Covid-19: Prophylactic-dose VTE Anticoagulation Associated with Lower 60-Day Mortality

In patients hospitalized with Covid-19, anticoagulation strategies for venous thromboembolism (VTE) were rapidly disseminated and implemented in a study of Michigan hospitals. However, only prophylactic-dose anticoagulation—and not treatment-dose anticoagulation—was associated with lower 60-day mortality, leading researchers to conclude that prophylactic dosing strategies may be best in these patients.

“Venous thromboembolism (VTE) has been a leading complication of Covid-19. Early publications of high VTE rates likely influenced clinical practice related to VTE prophylactic- and treatment-dose anticoagulation. First, there has been a concerted emphasis on VTE prophylaxis for hospitalized patients with Covid-19. Second, many experts have advocated for escalating doses of prophylactic anticoagulation for some patients hospitalized with Covid-19,” wrote Valerie M. Vaughn, MD, MSc, of the University of Utah, Salt Lake City, and colleagues in JAMA Network Open.

In a study from 2020, researchers demonstrated the benefits on mortality of treatment- or prophylactic-dose anticoagulation. In addition, preliminary findings from two recent clinical trials documented a decrease in combined in-hospital mortality and organ support free days when treatment-dose anticoagulation was used in patients hospitalized outside of intensive care.

Vaughn and fellow researchers sought to better identify the use of VTE prophylaxis and anticoagulation in patients hospitalized for Covid-19, and measure frequency of use, variations from hospital to hospital, and changes over time.

They used a pseudorandom sample of 1,351 patients (median age: 64 years; 47.7% women; 48.9% Black) from 30 hospitals throughout Michigan. Patients were those who had been hospitalized between March 7, 2020, and June 17, 2020.

Median length of hospital stay was 6 days, and 30.3% received intensive care during this time. Older patients, and those with a longer length of stay, more comorbidities, more severe disease, more Covid-directed treatments, and higher inflammatory markers such as ferritin were more likely to receive more intensive anticoagulation. Only 12.0% of patients were given no prophylactic- or treatment-dose anticoagulation during hospitalization.

Patients in the ICU were almost three times more likely to receive treatment-dose anticoagulation compared with patients under general care (31.1% versus 9.8%, respectively; P<0.001). Most of these patients did not undergo VTE diagnostic imaging, and this varied throughout the hospitals, from 0% to 29%, and increased over time from 4% during week 1, to 57% by week 13 (aOR: 1.46; 95% CI: 1.31-1.61 per week; P<0.001).

In all, 1.3% of patients had confirmed VTE, but 16.2% received treatment-dose anticoagulation, the most common of which were intravenous unfractionated heparin, subcutaneous low molecular weight heparin, and oral apixaban. (The most common prophylactic regimens used were subcutaneous heparin or enoxaparin injections.) Among these patients (n=1,127), 34.8% missed two or more days of prophylaxis. Across hospitals, missed prophylaxis varied, from 11% to 61%, and decreased significantly over time (aOR: 0.89; 95% CI: 0.82-0.97 per week).

Sixty-day VTE events occurred in 3.6% of patients, and 70.8% experienced this VTE during hospitalization. Among patients who received no anticoagulation, none had a 60-day VTE even, while 1.7% of those treated with prophylactic-dose, and 14.6% of those treated with treatment-dose anticoagulation did.

In all, 18.3% of patients died during hospitalization, and 23.2% died within 60 days of hospitalization.

Vaughn and colleagues also found that nonadherence to VTE was associated with higher 60-day but not in-hospital mortality. Receiving any dose of anticoagulative treatment was associated with lower in-hospital mortality (only prophylactic dose: aHR: 0.36; 95% CI: 0.26-0.52; and treatment dose: aHR: 0.38; 95% CI: 0.25-0.58).

But importantly, they also found that only the prophylactic dose of anticoagulation was still associated with lower mortality at 60 days (prophylactic dose: aHR: 0.71; 95% CI: 0.51-0.90; treatment dose: aHR: 0.92; 95% CI: 0.63-1.35).

“Our findings have important implications. First, more data from randomized trials are needed on long-term outcomes of treatment-dose anticoagulation in patients without a confirmed VTE diagnosis. Second, VTE prophylaxis in patients with Covid-19 is standard of care. Hospitals should implement processes to ensure use of VTE prophylaxis for hospitalized patients with Covid-19. Finally, the variable and increasing use of treatment-dose anticoagulation raises concerns especially given the lack of an association with 60-day mortality,” wrote Vaughn et al.

“We need better methods to risk stratify and diagnose patients with VTE and a stronger evidence-base on which to decide when to employ prophylactic vs therapeutic doses of anticoagulation for patients hospitalized with Covid-19. Participation in ongoing clinical trials will help identify whether any patient groups may benefit from therapeutic doses of anticoagulation. Otherwise, given the lack of mortality difference between groups, judicious therapeutic dosing may be necessary,” they concluded.

Data on the mortality benefits of prophylactic treatment for VTE are surprisingly lacking, noted Andrew B. Dicks, MD, and Ido Weinberg, MD, both of the Fireman Vascular Center, Massachusetts General Hospital, Boston, in an accompanying editorial.

“We know from many studies that pharmacological thromboprophylaxis reduces the risk of hospital-associated VTE in acutely ill hospitalized patients. However, and perhaps surprisingly, there are limited data to support a mortality benefit from VTE prophylaxis in this population. Aside from 1 study published almost 40 years ago that suggested a mortality benefit, most studies do not demonstrate a mortality benefit,” they wrote.

Thus, these results from Vaughn and colleagues are welcomed.

“Despite the limitations, this study (especially in the context of other published data) should make clinicians more confident that the use of prophylactic anticoagulation is warranted for hospitalized patients with Covid-19, as currently suggested by published societal guidelines. We eagerly await randomized trial data, while secretly hoping that by the time these are published, we will have little need for their conclusions,” they concluded.

Study limitations include its retrospective design and incomplete use of diagnostic VTE testing, lack of bleeding outcomes, treatment classification limitations, and increases in anticoagulation and decrease in mortality over time leading to possible residual confounding.

1. Use of only prophylactic- or treatment-dose anticoagulation was associated with lower in-hospital mortality compared with no anticoagulation in patients hospitalized with Covid-19.

2. Only prophylactic-dose anticoagulation was associated with lower mortality at 60 days.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Cat ID: 925

Topic ID: 915,925,728,932,730,933,309,118,190,926,192,927,151,928,925,934