key: cord-0964030-z11gxxfh
authors: Huisman, Menno V.; Klok, Frederikus A.
title: First do no harm
date: 2022-04-14
journal: Res Pract Thromb Haemost
DOI: 10.1002/rth2.12694
sha: 21f76b9a3903bc7b67274fb850e671ec868aeea2
doc_id: 964030
cord_uid: z11gxxfh

nan

For prevention of thrombotic events in patients hospitalized because of COVID-19, low molecular weight heparin (LMWH) and unfractionated heparin are the rational anticoagulants of choice, given that the overall majority of thromboses are of venous origin. [1] [2] [3] In view of the high incidence of venous thromboembolism in ward and in intensive care unit (ICU) patients, a plethora of 75 studies have been registered since the start of the COVID pandemic. 4 The majority of these compared therapeutic doses, and to a lesser extent, intermediate doses, versus a standard prophylactic dosis of LMWH in two sets of hospitalized COVID-19 patients (i.e., ward patients who were named moderately or not critically ill and ICU patients). In this issue, Sholzberg et al. performed a meta-analysis supporting the potential benefit of therapeutic LMWH in moderately ill patients. 5 However, limitations in the trials of this meta-analysis exist, and this may lead to severe limitations when taken together. In the RAPID trial, evaluating therapeutic LMWH versus standard prophylactic LMWH in noncritically ill patients with COVID-19, the primary outcome showed no difference between the groups in the primary composite outcome, which were ICU admission, noninvasive or invasive mechanical ventilation, or death. 7 Surprisingly, a lower incidence of death, albeit with very wide confidence limits occurred in the therapeutic anticoagulation group at 28 days and, as surprisingly and seemingly counterintuitive, was a notable lower incidence of major bleeding in the patients receiving therapeutic anticoagulation.

In a so-called multiplatform, randomized clinical, data were combined from patients from the ACTIV-4a, a conventional randomized trial, and from patients of REMAP-CAP and ATTACC, two trials using a response-adaptive randomization. 8, 9 Allocation was to either therapeutic or standard thromboprophylaxis with heparin or LMWH (the latter used in >90% in both groups). In critically ill patients, therapeutic heparin or LMWH did not improve the primary outcome of days without organ support and was associated with more major bleeding complications than standard thromboprophylaxis (3.8% vs. 2.3%). In the moderately ill patients, therapeutic-dose heparin or LMWH appeared to increase the probability of survival until hospital discharge and a reduced need for organ support; more major bleeding also occurred with therapeutic heparin or LMWH than with thromboprophylaxis (1.9% vs. 0.9%) and the median number of organ support-free days was the same in both treatment arms. Two factors may have led to the flawed results of this platform endeavor. First, in the control group, nonconcurrent patients were included, leading to potential spurious effects in the intervention group. 10 dilution of benefit of therapeutic-dose anticoagulation. In the patients with moderate disease, 20.4% of the therapeutic-dose group did not receive a therapeutic dose, whereas 26.5% in the control group received an intermediate dose.

In the HEP-COVID study of highly selective ward or ICU COVID-19 patients, with high risk based on D-dimer levels more than four times upper limit of normal, 11 therapeutic heparin led to a reduction in the primary composite outcome, consisting of venous thromboembolism detected by screening imaging tests or by imaging upon symptoms, arterial thromboembolism, or death, compared with standard prophylaxis (41.9% vs. 28.7%), including a reduction in venous thromboembolism (29.0% vs. 10.9%). This, however, was at the cost of more major bleeding (4.7% vs. 1.6%).

The reduction in the primary endpoint was seen in non-ICU patients, but not in ICU patients. Taken together, these studies all 

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Risk of thrombotic complications in influenza versus COVID-19 hospitalized patients

Risk of venous thromboembolism in patients with COVID-19: a systematic review and meta-analysis

Recent randomized trials of antithrombotic therapy for patients with COVID-19: JACC state-of-the-art review

Randomized trials of therapeutic heparin for COVID-19: a meta-analysis

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

Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial

Therapeutic anticoagulation with heparin in critically ill patients with Covid-19

Therapeutic anticoagulation with heparin in noncritically ill patients with Covid-19

Platform trials -beware the noncomparable control group

Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: the HEP-COVID randomized clinical trial

First do no harm