2019 Pulmonary Embolism (PE) Treatment Guidelines

2019 ESC Guidelines for Acute Pulmonary Embolism

Pulmonary disease has been on the forefront of concern in recent months. Included in care management for acute pulmonary diseases is knowledge of the latest evidence associated with treatment for pulmonary embolism.

With the publication of the September 2019 ESC Guidelines for Acute Pulmonary Embolism, significant updates in recommendations have occurred, including, among several, a Class I recommendation for referral to an expert chronic thromboembolic pulmonary hypertension center for those symptomatic patients with mismatched defects on V/Q scan > 3 months post- acute PE.

Review evidence-based care for prevention of complications and recurrence post- PE, as well as chronic therapeutic management of these patients with Dr. Phil Green in K2P’s module entitled. For CurrentMD users, the module is linked below. Please check out the full transcript of the lecture below.

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Contemporary Management of Pulmonary Embolism: Chronic Management to Prevent Complications and Recurrence

Faculty: Philip Green, M.D.

Learning Objectives

By the end of this activity, you should be able to:

1. list three potential complications of acute pulmonary embolism
2. describe recommendations for a chronic therapeutic plan in a patient with pulmonary embolism
3. explain the role of inferior vena cava filters in the treatment and prevention of pulmonary embolism
4. clarify the role of chronic oral anticoagulation therapy in the prevention of recurrent pulmonary embolism

Pre-Assessment Questions

Question 1: Potential long-term complications of acute pulmonary embolism are:

A. recurrent venous thromboembolism
B. chronic thromboembolic pulmonary hypertension or CTEPH
C. post-thrombotic syndrome

Question 2: Which of the following are indications for inferior vena cava filter placement?

A. absolute contraindication to anticoagulation
B. large, deep venous thrombosis
C. acute pulmonary embolism despite therapeutic anticoagulation
D. patient does not want to be on anticoagulation

Question 3: Indefinite treatment with anticoagulation reduced the risk of recurrent venous thromboembolism by:

A. 5%
B. 10%
C. 30%
D. 70%
E. 90%

Sequela of Venous Thromboembolism

Sequela of venous thromboembolism include chronic thromboembolic pulmonary hypertension, postthrombotic syndrome, and recurrent venous thromboembolism.

When we look at the incidents of chronic thromboembolic pulmonary hypertension or CTEPH after pulmonary embolism, there’s an important cohort study of patients with acute episodes of pulmonary embolism without prior venous thromboembolism that followed 223 patients with acute symptomatic pulmonary embolism for two years.

Eighteen patients died within two days of the presentation, about 8%. Thirty-two patients presented with recurrent venous thromboembolism, two-thirds of which occurred after stopping anticoagulation. And seven patients or 4% of those patients developed chronic thromboembolic pulmonary hypertension.

Post-Thrombotic Syndrome

Post-thrombotic syndrome is defined as chronic pain edema and fatigue of an affected limb after deep venous thrombosis.

Severe post-thrombotic syndrome may result in venous claudication, stasis dermatitis, subdermal fibrosis and ulceration, and potentially, in the most severe cases, tissue loss. Over 40% of patients within two years of their first lower extremity deep venous thrombosis suffer from some degree of post-thrombotic syndrome.

More severe post-thrombotic syndrome is predicted by a common femoral or iliac DVT, higher body mass index, prior DVT in the same extremity, older age, and female gender.

Patients with post-thrombotic syndrome have an overall lower quality of life and less improvement in symptoms over time with conventional therapy.

The CaVenT Study

The CaVenT study of the long-term outcomes after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep venous thrombosis, there’s a randomized control trial with 176 iliofemoral DVT patients followed for 5 years.

It was a one-to-one randomization to catheter-directed thrombolytics or the DVT plus anticoagulation versus anticoagulation alone.

Forty-three percent of the patients in catheter-directed group versus 71% of the patients in the control group developed post thrombotic syndrome with a 28% absolute risk reduction. However, there was no difference in quality of life or bleeding.

The ATTRACT Trial

The ATTRACT Trial was intended to be the definitive trial, randomizing patients with a proximal deep venous thrombosis to pharmaco-mechanical percutaneous clot reduction therapy for DVT versus no clot reduction therapy and anticoagulation alone.

The primary objective was to determine if percutaneous pharmacomechanical catheter-directed therapy reduced the development of post-thrombotic syndrome after 24 months compared to standard DVT therapy alone.

The results of this trial were relatively disappointing.

PCDT did not reduce the incidence of post-thrombotic syndrome compared to anticoagulation alone. When iliofemoral DVT was looked at as a subgroup, there was a reduction in the development of moderate to severe post-thrombotic syndrome with 18% in the percutaneous catheter-directed therapy arm versus 28% with standard anticoagulation without catheter-directed therapy. When femoral popliteal DVT was looked at, there was no difference at all.

So, there is a hypothesis that in the more severe iliofemoral DVT, percutaneous clot reduction therapy is effective at reducing post-thrombotic syndrome. It’s important to note that percutaneous catheter-directed therapy was less effective in the elderly group.

Preventing Recurrence

How about preventing recurrence of venous thromboembolism?

What’s the role of IVC filter, anticoagulation or other therapies?

The role of the inferior vena cava filter is quite limited from that perspective. Venous filters are usually placed in the infrarenal portion of the inferior vena cava. They’re indicated in patients with acute pulmonary embolism who have absolute contraindication to anticoagulation and in patients with objectively confirmed recurrent pulmonary embolism despite adequate anticoagulation.

Filter overuse and failure to remove temporary IVC filters remain a significant problem. And the long-term sequelae of filters can be significant with filter embolization, fracture and break down.

Anticoagulation

Anticoagulation, what type of anticoagulation should we use, oral, whether it’s warfarin or not, or a direct oral anticoagulant, low-molecular-weight heparin, and how long should we anticoagulate patients for?

ESC Guidelines: Duration of Treatment

European guidelines say that for provoked pulmonary embolism, anticoagulation treatment for three months after provocation is no longer present.

For unprovoked PE, clinical trials have evaluated various durations of anticoagulation therapy for venous thromboembolism. It’s well-known a patient should receive at least three months of anticoagulation treatment.

After withdrawal of anticoagulation treatment, the risk of recurrence, and the anticoagulants are stopped after 6 or 12 months, can be similar to that of after 3 months. And indefinite treatment with anticoagulants does reduce the risk of VTE by about 90%, but this benefit is partially offset by a 1% or higher of annual risk of major bleeding.

Anticoagulation is discontinued when a perceived risk of anticoagulation, risk of bleeding and the inconvenience of remaining on treatment outweigh the risk of recurrent VT.

In the European Society 2017 update, they divide the treatment into three phases. Initial and long-term treatment are mandatory for all non-cancer DVT patients. Extended treatment requires a risk-benefit discussion, which is extended treatment following initial three to six months. Options for extended treatment are apixaban, dabigatran, edoxaban, rivaroxaban and coumadin.

Extended Treatment for Prevention of Recurrence

Extended treatment for the prevention of recurrent multiple oral anticoagulant drugs have been shown to prevent recurrent venous thromboembolism in patients with pulmonary embolism. Guidelines have not yet standardized criteria for extended treatment in the absence of ongoing provocation like incurable malignancy. We will review the data of our extended treatment using apixaban as one example.

AMPLIFY-EXTEND Study

The AMPLIFY-EXTEND study enrolled patients who are treated for 6 to 12 months with anticoagulation therapy for objectively confirmed symptomatic proximal DVT or pulmonary embolism without recurrence.

In those, there was a clinical uncertainty regarding the continuation or cessation of anticoagulation therapy. Ninety-two percent of these patients had unprovoked DVT or pulmonary embolism, and 8% had a provoked DVT or PE with one additional risk factor for recurrence. Eight hundred patients, approximately were put in three arms — a 2.5 twice-daily dose of apixaban, a 5 mg twice-daily dose of apixaban, and a twice-daily dose of placebo

The primary efficacy endpoint was recurrent VTE or all-cause death. And the major safety endpoint was major bleeding.

The findings of the study were remarkable in the 2.5 twice daily Eliquis dose arm, it was a 67% relative risk reduction and an 8% absolute risk reduction in recurrent VTE or all-cause death compared to the placebo arm. And remarkably, no increase in major bleeding whatsoever.

We focused on the 2.5 mg apixaban dose because that was the dose that was ultimately FDA-approved for extended therapy.

Lest we think that this bleeding result is an anomaly of how bleeding was measured, when we look at clinically relevant non-major bleeding, major and clinically relevant non-major bleeding, minor bleeding and all bleeding, the results were remarkably similar with almost no increase in bleeding in the 2.5 mg of apixaban arm compared to that of placebo.

Based on this data and other studies, it’s reasonable to consider extended therapy in patients with a low bleeding risk profile who are at risk for recurrent venous thromboembolic events.

Post-Assesment Questions

We’re going to turn now to our assessment questions.

Question 2: Which of the following are indications for inferior vena cava filter placement?

A. absolute contraindication to anticoagulation
B. large, deep venous thrombosis
C. acute pulmonary embolism despite therapeutic anticoagulation
D. patient does not want to be on anticoagulation

Question 3: Indefinite treatment with anticoagulation reduces the risk of venous thromboembolism by:

A. 5%
B. 10%
C. 30%
D. 70%
E. 90% Check Answer Here, choices A and C are correct. Absolute contraindication to anticoagulation and acute pulmonary embolism despite therapeutic anticoagulation are indications for inferior vena cava filter placement. Check Answer Here, the correct answer is 90%. There is a relative risk reduction of 90% when anticoagulation is used to prevent recurrent venous thromboembolism, but the benefit is partially offset by 1% or higher annual risk of major bleeding.

Learning Objectives Revisited

After completing this activity, you should now be able to:

1. list three potential complications of acute pulmonary embolism
2. describe recommendations for a chronic therapeutic plan in a patient with pulmonary embolism
3. explain the role of inferior vena cava filters in the treatment and prevention of pulmonary embolism
4. clarify the role of chronic oral anticoagulation therapy in the prevention of recurrent pulmonary embolism