Patients With Subsegmental Pulmonary Embolism Face Increased VTE Risk

You may want to think twice before skipping anticoagulants in patients with isolated single or multiple subsegmental pulmonary embolism, according to findings from the prospective, multicenter SubSegmental Pulmonary Embolism (SSPE) study, reported in Annals of Internal Medicine.

Marc Carrier, MD, MSc, of the Ottawa Hospital in Ottawa, Ontario, Canada, and colleagues explained that patients in this population who don’t have proximal deep venous thrombosis face a higher-than-expected risk of recurrent venous thromboembolism (VTE). That finding contradicts previous observational, retrospective studies suggested that some patients with subsegmental pulmonary embolism—i.e., no pulmonary embolism in segmental or more proximal blood vessels—experience low rates of VTE despite management without anticoagulation.

The American College of Chest Physicians’ clinical practice guidelines recommend “clinical surveillance over anticoagulation in selected patients with subsegmental pulmonary embolism without lower-extremity deep venous thromboembolism who have low risk for recurrent venous thromboembolism,” they wrote. “However, this is a weak recommendation with a low level of evidence (grade 2C).”

Carrier and coauthors performed their prospective, international, multicenter management cohort study in order to better determine the rate of recurrent VTE among patients with either single or multiple isolated subsegmental pulmonary embolism without proximal deep venous thrombosis managed without anticoagulation.

“The SSPE study showed that, among patients who had isolated subsegmental pulmonary embolism without proximal deep venous thrombosis on repeated bilateral ultrasonography and were managed without anticoagulation, the cumulative incidence of recurrent venous thromboembolism was 3.1% (CI, 1.6% to 6.1%) over the 90-day follow-up,” they found. “No patient had a fatal recurrent pulmonary embolism.”

The study authors noted that study recruitment was stopped prematurely due to an a priori stopping rule that was put in place—the study would cease “once the upper bound of the 95% CI of the 90-day rate of recurrent venous thromboembolism was to exceed 5.0% at the end of the study,” a rule which was met after 292 of the projected 300-patient cohort was enrolled. The “conservative” stopping rule, they explained, was created due to “uncertainty in the expected rate of recurrent venous thromboembolism and concerns about potential harms in managing these patients without anticoagulation.”

The study authors concluded that their study “has implications for management of these patients with anticoagulation in clinical practice.”

The SSPE study was conducted across 18 sites from the Investigation Network on Venous Thromboembolism (INNOVTE), the Dutch Thrombosis Network, and the Canadian Venous Thromboembolism Research Network (CanVECTOR) from February 2011 through February 2021. All patients with newly diagnosed isolated subsegmental pulmonary embolism—defined as a computed tomography scan showing one or more intraluminal filling defects in a subsegmental artery with no filling defects visualized at more proximal pulmonary artery levels—were potentially eligible; patients were excluded if they had active cancer, a history of VTE, required oxygen therapy, had an indication for long-term oral anticoagulant therapy, were pregnant, had received more than 48 hours of anticoagulation before enrollment, or were hospitalized at the time of diagnosis.

Eligible participants underwent bilateral lower-extremity venous ultrasonography, Carrier and colleagues explained. “Patients with no evidence of deep venous thrombosis did not start anticoagulant treatment, and repeated ultrasonography was performed on day five, six, or seven. Patients who remained without deep venous thrombosis on the second bilateral lower-extremity venous ultrasonography did not receive anticoagulant therapy.” Patients with proximal deep venous thrombosis on initial or repeated ultrasound were given anticoagulants; whether or not to use anticoagulants for those with distal deep venous thromboembolism was left to the treating physician to decide.

The study’s primary outcome was recurrent VTE during follow-up, which began on the date of the repeated bilateral ultrasonography and continued for up to 90 days. Secondary outcomes included death due to pulmonary embolism and major/minor bleeding during the overall study period.

A total of 292 patients were included in the study; mean patient age was 56 years, and most (53%) were women. The most common presenting symptoms were chest pain (73%) and shortness of breath (59%).

“Among the 266 patients with isolated subsegmental pulmonary embolism managed without anticoagulation, the primary outcome occurred in eight patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up,” the study authors found. “The incidence of recurrent venous thromboembolism was 1.1% (CI, 0.5% to 2.1%) per month. Four (1.4%) patients had recurrent proximal pulmonary embolism, and four (1.5%) had proximal deep venous thrombosis. No patients had a fatal recurrent pulmonary embolism.”

Also among the findings:

• Of the 292 included patients in the overall study, two (0.7%) had a major bleeding episode over the 90-day follow-up. These patients were not on any antithrombotic therapy, and one of the bleeding events was fatal (massive hemoptysis). Four patients had minor bleeding events.
• One of the eight patients with distal deep venous thrombosis managed without anticoagulation had recurrent VTE, leading to an incidence rate of 12.5% (CI, 1.9%-61.3%) over 90-day follow-up.
• The cumulative incidence of recurrent VTE in the 191 patients with isolated subsegmental pulmonary embolism who were ages 65 years or younger was 1.8% (CT, 0.6%-5.4%), while those older than 65 years (n=101) had a VTE rate of 5.5% (CI, 2.3%-12.7%) over the 90-day follow-up (hazard ratio, 3.2 [CI, 0.8-13.5]).

“Our study can inform patients and clinicians about the risks of managing isolated subsegmental pulmonary embolism without anticoagulation,” the study authors wrote. “Our subgroup analyses suggest that the rate of recurrent venous thromboembolism may differ in younger versus older patients or those with single versus multiple isolated subsegmental pulmonary embolism. A subgroup of patients with lower risk for recurrent events might be identifiable in future studies; however, our results support the use of anticoagulation in this patient population. The risk for recurrent venous thromboembolism was identified by the American College of Chest Physicians clinical practice guideline as the most important factor in the decision-making process, in addition to other parameters such as the presence of deep venous thrombosis, cardiopulmonary comorbidities, underlying risk for bleeding, and the patient’s values and preferences.”

Study limitations included the exclusion of patients with high-risk features; interobserver reliability of subsegmental filling defect detection has been reported to be low; central adjudication of subsegmental pulmonary embolism diagnoses could not be performed at enrollment; and the relatively short 90-day follow-up.

1. Patients with isolated single or multiple subsegmental pulmonary embolism had a higher-than-expected risk of recurrent venous thromboembolism when managed without anticoagulation.

2. Results from the SubSegmental Pulmonary Embolism (SSPE) trial supports the use of anticoagulants in this patient population.

John McKenna, Associate Editor, BreakingMED™

Cat ID: 309

Topic ID: 74,309,730,309,914,192,195