Withholding Anticoagulation for ISSPE

All else being equal, I'd prefer to do nothing. Whether this is nihilism, laziness, or experience is a matter of debate. The American College of Chest Physicians (CHEST) Guidelines on therapy for venous thromboembolism (VTE) opened a door for withholding treatment for isolated subsegmental pulmonary embolism (ISSPE) in 2016 and kept it open in 2021. I was happy to walk through it and withhold therapy if it wasn't indicated.

ISSPE is truly a conundrum. With advances in technology, the distal vessels in the lung became visible on commercial CT a little more than 10 years ago. The subsegmental branches are located after the fourth bifurcation of the pulmonary arterial system, and the new technology offered resolution adequate to identify clot in these vessels. But the new technology told us nothing about how to manage clot isolated to the subsegmental vasculature.

Autopsy data say clot in these vessels is common, even in patients who were never diagnosed with VTE while they were alive. To some degree then, the pulmonary arterial system is thought to serve as a filter to prevent clot from crossing to the systemic circulation and causing stroke. This led some to speculate that the subsegmental pulmonary arteries are supposed to contain clot and that we simply couldn't see it before now. If this theory is correct, the practice of providing anticoagulation for ISSPE could increase bleeding without reducing the risk for VTE recurrence.

Management studies generally supported this concept. In 2007, a trial that was published in JAMA randomized patients to two different diagnostic strategies: one was ventilation-perfusion (VQ) and the other was CT. CT detected more clot than VQ did, so more anticoagulation was given in the CT arm. Yet, the VTE rate during follow-up was not significantly different between arms. The implication? Some of the clots detected by CT were of lesser clinical significance and didn't need to be treated.

Meta-analytic data from management trials also suggested that some pulmonary emboli (PE) need not be treated. Data also show when compared with patients who have more proximal PE, those with ISSPE have lower pretest probability for VTE, are less symptomatic, and have a lower burden of coexistent lower extremity thrombosis (deep vein thrombosis [DVT]).

In response to this data, the CHEST Guidelines began cautiously providing the option for withholding therapy in patients who were diagnosed with ISSPE in 2016. Their recommendations stated that patients should be stratified for recurrence risk and have lower extremity ultrasonography performed to rule out DVT. A patient with ISSPE, a low recurrence risk, and a negative ultrasound can have anticoagulation withheld. This made perfect sense to me based on what I thought I knew at the time.

Recently published data cast doubt on my nihilism. The first prospective study designed specifically to assess the safety of withholding therapy for ISSPE suggests that this practice could be dangerous. How did this happen? The trial was very well done, and the authors enrolled the right population. All of the patients had ISSPE, low recurrence risk, and negative lower extremity ultrasound. The authors were anticipating a 1% VTE rate at 90 days based on prior data but instead found a rate of 3.1% (1.6%-6.1%). They point out that this rate is not different from those seen in patients with more proximal PE who are treated with anticoagulation. However, they acknowledge that it is higher than what's considered acceptable and warrants therapeutic anticoagulation.

So what should we do now? We treat ISSPE, that's what. All the arguments for withholding therapy remain valid, the recurrence rate is reasonably low, and none of the recurrent VTEs in the new study were fatal. There's still no doubt that some patients with PE won't benefit from anticoagulation. Unfortunately, we currently lack the tools to identify them. The risk-benefit ratio for recurrence vs bleeding will be tighter with ISSPE, particularly when there's only one clot. Unless the bleeding risk is elevated though, the ratio still favors treatment.

Aaron B. Holley, MD, is an associate professor of medicine at Uniformed Services University and program director of pulmonary and critical care medicine at Walter Reed National Military Medical Center. He covers a wide range of topics in pulmonology, critical care, and sleep medicine.

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