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Chapter 5

The PE Bounceback

Jeff Kline, MD and Rob Orman, MD
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When a patient with a known and treated pulmonary embolism returns to the ED with increased pain or shortness of breath, what’s the next step? There is no textbook answer for this one, so we reached out to the PE expert, Jeff Kline, to give his approach.

Pearls:

  • For patients recently diagnosed and treated for PE or DVT, a change in symptoms alone does not warrant a diagnostic workup to search for progressive thromboembolic process.

  • New signs, such as ECG changes, new hypoxemia, or increased leg swelling, may warrant a diagnostic workup.

  • Patients with pulmonary infarcts typically have worsening chest pain for 2 days after starting anticoagulation and resolution of pain within 1-2 weeks.

  • A D-dimer can be used to assess the effectiveness of anticoagulation, even if the patient is on a DOAC or warfarin.



  • How do you approach the patient who is currently anticoagulated for a PE and comes back with recurrent chest pain, shortness of breath, or other perceived symptoms that could be attributed to worsening thromboembolic disease?

    • The big question: Is there failure of anticoagulation? Do we need to change the anticoagulant or add something to therapy?  Would the patient benefit from a filter or fibrinolysis?

    • Before embarking on a diagnostic workup, you need to determine if the results will change patient management. The answers to these questions are based solely on expert opinion; there are no clinical trials to drive the evidence.

    • “Never on symptoms, sometimes on signs.”

      • For a reliable patient who is compliant with anticoagulation, diagnostic testing to search for a worsening thromboembolic process is unnecessary based on a change in symptoms alone.

      • New signs (such as tachycardia, ECG findings suggesting pulmonary hypertension, new hypoxemia, or increased leg swelling) may warrant a diagnostic workup.

        • Consider a repeat ultrasound in a patient on a DOAC for a DVT who has increased leg swelling.  Extension of clot can occur in the setting of antiphospholipid syndrome (APS), as these patients tend to fail DOACs. APS can overwhelm single enzyme inhibition and needs multilevel depletion with warfarin to prevent clotting.

        • For patients with new tachycardia, only do a diagnostic workup if there is an additional indicator that suggests ongoing clotting (such as new hypoxemia, ECG changes, elevated BNP, or increased troponin).  Tachycardia alone, as a single indicator, does not warrant testing for worsening thrombosis.

        • A D-dimer is Kline’s first step in this diagnostic workup. It can be used to assess the effectiveness of anticoagulation, even if the patient is on a DOAC or warfarin.  It is especially helpful if there is a comparative, pretreatment value

          • The half life of a D-dimer is 8-10 hours, so a patient who is therapeutic on an anticoagulant should have a normal D-dimer within approximately 3 days.

          • If the tachycardic patient has a normal or near-normal D-dimer, then no further testing or change in therapy is necessary.

          • If the D-dimer returns elevated, inquire about adherence. While anticoagulant failure could be the cause (often due to APS), poor adherence is commonly the culprit. Remind patients on Xarelto of the importance of taking the medication with food.

        • Patients with an elevated D-dimer will need to be reimaged to look for a new filling defect.  If found, the next steps include:

          • For patients on a DOAC:  

            • Send an anti-Xa to determine if the drug is affecting the enzyme as it should be.

            • Give a dose of enoxaparin.  It can be more effective than a DOAC in those rare individuals who have poor DOAC absorption.

            • Admit the patient.

          • For patients on warfarin with a therapeutic INR:

            • Consider the very real possibility that they are therapeutic now, but were subtherapeutic recently. Even the most compliant patients are only in the therapeutic range ⅔ of the time.

            • Give a dose of low molecular weight heparin and admit. The patient may do better on a target specific oral anticoagulant (like dabigatran or a Xa antagonist). An IVC filter may be required.

    • After what duration of therapy should we consider that there could be a treatment failure?  

      • Worsening dyspnea is more concerning that worsening chest pain. For patients with pulmonary infarction, increasing pain is part of the normal process of PE resolution on therapeutic anticoagulation. These patients will hurt more on day 2 and will have pain for up to 2 weeks. If a patient’s dyspnea is getting worse, however, a workup should be done to rule out other things (such as coronary syndrome or heart failure).

      • Kline observes that 90% of patients feel better the day following initiation of therapy.

      • The rate at which people fibrinolyse clots varies. The majority never get rid of all of their clot. Anticoagulants keep clot from progressing by blocking thrombin, while the existing clot is whittled away by one’s internal plasmin.  

  • Is a D-dimer more sensitive than a  CT pulmonary angiogram in ruling out a pulmonary embolism in a patient with a moderate risk Wells score?

    • The sensitivities are roughly equivalent:  D-dimer is 97% and CT is 95% sensitive. Every clinical guideline agrees that in moderate pretest probability patients, a D-dimer should be done first. If it’s negative, no further workup is necessary. The only reason to start with a CT is if there’s a clinical reason to believe the D-dimer is going to be positive.

  • Some guidelines recommend vascular surgery consult for patients with occlusive clot in the femoral-popliteal/iliofemoral system or for those with severe symptoms.  Is there evidence that these patients benefit from intervention beyond regular anticoagulation?

    • The ATTRACT trial is the definitive trial to answer this question.  It showed that overall there is no benefit of catheter-directed thrombolysis of DVTs compared with heparin. For all-comers, the risk of major bleeding was higher in the catheter-directed lysis group.

    • The subgroup and secondary analyses of more severe DVTs, however, demonstrated that patients with high and tight iliofemoral thromboses and those with severe symptoms  had improvement in post-thrombotic syndrome with pharmacomechanical thrombolysis.

    • Vedantham, Suresh, et al. "Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis." New England Journal of Medicine 377.23 (2017): 2240-2252. PMID: 29211671

    • Vascular News article on ATTRACT trial https://vascularnews.com/attract-fails-to-meet-primary-endpoint-but-experts-agree-results-are-hypothesis-generating/

    • Barco, Stefano, et al. "Diagnosis of recurrent venous thromboembolism." Thrombosis research 163 (2018): 229-235. PMID: 24278687

Don Z. -

1.can you make these summaries printable?

2. what factor xa level is adequate and does it matter how long after last dose?

Rob O., MD -

Hey Don!
Regarding question 1, I have asked for that in the next website update/build, so be assured that it is a priority for both you and I!
Regarding question 2, I'm not sure what you mean by what factor Xa level is adequate, can you expound on that?

Rob O., MD -

Here is the response from Jeff Kline....

I would not worry about hung up on cut offs Because it does depend on the reference range that they use, but the general number is 0.8 international units per ML. But the main question was if someone were in the emergency department at 10 AM, and said here she took their Xarelto at 7 AM and for whatever reason I suspected VTE recurrence, then that is when an anti-10 a level can be helpful. By the way, the wording matters a little bit because what you want is an anti-10 a, not a 10 a level. Technically a 10 A level is a measurement of that actual protein.
The reason the anti 10a can help is let’s say the patient does have evidence of clot in the new location. If the anti-10 A is sub therapeutic then this is a person who is either hyper metabolizer or a poor absorber of the drug. There are a few people like that out there and they have to be on warfarin. The other thing about Xarelto is you just have to make sure the patient is taking it with food. That is not the case with Eliquis. If on the other hand the level is clearly therapeutic that makes it much less useful to think about switching the drug. Then the situation becomes more like yes “you took it this morning but you probably haven’t been taking it regularly.”

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