studies and clinical trials [35], as well as those that included only randomised clinical trials [24, 28], have shown that higher anticoagulation dose (intermediate or therapeutic) is not associated with lower in-hospital mortality or incidence of thrombotic events, but increases the risk of bleeding events. There is currently insufficient evidence of survival benefit of therapeutic or intermediate dose anticoagulation compared with prophylactic dose anticoagulation in hospitalised patients with COVID-19.

The meta-analysis by Jorda et al. [24] included 10 randomised controlled openlabel trials with a total of 5753 patients. The risk of death was similar between therapeutic dose versus prophylactic dose anticoagulation (RR 0.92, 95% CI 0.69–1.21, P = 0.54) and between intermediate dose versus prophylactic dose anticoagulation (RR 1.01, 95% CI 0.63–1.61, P = 0.98). In patients with markedly increased D-dimer levels, higher-dose anticoagulation was also not associated with a lower risk of death compared with prophylactic dose anticoagulation (RR 0.86, 95% CI 0.64–1.16, P = 0.34). In the meta-analysis by Ortega Paz L et al. [28] including seven randomised controlled trials with 5154 patients, prophylactic dose-escalated anticoagulation was not associated with a reduction in all-cause death [17.8% vs. 18.6%, hazard ratio (HR) 0.96, 95% confidence interval (CI) 0.78–1.18], but was associated with an increase in major haemorrhage.

In conclusion, the literature that has so far been published provides evidence for the use of prophylactic anticoagulation at standard doses over a dose-escalating regimen in routine care for patients hospitalised for COVID-19, irrespective of disease severity. There may be a subgroup of patients with moderate disease where heparin at therapeutic doses may be beneficial; however, further studies are needed to define this subgroup of patients.

## *3.2.2 Severely ill/critically ill patients*

Patients with severe/critical COVID-19-related illness are those requiring respiratory or cardiovascular support (oxygen *via* high-flow nasal cannula, non-invasive or invasive mechanical ventilation, extracorporeal life support, vasopressors or inotropes) usually in an intensive care unit [5]. For thromboprophylaxis in critically ill hospitalised COVID-19 patients, prophylactic dosing is recommended rather than more intensive (intermediate or therapeutic) dosing. Randomised trials published to date have not consistently demonstrated better outcomes with more intensive dosing in critically ill patients, but have found an association with a higher likelihood of side effects (bleeding) and most institutions have adopted prophylactic dosing

### *COVID-19 and Thrombosis: Pathophysiological Mechanisms and Therapeutic Update DOI: http://dx.doi.org/10.5772/intechopen.102834*

standards [7]. In the multi-platform ACTIV-4, REMAP-CAP and ATTACC study, a parallel analysis of the same trial mentioned above, in patients with COVID-19 critical illness, empirical anticoagulation at therapeutic doses was not beneficial in this group of patients [8]. Nor did heparin at anticoagulant doses show benefit in the group of critically ill patients in the HEP-COVID study [34]. The randomised clinical trial (INSPIRATION) in critically ill patients with COVID-19 showed no benefit of intermediate-dose heparin either [36]. Patients with COVID-19 who require ECMO or continuous renal replacement therapy or who have catheter or extracorporeal filter thrombosis should be treated according to standard institutional protocols for non-COVID-19 patients [26].
