In COVID-19 Pulmonary Embolism, Nontraditional Risk Factors Dominate

Risk factors for pulmonary embolism (PE) among patients with COVID-19 diverge from those traditionally observed, but that risk is attenuated by the use of therapeutic doses of anticoagulation at the time of hospitalization, according to observational data from France.

Prior smaller studies have highlighted the increased incidence of PE among COVID-19 patients, but little consensus has been reached regarding how and when anticoagulation should be initiated and at what dose.

“This study suggests that anticoagulation therapy with a therapeutic dose administered before admission or anticoagulation therapy with a prophylactic dose introduced during hospitalization could reduce the PE occurrence in accordance with the guidelines,” write Charles Fauvel, MD (Rouen University Hospital, France), and colleagues. “This result, together with the protective role of a short delay between onset of symptoms and hospitalization, reflects the importance of preventive treatment administered at the earliest opportunity.”

Commenting on the study for TCTMD, Jeffrey Kline, MD (Indiana University School of Medicine, Indianapolis), noted in an email that it “helps address a critical gap in knowledge about clots and the novel coronavirus, with an overarching finding that the prognosis of COVID-19 is worsened with coincident diagnosis of PE,” given the associated increase in risk for mechanical ventilation.

Nontraditional Risk Factors

Published online last week ahead of print in the European Heart Journal, the study included 1,240 patients hospitalized for COVID-19 among 24 French centers between February 26 and April 20, 2020. Overall, 103 (8.3%) were diagnosed with PE by computed tomography pulmonary angiography (CTPA).

Those with PE were more likely to be transferred to the ICU (31.1% vs 13.5%) and put on mechanical ventilation (24.3% vs 7.3%) compared with those without (P < 0.001 for both). Interestingly, PE occurrence did not appear to affect the risk of mortality (P = 0.338).

Univariate analysis pointed to male sex, history of stroke, history of A-fib, and the presence of chest pain or dyspnea as significant predictors of PE. Additionally, those who received anticoagulation (either a vitamin-K antagonist or non-vitamin K antagonist oral anticoagulant) with a therapeutic dose before admission (OR 0.40; 95% CI 0.14-0.91) or anticoagulation with a prophylactic dose introduced during hospitalization (OR 0.11; 95% CI 0.06-0.18) were less likely to experience PE—a finding that held up in multivariate analyses. However, traditional venous thromboembolic (VTE) risk factors including age, history of malignancy, history of venous thromboembolic disease, smoking, and obesity were not associated with PE incidence, nor were cardiovascular comorbidities like diabetes, hypertension, chronic heart failure, or CAD (P > 0.05 for all).

Multivariate analysis confirmed that male sex, a longer delay from symptom onset to hospitalization, and biomarker evidence of systemic inflammation were independent predictors of PE.

Confirms Need for Anticoagulation

Kline noted that the prevalence of PE here “was not strikingly high, perhaps even lower than has been observed pre-COVID-19 in French emergency department patients selected for imaging with computed tomographic pulmonary angiography.”

Also, while he acknowledged that “the study does not allow a true estimate of the independent risk of COVID-19,” it confirms that “either prophylactic or full dose anticoagulation help reduce the probability of PE in patients with probable COVID-19.”

In an accompanying editorial, Adam Torbicki, MD, PhD (Center of Postgraduate Medical Education, Otwock, Poland), says that “these data may help to limit one of the recently recognized cardiovascular complications of COVID-19 infection, complications which may have a significant influence on morbidity and mortality, ie pulmonary embolism. . . . So far indications for prophylaxis in COVID-19 infection have been supported mostly by data collected from severely ill ICU patients. The French study extended our knowledge to those patients who were initially stable.”

Torbicki agrees with the authors that the available evidence now suggests “immediate initiation of prophylactic anticoagulation in all hospitalized patients with COVID-19, regardless of the presence or absence of usual risk factors or of results of VTE risk scores. Moreover, in contrast to, for example, cancer patients, COVID-19 patients seem to represent relatively safe candidates for anticoagulation.”

What still remains unknown, he adds, is information regarding on bleeding complications, the effectiveness and safety of doubling the dose of primary prophylaxis or reaching therapeutic doses for preventive reasons, as well as the in-hospital course of infected patients.

“Despite knowledge gaps and lack of randomized controlled trials, there is little doubt that antithrombotic VTE protection should be recommended for hospitalized COVID-19 patients to reduce morbidity and mortality regardless of the presence or absence of classical risk factors for VTE,” Torbicki writes. “Whether the dose should be higher than usually recommended for prevention, whether we should adjust the doses to the objectively assessed level of heparin resistance, whether there is any role for new anticoagulants, and whether we should be concerned about drug interactions remain to be resolved by future prospective trials.”

Kline added that he would like to see “larger, prospectively designed registries that allow insight into timing of PE diagnosis and more detailed collection of symptoms that might distinguish patients with COVD-19 and PE and regional variations.”