The puzzle of submassive PE

Treating the middle of the pulmonary embolism spectrum can be tricky.

If you've seen one pulmonary embolism (PE), you have not seen them all.

“Patients with acute PE represent a very wide spectrum of disease,” said Lisa K. Moores, MD, MACP, during her ACP CME 30 talk, “Pulmonary Embolism and Deep Vein Thrombosis: Management Options.” “Luckily, about 70% of them will be normotensive and have normal right ventricular function on presentation, and these patients have an excellent prognosis.”

Then there's the other end of the spectrum. “Unfortunately, there are about 5% of patients that when they present are manifesting sustained hypotension, may experience cardiogenic shock, syncope, even cardiac arrest, and these are patients that we classify as having a massive PE. And we know these patients have a very high short-term mortality,” she said.

Photo courtesy of Dr Moores
Photo courtesy of Dr. Moores

The 25% of patients that fall between these groups can pose particular dilemmas in treatment and were a focus of the talk by Dr. Moores, professor of medicine at the Uniformed Services University School of Medicine in Bethesda, Md. These patients have submassive or intermediate-risk PEs, which typically present with hemodynamic stability but also evidence of right ventricular (RV) dysfunction.

“Why do we focus on the RV? Well, because we know the mortality in patients with acute PE is higher when RV dysfunction is present. This makes sense when we think about the underlying pathophysiology. Patients don't die of hypoxemia or respiratory failure in the setting of acute PE. They die from right ventricular failure,” said Dr. Moores.

The challenge is figuring out which patients these might be. “Patients that present with submassive or intermediate-risk pulmonary embolism are actually a very heterogeneous group,” she said. “Over the last 10 to 15 years, research has focused on our ability to further stratify these patients in hopes of identifying those on the high-risk end of this spectrum.”

Tools for risk stratification include clinical prediction scores, such as the full or simplified Pulmonary Embolism Severity Index (PESI), and assessment of RV function by either imaging (CT or echocardiography) or cardiac biomarkers. Research has shown that the ratio of the right ventricle to the left predicts risk of adverse outcomes, as do troponins T and I, B-type natriuretic peptide (BNP), N-terminal-proBNP, and heart-type fatty acid-binding protein. Patients with concomitant deep venous thrombosis are also at higher risk of negative outcomes, Dr. Moores noted.

Current guidelines categorize patients on a combination of these measures. The European Society of Cardiology uses the PESI to identify intermediate-risk patients and then further subdivides them by whether they have RV dysfunction or elevated troponin levels. U.S. guidelines focus on blood pressure, RV dysfunction, and myocardial necrosis to categorize patients.

Those who are found to be low risk can safely be treated with anticoagulants. “This should be done in the hospital setting. Patients should be monitored closely for signs of deterioration,” said Dr. Moores. She recommended initial therapy with unfractionated heparin rather than low-molecular-weight heparin, until it's clear the patient will remain stable. At that point, therapy can be switched to direct oral anticoagulants or vitamin K antagonists or low-molecular-weight heparin.

What about systemic thrombolytics like recombinant tissue plasminogen activator and tenecteplase? Data gathered for the 2016 CHEST guideline on antithrombotic therapy showed that thrombolytics reduce deaths from acute PE. “For all-cause mortality, there is a benefit, with an odds ratio of about 0.5, with 18 fewer per 1,000 patients experiencing mortality in the setting of systemic thrombolytic therapy,” Dr. Moores cited.

Recurrence of PE was also lower, but these benefits came at a cost. “Major bleeding is increased at an odds ratio of almost 3. Most importantly, the risk of intracranial hemorrhage goes up with an odds ratio of 4.6,” she said. “When we look at this whole evidence profile, we're left with the onus of figuring out who's most likely to benefit.”

It seems clear that the sickest patients are in that category. “Mortality is likely lower in patients that present with hemodynamic instability if they receive thrombolytic agents,” said Dr. Moores. “But the clinical benefit in normotensive patients is still uncertain.”

Researchers have been trying to help with this dilemma by assessing the effects of thrombolysis in intermediate-risk patients. “We have several meta-analyses that have tried to look at that subgroup to come up with some consensus as to whether it will benefit from systemic thrombolytic therapy,” she said.

Three meta-analyses have tackled this topic, the most highly cited of which was published in JAMA in 2014. “They found that thrombolytic therapy did show a reduction in mortality and also a reduction in the number of patients who developed clinical deterioration. However, this did come at the risk of increased bleeding,” said Dr. Moores. “The othertwo meta-analyses actually failed to find any significant difference in mortality but did see the consistent finding of a reduction in clinical deterioration and an increase in bleeding.”

Taken together, these results don't make a convincing case to give the drugs to intermediate-risk patients, Dr. Moores summarized. “Overall, there's not any clear evidence that the submassive [PE] group is going to benefit, at least as a whole, from systemic thrombolysis,” she said.

Further data were provided by the PEITHO trial, published in the New England Journal of Medicine in 2014, which randomized more than 1,000 patients with submassive PE to anticoagulation alone or anticoagulation plus tenecteplase. On the study's combined primary outcome of mortality and hemodynamic collapse, thrombolysis performed significantly better.

“However, similar to an earlier study, when you break down that primary outcome into component parts, you can see that there was no difference in all-cause mortality. What drove the difference in the outcome was hemodynamic collapse within seven days,” said Dr. Moores. And as expected, bleeding rates were higher in the thrombolysis group.

There was another outcome that was significantly different between groups: the open-label use of thrombolysis by the patient's treating physician. This occurred more often in the group receiving only anticoagulation.

“One of the important take-home points from the PEITHO trial is that 18 patients in the placebo group who experienced hemodynamic compromise underwent secondary thrombolysis and the success rate was almost 90%,” said Dr. Moores.

These data led to a recommendation from CHEST that systemic thrombolytic therapy shouldn't be used as initial therapy for most PE patients without hypotension but that it can be considered in patients who deteriorate after starting anticoagulant therapy, she explained. “This is a group in which we can consider rescue thrombolytic therapy,” Dr. Moores said, noting that the European Society of Cardiology offers a similar recommendation.

Of course, ideally, there'd be a way to predict this deterioration before it occurs. “I don't know that we have the best answer for that yet,” she said. One possible tool is the modified Bova score, which uses four factors to evaluate risk: a systolic blood pressure under 100 mm Hg, a troponin I level greater than 0.04 ng/mL, RV dysfunction, and heart rate of 110 beats/min or above.

“This might be a way to identify patients that we are very concerned about and might benefit from admission to the ICU or stepdown unit for very close monitoring while anticoagulation is started, allowing us to rapidly revert to rescue thrombolysis if deterioration does develop,” said Dr. Moores.

Clinicians should keep a close eye on both their intermediate-risk patients and the emerging literature about them. “There are multiple advanced options to treat these patients, but they all lack a robust collection of evidence to support them,” Dr. Moores concluded.