By Kathryn Radigan, MD, MSc

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

SYNOPSIS: In a multicenter, randomized clinical trial of critically ill COVID-19 patients, intermediate-dose compared to standard-dose prophylactic anticoagulation did not result in significant differences in the rates of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days.

SOURCE: INSPIRATION Investigators, Sadeghipour P, Talasaz AH, Rashidi F, et al. 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. JAMA 2021;325:1620-1630.

Thrombotic complications are not uncommon in critically ill patients with COVID-19. The INSPIRATION investigators conducted a multicenter, randomized clinical trial that included 562 critically ill COVID-19 patients across Iran, with 10 enrolling centers in Tehran and Tabriz, between July 29 and Nov. 19, 2020. The trial had a 2 × 2 factorial design that compared intermediate-dose vs. standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs. matching placebo (second hypothesis; not addressed in this publication). Eligible patients were allocated in a 1:1 ratio. Enoxaparin was the primary anticoagulant agent in both groups. For patients weighing less than 120 kg and with a creatinine clearance greater than 30 mL/min, enoxaparin at 1 mg/kg daily was assigned as intermediate-dose anticoagulation. The control group standard-dose prophylactic anticoagulation regimen was enoxaparin 40 mg daily. Predefined modifications were advised according to body weight and creatinine clearance. In the case of severe kidney insufficiency, unfractionated heparin was used.

Patients admitted to the intensive care unit (ICU) with a polymerase chain reaction (PCR)-confirmed COVID-19 test within seven days of hospitalization were included in the trial, but patients with a life expectancy of less than 24 hours, an established indication for therapeutic-dose anticoagulation, weight less than 40 kg, pregnancy, history of heparin-induced thrombocytopenia, platelet count < 50 × 103/μL, or overt bleeding were excluded. The primary efficacy outcome was a composite of adjudicated acute venous thromboembolism (VTE), arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality within 30 days of enrollment. Secondary efficacy outcomes included all-cause mortality, adjudicated VTE, and ventilator-free days. 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 platelet count < 20 × 103/μL.

The primary analysis included 562 of 600 randomized patients (93.7%). The primary efficacy outcome of acute VTE, arterial thrombosis, ECMO treatment, or all-cause 30-day mortality 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% confidence interval [CI], −6.6% to 9.8%; odds ratio 1.06, 95% CI, 0.76-1.48; P = 0.70). Seven patients (2.5%) in the intermediate-dose group and four patients (1.4%) in the standard-dose prophylaxis group experienced major bleeding (risk difference 1.1%, one-sided 97.5% CI, − to 3.4%; odds ratio 1.83, one-sided 97.5% CI, 0.00-5.93), not meeting the noninferiority criteria (P for noninferiority > 0.99). Patients assigned to the intermediate-dose group were the only patients who experienced severe thrombocytopenia, defined as a platelet count < 20 × 103/μL (6 vs. 0 patients; risk difference 2.2%, 95% CI, 0.4%-3.8%; P = 0.01). These results fail to support the routine use of intermediate-dose prophylactic anticoagulation in critically ill COVID-19 patients.

COMMENTARY

More recently, the United States has reported more than 40 million COVID-19 cases and more than 600,000 deaths.1 It is now well-established that when patients are infected with COVID-19, they often experience profound inflammation with a coinciding prothrombotic state.2 A number of studies that included ICU patients early in the pandemic reported higher rates of VTE. These studies reported a broad range of VTE incidence (up to 42% in one study), with pulmonary embolism as the most common form, despite prophylactic-dose anticoagulation.3-5 A meta-analysis of studies in hospitalized patients with COVID-19 raised further concerns and found an overall VTE prevalence of 40.3% with ultrasound screening, 9.5% without screening. A subgroup analysis revealed an overall VTE prevalence of 22.7% in ICU patients.6 In light of these data, intermediate-dose prophylactic anticoagulation was proposed and often used in an attempt to reduce VTE and optimize mortality. This practice persisted in many institutions until this study reported that, compared with standard-dose, intermediate-dose prophylactic anticoagulation did not result in improved outcomes.

Although the INSPIRATION Investigators studied intermediate-dose vs. standard-dose prophylactic anticoagulation, the REMAP-CAP, ACTIV-4a, and ATTACC trials randomized severely ill hospitalized COVID-19 patients to therapeutic-dose anticoagulation vs. standard-dose prophylactic anticoagulation.7 The percentage of patients who survived to hospital discharge was similar in both anticoagulation strategy groups (62.7% and 64.5%, respectively; adjusted odds ratio, 0.84, 95% credible interval, 0.64 to 1.11). The investigators concluded that therapeutic-dose anticoagulation also was not beneficial.

Obesity is one of the strongest predictors of severe disease and mortality in COVID-19.8 Although the authors described the trial as a comparison between intermediate-dose and standard-dose thromboprophylaxis, it is important to note that the authors actually compared two weight-based low molecular-weight heparin (LMWH) thromboprophylaxis dosing protocols that differ between individuals < 120 kg and 120 kg. The dose of anticoagulation was escalated for patients who weighed > 120 kg or who had a body mass index (BMI) > 35 to enoxaparin 0.6 mg/kg twice daily in the intermediate-dose group and 40 mg twice daily in the standard-dose group. It also is important to note that the number patients weighing > 120 kg was very limited in the trial. For the REMAP-CAP, ACTIV-4a, ATTACC trials, investigators also escalated the dose of anticoagulation for patients with a BMI 40 or weight 120 kg. Although weight-based prophylaxis dosing is practiced by most, both trials specifically included two weight-based thromboprophylaxis dosing protocols that differ between individuals < 120 kg and 120 kg.

Although it is clear that anticoagulation was altered appropriately for the obese patients, the optimal dose of anticoagulation and whether this optimal dose is superior to standard-dose prophylactic anticoagulation remains unclear. As detailed, the researchers used an intermediate dose of anticoagulation, but why this regimen was chosen over other potential regimens is uncertain.9-11 The REMAP-CAP, ACTIV-4a, and ATTACC trials attempted to address these issues further and compared therapeutic anticoagulation and usual-care thromboprophylaxis anticoagulation. Unfortunately, these trials were limited in that a substantial majority of the patients who were enrolled in the severe-disease cohort were in the United Kingdom, where the national practice guidelines changed during the trial, and the usual-care thromboprophylaxis group was transformed to an intermediate-dose thromboprophylaxis group.12 As a result of these modifications and the fact that the method of standard prophylaxis was left to the physicians’ discretion, 22.4% of patients in the therapeutic-dose group did not receive a therapeutic dose, whereas 51.7% of the patients in the control group received intermediate-dose anticoagulation.

Even though the rates of VTE were noted to be higher early in the pandemic, and patients often were placed on higher doses of prophylactic anticoagulation as a result, a number of subsequent randomized trials did not consistently find that higher doses of prophylactic anticoagulation (both intermediate-dose and therapeutic-dose) resulted in a lower risk of VTE in critically ill patients. Instead, a number of trials observed a decline in rates of VTE, which was thought to be because of decreased severity of illness as a result of better knowledge on how to treat COVID-19 patients.13 Essentially, baseline VTE risk declined, and as a result, the number of events was lower than expected in both the standard-dose and higher-dose anticoagulation groups.

The most recent National Institutes of Health guidelines state, “There is currently insufficient evidence to recommend either for or against the use of thrombolytics or higher than the prophylactic dose of anticoagulation for VTE prophylaxis in hospitalized COVID-19 patients outside of a clinical trial.”14 Since the most recent update to these guidelines, it is worth mentioning that the REMAP-CAP, ACTIV-4a, and ATTACC trials recently found that non-critically ill COVID-19 patients treated with therapeutic-dose anticoagulation increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support compared with usual-care thromboprophylaxis.7 Further studies are needed to guide whether there are additional subgroups of COVID-19 patients that may benefit from higher-dose anticoagulation strategies. For now, until data support otherwise, prophylactic rather than higher doses of anticoagulation are recommended for critically ill COVID-19 patients.

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