Quick Guide: Anticoagulation Road Map-Pulmonary Embolism

Acute venous thromboembolism (VTE) manifests as deep venous thrombosis (DVT), pulmonary embolism (PE), or both. It is a common disorder with an annual incidence of 1 to 2 cases per 1000 people.^1,2 PE is the third most common cause of cardiovascular mortality, after myocardial infarction and cerebrovascular accident. Symptoms range from leg swelling to dyspnea and sometimes even cardiogenic shock and death. Depending on the location and extent of PE, there are a variety of treatment options available, from oral anticoagulation to systemic and catheter-guided thrombolysis and surgical embolectomy. VTE can have serious economic and health consequences. The mortality is around 30% in untreated PE, and even with adequate treatment it can range anywhere between 5% to 17%.^3,4 It is important to classify PE as high, intermediate, and low risk.

• High-risk PE: All patients who are in cardiogenic shock—ie, hemodynamically unstable.
• Intermediate-risk PE: These patients are hemodynamic stable, but have evidence of right ventricular dysfunction, diagnosed by an echocardiogram or a CT scan. They may also exhibit elevated levels of brain natriuretic peptide (BNP) or troponins, or both. Some studies also define intermediate risk by size—ie, PE occupying 50% to 70% of their right or left main pulmonary artery.^5-7
• Low-risk PE: All other patients fall into this category.

Low-Risk Pulmonary Embolism
For more than half a century, the anticoagulant of choice has been warfarin, still the gold standard to which all newer treatments are compared. However, over the past few years, there have been many noteworthy trials testing different anticoagulants. Initially 2 anticoagulants—an oral thrombin inhibitor (ximelagatran) and an injectable factor Xa inhibitor (idraparinux)—were tested against warfarin in patients with VTE.^8,9 Both drugs were not approved: ximelagatran was linked to increases in liver enzymes and coronary events and idraparinux reported a higher rate of fatal and nonfatal PE.

Subsequently, 4 other nonvitamin K dependent, newer oral anticoagulants (NOACs)—an oral thrombin inhibitor (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban)—have all been compared to warfarin for the treatment of VTE.^10-14 The Table summarizes the principle findings of these phase III clinical trials.  

These NOACs were deemed to be noninferior to warfarin; research found that rivaroxaban¹⁵ and apixaban¹³ and edoxaban¹⁴ showed statistically significant less major bleeding events than warfarin. With NOACs, the major advantage is that there is no longer the need for frequent blood draws to check the international normalized ratio. Dietary restrictions are also no longer necessary with these newer agents. Rivaroxaban, dabigatran, and apixaban have all been FDA approved for the treatment of VTE. Edoxaban is awaiting approval.

No article about NOAC is complete without a short discussion about treatment options to reverse their anticoagulant effects. Clinicians are usually worried when a patient on a NOAC comes in with a major bleed due to the lack of an established antidote. Guidelines and expert opinions suggest administration of prothrombin complex concentrates and recombinant activated factor VII.^16,17 Also, hemodialysis is a potential option with dabigatran, as only about 30% to 35% of the drug is protein bound.

There are several newer, specific reversal agents under development, including idarucizumab for dabigatran, andexanet alfa for factor Xa inhibitors, and PER977 for both factor Xa and thrombin inhibitors.¹⁷

Clinicians should tailor the anticoagulant for the particular patient. While the NOACs certainly are more attractive and hold many advantages, the initial optimism has to be tempered with a certain degree of caution, especially while treating elderly patients with chronic kidney disease, multiple medical problems, and with a high risk of bleeding.

Duration of Anticoagulation
The main aim of anticoagulation is to prevent recurrence of VTE while the body’s endogenous mechanisms work on dissolving the clot. In order to determine the duration of anticoagulation, know the rate of recurrence for VTE, which varies according to the etiology. The rate of recurrence in patients after a first episode of VTE due to a transient risk factor (a provoked risk factor such as surgery) is around 3.3% per patient year. This figure ranges from 0.7% for patients with a surgical risk factor to 4.2% for patients with nonsurgical risk factors (ie, trauma, pregnancy, use of hormonal therapy, and medical illnesses).¹⁸

The rate of recurrence after unprovoked VTE has not been well studied. However, one of the largest studies evaluating the risk of recurrence of  VTE after a DVT (both transient and unprovoked) puts the risk at 11% after 1 year, 19.6% after 3 years, and 39.9% at the end of 10 years.¹⁹

To determine the recurrence risk in a particular patient, clinicians can use either a population-based or an individual-based strategy.²⁰

• Population-based: This strategy is simple and economical to use. Patients who have an unprovoked VTE are determined to be high risk. These patients should be treated for at least 3 months, and may benefit from lifelong anticoagulation.

Those who have a VTE following a transient risk factor are determined to be low risk and usually get 3 months of anticoagulation. The disadvantage of this method is that is does not account for heterogeneity between populations and may miss individuals with high risk of recurrence even with a transient risk factor.

• Individual-based: This approach is more time-consuming and requires obtaining a detailed history and considerable testing to determine the risk of recurrence for the individual patient. One individualized approach is to check a D-dimer (a blood test that measures a substance that is released when a blood clot breaks up) after 1 month of stopping anticoagulation. In a large meta-analysis,²¹ it was shown that an elevated D-dimer was associated with a risk of 8.8% versus 3.7% in patients with a negative D-dimer for recurrent VTE.

Another approach suggested by some experts is to repeat a lower extremity venous ultrasound to establish recanalization of the vein and using this as the guide towards cessation of anticoagulation. However, a systemic review and meta-analysis has determined that residual vein obstruction was not associated with an increased risk of VTE (odds ratio of 1.24).²² Also, checking for residual vein obstruction to determine duration of treatment is not part of current guidelines.

The following factors may help to identify patients with a higher risk for recurrence:^23,24  

• One or more episodes of VTE
• Hereditary thrombophilia
• Anti-phospholipid antibody syndrome
• Presence of right ventricular dysfunction on echocardiography at hospital discharge
• Obesity
• Male sex

Cancer should be considered in a category by itself as it has a very high rate of recurrence. In a study done by Hutten et al,²⁵ patients with cancer had a recurrence rate that was 3 times higher than in nonmalignant patients. It is recommended that patients with active malignancy should receive anticoagulation for an indefinite period of time. Based on a study by Lee et al,²⁶ the American College of Chest Physicians (ACCP) recommends treatment with a low-molecular-weight heparin (LMWH) for VTE in patients with malignancy (grade II B).

To make things simpler and to put all the available data into perspective, we propose dividing patients into 3 groups. The first group consists of patients diagnosed with VTE due to a transient risk factor. In this population, for most patients, treatment with anticoagulation for 3 months should suffice. The second group consists of patients with cancer, antiphospholipid syndrome, and irreversible risk factors, who need lifelong anticoagulation.

Determining the duration of treatment is the trickiest for the third group—the group with an unprovoked or idiopathic VTE. Here, the physician should have a detailed discussion with the patient about the risks and benefits of anticoagulation. Generally anticoagulation is advocated as long as the bleeding risk remains minimal or less than the risk of recurrence. The International Society on Thrombosis and Hemostasis has proposed a statement that a recurrence rate of 5% at 1 year and 15% at 5 years can be considered acceptable to justify discontinuation of anticoagulation.²⁷ A recurrence risk of 10% at 1 year and 30% at 5 years is unacceptably high to discontinue anticoagulation. Although this statement was proposed for studies, it may reflect current physician practices.

Intermediate- and High-Risk PE
Intermediate-risk PE is the hardest to treat, as there is paucity of literature and lack of sufficient large, randomized clinical trials. Also, trials define intermediate-risk PE differently as mentioned before. Treatment options for intermediate and high-risk PE can be divided into 3 categories: systemic thrombolytics, catheter directed thrombolysis (CDT), and surgical embolectomy.

Thrombolytics. Thrombolytics are the mainstay of treatment for high-risk patients. The main advantages are ease of availability and backing by extensive data and guidelines. Both the American and European societies recommend systemic thrombolysis as the first-line of treatment unless there are contraindications in high-risk PE.^23,28 Also, the important thing to remember is that all contraindications are relative and in cases of high-risk PE, physicians should be aggressive with the usage of thrombolytics, especially if alternative resources are unavailable. Thrombolytics should be administered through a peripheral vein and a 2-hour infusion time is sufficient. The greatest benefit is obtained within 48 hours, but it can be extended up to 14 days.

One of the largest trials in patients with intermediate-risk PE was performed by Meyer et al,²⁹ where they compared tenecteplase to conventional anticoagulation. They found that there were decreased rates of hemodynamic decompensation in patients receiving tenecteplase, but the rates of hemorrhagic stroke and major bleeding events were increased, especially in patients above 75 years of age. The same findings were echoed in a meta-analysis performed by Chatterjee et al,³⁰ where they compared 8 studies in patients with intermediate-risk PE. There was an overall mortality benefit in patients treated with thrombolytics that was offset by higher rates of intracranial and other major bleeding events in patients over the age of 65.

Some have advocated the use of half-dose thrombolytics as opposed to conventional doses in these intermediate-risk patients. This is because the lung is the only organ receiving 100% of the cardiac output and there is no dose attrition. Thus, there is a potential to minimize bleeding risk while preserving the benefits of thrombolytics.

A small trial done by Wang et al³¹ compared low-dose intravenous recombinant tissue plasminogen activator (rtPA) to conventional doses in patients with intermediate- and high-risk PE. No differences were shown in outcomes (right ventricular dysfunction and pulmonary artery obstruction on CT angiogram). There was less bleeding in the group receiving low-dose rtPA but it was not statistically significant. Further studies are clearly needed in this area.

The treatment for high-risk PE is straightforward if there are no major contraindications to anticoagulation. The waters become murky when treating intermediate-risk PE. Based on the current data, treatment decisions have to be individualized and extreme caution needs to be exercised while giving thrombolytics in patients 65 years and older in this intermediate-risk group. The European Society of Cardiology recommends thrombolytics in patients with right ventricular dysfunction and elevation of biochemical markers (troponins or BNP).²³

Catheter-directed thrombolysis (CDT). CDT has the theoretical advantage of delivering thrombolytic medication directly to the site of thrombosis, while using a lower dose with less potential for bleeding. There is only 1 trial evaluating the role of CDT in intermediate-risk PE, which showed that CDT was superior to heparin alone in reversing right ventricular dilation at 24 hours with no significant increase in bleeding events.³²

A meta-analysis was performed by Kuo et al,³³ evaluating the role of CDT in high-risk PE. A total of 35 studies were included. The primary endpoints were resolution of hemodynamic instability and hypoxemia, and a resolution in mortality. Their pooled success rate was 86.5% with a rate of 7.9% for minor complications and 2.4% for major complications. Most studies included had very small sample sizes, usually less than 20 patients. Most complications were seen with the usage of the AngioJet rheolytic thrombectomy system, which had subsequently received a Black Box Warning from the FDA. In this meta-analysis, the rates of complications were less than those seen with thrombolytics. However, there were no trials directly comparing CDT and thrombolytics in high-risk PE.

Surgical embolectomy. One of the largest case series involving 47 patients who had undergone surgical embolectomy was published by Leacche et al.³⁴ The most common indication for surgery was a contraindication to thrombolysis, while the next one on the list was right ventricular dysfunction. They performed surgery on patients with both high- and intermediate-risk PE. Actuarial survival at the end of 1 and 3 years of follow-up was 86% and 83%, respectively. This study reported higher success rates than previously described, which may have been due to the fact that they also operated on patients with intermediate-risk PE.

Another study evaluated surgical embolectomy versus thrombolytic therapy in 80 patients.³⁵ The early mortality rate was not statistically different between the 2 groups, but the group that underwent surgery had less major bleeding events, a statistically significant piece of data. One interesting finding that came out of this study was that the right ventricular to left ventricular (RV/LV) diameter ratio in the surgical group was 1.66, while in the thrombolysis group, it was 1.44. Patients who underwent surgery after failed thrombolysis showed a RV/LV ratio of 1.63. Based on this data, the authors suggest that a surgical option be explored in patients with a RV/LV ratio >1.5.

CDT and surgical embolectomy certainly are viable options but thrombolysis remains the gold standard in the treatment of high-risk PE. Considerable expertise and resources are needed for CDT and surgery, while anyone can administer systemic thrombolytics. In most cases, there is not enough time to pursue treatment options other than thrombolysis once the patient is hemodynamically unstable. For these reasons and more, both the American and European societies recommend thrombolysis as the first-line of treatment. If that fails, or if the patient has certain contraindications, it is sensible to begin other treatment options.

Conclusion
PE is a challenging disease to diagnose which carries a substantial amount of morbidity and mortality. Once diagnosed, there are a myriad of treatment options available. Considerable expertise and knowledge about the existing literature is needed to make the correct decisions, especially when dealing with intermediate- and high-risk PE. While dealing with low-risk PE, the most daunting aspect is to figure out the duration of anticoagulation, especially in cases of unprovoked PE.

A version of this article originally appeared in the May 2015 issue of Consultant with the title, “Treatment Options in Pulmonary Embolism with a Focus on Anticoagulation.”

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