Considering the complexities of diagnosing, treating PE

Due to nonspecific symptoms and a wide variety of therapeutic options, diagnosis and treatment of pulmonary embolism can be challenging.

With treatments ranging from anticoagulation to catheter-directed clot extraction, input from a number of specialists is essential to selecting the safest, most effective therapy for a specific patient, according to Victor F. Tapson, MD, director of clinical research for the Women’s Guild Lung Institute and director of the Venous Thromboembolism and Pulmonary Vascular Disease Research Program at Cedars-Sinai Medical Center and vice president of medical affairs at Inari.

Victor F. Tapson

“Any time we consider a treatment that is more aggressive than anticoagulation, we want input from pulmonologists, surgeons, interventional cardiologists, interventional radiologists and others who may be involved in the patient’s care,” Tapson said.

In an interview with Healio, Tapson delved deeper into the diagnosis and risk stratification of patients with PE as well as how to approach treatment selection in this complex patient population.

A ‘strong suspicion’ for PE

The nonspecific symptoms of PE — which can include shortness of breath, syncope, dizziness and, depending on the clot, chest pain — are fairly nonspecific and a physical examination often does not yield much conclusive information, especially when the patient has underlying conditions, according to Tapson.

“If a patient has calf pain or swelling in addition to sudden shortness of breath or syncope, suspicion for PE or deep vein thrombosis, which can lead to PE, would be higher, but there is not much else in the physical exam that will help confirm PE,” Tapson told Healio. “There are no crackles like with pneumonia or heart failure and there usually is no wheezing like with asthma.”

It is also important to remember, Tapson noted, that patients may present with other problems, such as heart failure exacerbation or a COPD flare, though PE may actually be the culprit.

“Our ED doctors have to consider all different situations, as they may see at least 30 people in a week who present with syncope and can’t CT scan all of those patients,” Tapson said.

Therefore, the first step to diagnosis is having a “strong suspicion” for PE, followed by evaluation of risk factors, according to Tapson. In this case, use of scoring systems, such as the revised Geneva score, the Wells score or, if the physician has low suspicion for PE, the Pulmonary Embolism Rule-out Criteria (PERC), can be beneficial in identifying patients who require further testing to confirm a diagnosis of PE.

Additionally, a study published in the Annals of Emergency Medicine in 2013 also indicated that clinician gestalt works as well as these scoring systems, Tapson noted.

“Physicians who have seen many of these patients or who specialize in diagnosis and treatment of PE may not rely on scoring systems, but these systems may help other physicians who see a number of different conditions take a more organized approach to acute PE,” Tapson said.

Once PE is suspected, physicians may perform a lab test, such as a D-dimer test, in patients for whom they have a low suspicion of PE, but the chest CT scan is the classic test used to confirm a diagnosis, according to Tapson.

If a patient cannot undergo a chest CT scan due to a dye allergy, for instance, physicians can perform a ventilation perfusion scan. Although not as specific, a physician who has significant experience can determine whether abnormal results indicate PE, Tapson said.

Importance of risk stratification

After diagnosis, physicians are tasked with selecting the most appropriate treatment option for each patient. A large part of this decision boils down to risk stratification and how the PE is classified, according to Tapson.

Generally, high-risk, or massive, PE is defined by hemodynamics.

“If you are hypotensive from PE, which technically means a systolic blood pressure of less than 90 mm Hg for more than 15 minutes or a persistent drop in systolic BP by at least 40 mm Hg, then you have high-risk, or massive, PE,” Tapson said. “Usually, this goes along with other findings, such as shortness of breath, tachypnea, tachycardia, potentially a low oxygen level, abnormal brain natriuretic peptide and troponin levels and an ECG often showing an abnormal right ventricle.”

However, physicians also use additional tools, such as the simplified Pulmonary Embolism Severity Index (sPESI) score, to determine whether a patient has high-, intermediate- or low-risk PE. Patients can then be divided further into intermediate-low-risk and intermediate-high-risk. Intermediate-low-risk patients have either abnormal troponin levels or an abnormal right ventricle, whereas both are abnormal in intermediate-high-risk patients, according to Tapson.

“That is the general breakdown, but it is important to say these different categories are heterogeneous,” Tapson said. “You can have someone who appears fine and is talking with you, but they have a systolic BP of 88 mm Hg and are technically massive PE, so you would elect to take them to the cath lab.”

In addition to troponin, appearance of the right ventricle and vital signs such as BP, physicians should consider several other factors, including heart rate, according to Tapson.

“Heart rate has made me make decisions more than any other single parameter in my career when I see a patient with PE,” Tapson told Healio. “If a patient has a large PE and a heart rate of 90 bpm, I’m more confident that they might do OK without more aggressive therapy than if their heart rate is 120 bpm, and if their heart rate is between 120 bpm and 130 bpm, even if they’re not hypotensive, I generally want to be more aggressive.”

Tapson noted, however, that physicians should interpret heart rate with caution, adding that some patients, such as those who are elderly or those who are on certain drugs like beta-blockers, may not be able to mount a heart rate response.

Next steps

A patient’s risk forms the basis for treatment strategies, but anticoagulation is usually the first step, according to Tapson.

“Unless there are bleeding concerns or some kind of contraindication, every patient gets anticoagulation because it has been shown to reduce mortality with PE. Then, the next step is to decide whether we need to be more aggressive,” Tapson told Healio.

Patients deemed high risk will likely go on to receive more intensive therapy while anticoagulation may suffice for low-risk patients. Optimal treatment for those with intermediate-risk PE, however, is up for debate, Tapson noted.

“What to do for these intermediate-risk patients is sort of the holy grail of acute PE because we don’t have good proof that those patients need anything more than anticoagulation and then more aggressive therapy if they deteriorate, which is what’s recommended in the European Society of Cardiology guidelines,” Tapson said. “However, many of us feel that certain intermediate-risk patients require more aggressive treatment, and this is where there is a lot of controversy.”

Specifically, intermediate-high-risk patients with only mild elevations in troponin and a mildly abnormal ECG of the right ventricle, may fare well with anticoagulation only, but those with normal BP and significant elevations in troponin and abnormalities on ECG of the right ventricle may require more intervention.

“We don’t have much information on the intermediate-high-risk patient. These risk groups are all heterogeneous, and no one can really tell you there is an absolute answer for each of these groups,” Tapson said.

Team approach to treatment

In addition to anticoagulation, there are a number of treatment options for PE, including thrombolysis, which can be delivered via IV or catheter, according to Tapson.

“IV thrombolysis, usually in the form of tissue plasminogen activator, has been very effective over the years,” Tapson said, noting that if a patient presents with high-risk, or massive, PE and appears to be declining quickly, IV thrombolytic therapy can be done fast and often yields quick benefits. “If a patient is unstable, this can sometimes be done before we can get them to the cath lab.”

The treatment, however, is not without risks, according to Tapson.

“It’s a very potent form of therapy, but it can cause bleeding in the brain in approximately 1% to 3% of people, especially in elderly patients, so we have to be very careful with it. We can use lower-dose therapy, which helps, but it does make us nervous,” Tapson told Healio.

Other catheter-directed therapies, such as catheter-directed clot extraction and catheter-directed thrombolysis with different devices, are also potential options. However, with a lack of data showing superiority of one catheter-based therapy over another, coupled with the uncertainty about how best to treat intermediate-risk patients, a multidisciplinary approach is key in this decision-making process, according to Tapson.

“The best way to sort out treatment for patients who may require more aggressive therapy is through the concept of the Pulmonary Embolism Response Team, or PERT, which involves an experienced team of physicians from different specialties,” Tapson said.

Each health care system with a PERT organizes it differently, though all are composed of a number of specialists, including pulmonologists, cardiologists, interventional cardiologists, interventional radiologists and surgeons, among others, according to Tapson. These specialists, particularly the interventionalists and surgeons who would perform catheter-directed therapies, are consulted after a PE diagnosis is confirmed and it has been determined that more aggressive treatment may be warranted.

“There is still the possibility of bleeding when we give thrombolytics with a catheter, so one option is low-dose catheter-directed therapy, which works well, and this is often a good approach for intermediate-high-risk patients as well as certain high-risk patients, but it is still a decision that needs to be individualized,” Tapson said.

More research necessary

Looking ahead, one of the greatest unmet needs at this point is the ability to immediately identify patients with PE, according to Tapson, who noted that several autopsy studies have shown that acute PE is often not diagnosed or even suspected until after death.

“That’s a huge problem. Sometimes it happens because someone presents so suddenly, but I think the PERT concept has really moved this along, so when someone does present with symptoms, we can move in and make some decisions quickly,” Tapson said.

Understanding why some people develop chronic thromboembolic pulmonary hypertension (CTEPH) is also an important question, according to Tapson.

“We know that some of these patients have thrombophilias, but there are patients who do not and still develop CTEPH,” Tapson said. “It would be nice to be able to find out why PE resolves in some patients but persists and causes pulmonary hypertension in approximately 1% to 2% of patients.”

Furthermore, physicians also hope to find an answer as to why patients develop PE at all, which may require more investigation into genetics, Tapson added.

“Can we learn more about some of these thrombophilias and decide what they mean? We know about several, including factor V Leiden and prothrombin gene mutations, but there are many that we don’t even know about yet, and these may be responsible for people having unprovoked idiopathic venous thromboembolism. Therefore, we need more information on genetics and these thrombophilias,” Tapson said, noting that gene therapy may even be possible in the future.

One of the major issues, though, is how to treat intermediate-risk patients. In addition to determining when more than anticoagulation is required, other questions persist about optimal treatment, according to Tapson.

“Is there one device that’s better than the others for treating these patients? When do we opt for catheter-directed therapy? How much clot do we need to remove from patients’ lungs? Should you try to suction or lyse it all out? Can you suction out a little bit of clot and then quit?” Tapson said. “These are some of the questions we need answers to.”

References:

Konstantinides SV, et al. Eur Heart J. 2020;doi:10.1093/eurheartj/ehz405.

Penaloza A, et al. Ann Emerg Med. 2013;doi:10.1016/j.annemergmed.2012.11.002.