Discussion
bleeding, thromboembolic, DVT, thrombotic, VTE
BLEEDING, MINOR, EVENT, DEEP VEIN THROMBOSES, ADVERSE EVENT, BLIND, EVENTS, COMPLICATIONS, DVT
This phase II pilot study showed that thromboprophylaxis with intermediate dose heparin with anti-FXa monitoring in patients with moderate or severe COVID-19 and moderately increased D-dimer was not associated with a higher risk of major bleeding compared to patients receiving standard dose prophylaxis. Indeed, there was only one major bleeding event in the interventional cohort in a subject on aspirin. Our results suggest that intermediate dose heparin with anti-FXa adjustment could be considered safe. Regarding efficacy assessment, although at the unadjusted analysis the rates of clinical improvement over study visits and the length of hospital stay were more favorable in the interventional group patients, their significance was reduced after the propensity score matching.Differently from the RAPID [Several other randomized clinical trials have been conducted evaluating increased subtherapeutic doses or intermediate dose of LMWH in comparison with standard dose prophylaxis such as the study by Perepu et al. [Several systematic reviews and meta-analyses have also been conducted to assess the efficacy and safety of intermediate/therapeutic in comparison with standard prophylactic doses in hospitalized patients with COVID-19 [Five-thousand four-houndred and five hospitalized patients with COVID-19 were analyzed in a meta-analysis including 8 randomized controlled trials. This meta-analysis showed a statistically significant reduction in the odds of development of thrombotic events in patients underwent to intermediate dose prophilaxis or to therapeutic anti-coagulation relative to ones underwent to prophylactic anticoagulation. However, the main problem was an increased risk of bleeding [A meta-analysis including 33 studies (31 observational, 2 RCT) for a total overall population of 32,688 patients showed that both prophylactic and full dose heparins reduced mortality. However, the full dose was associated with a higher risk of major bleeding compared to prophylactic dose [A Cochrane systematic review included seven RCT (16,185 participants) and showed little to no difference in all-cause mortality or DVT with higher dose UFH, LMWH or rivaroxaban when compared with standard thromboprophylaxis with higher risk of minor bleeding and a slightly higher risk of major bleeding [Finally, a systematic review including a total of 5470 patients from 9 RCTs showed that in hospitalized patients with COVID-19, high-dose thromboprophylaxis with either UFH or LMWH or fondaparinux is more effective than low-dose for the prevention of VTE but increases the risk of major bleeding [The most important results of the INHIXACOVID study appear to be the safety of intermediate dose heparin. anti-Xa adjustment led to a change of dosage in 30 patients and this seems to have increased the safety of intermediate dose heparin. No serious adverse event was correlated to the study drug.Regarding a potential favorable impact on COVID-19 course, although the length of hospitalization was lower in the interventional cohort compared to the observational cohort (median 13 vs. 14 days, The main limitation of this study is the lack of a randomized control group. However, at the time of trial design, a double blind randomized clinical trial was deemed not feasible, to limit the burden on extremely strained healthcare systems because of the pandemic, especially in Italy. Another limitation is the limited sample size with reduced statistical power and the lack of assessment of thromboembolic complications at 90 days of the patients of the observational cohort. Patient’s characteristics may have influenced the decision to enroll patients (selection bias). In addition, clinicians’ decisions to admit patients to ICU or treat them with non-invasive mechanical ventilation could have been influenced by knowledge of the allocated treatment (performance bias). Moreover, random variation could have been caused by the pandemic’s variable impact on hospital resources over time and across regions. Investigation or reporting of potential events (especially incidental deep vein thromboses or bleeding) in patients receiving intermediate heparin could have been less likely than events in patients receiving prophylactic heparin (detection bias). However, an independent clinical events committee blindly adjudicated all relevant outcomes based on clinical reports. Propensity score matching was employed to reduce or eliminate the effects of confounding when using observational data to estimate treatment effects and it was based on those variables which were different at baseline in the two cohorts.