The American College of Chest Physicians has provided evidenced-based guidelines for clinicians to use for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) for the past 30 years.

Since their previous publication, Antithrombotic Therapy 9th Edition (AT9) in 2012, we have seen an expansion in our therapeutic options as multiple non-vitamin K direct oral anticoagulants (DOACs) hit the market and entered the acceptance in daily practice due to their ease of use and lack of need for regular hematologic testing.^[1] Earlier this year in February, the CHEST physicians released their updated Antithrombotic Therapy 10th Edition (AT10). The goal of this article is to highlight the changes made in the new guidelines.^[2]

Non-Vitamin K aral anticoagulantsas

First-Line Treatment of DVT and PE Length of anticoagulation has not changed with AT10. Patients with a first-time proximal DVT or PE with a transient risk factor should be treated with anticoagulation for three months. For patients with unprovoked DVT or PE with a low or moderate bleeding risk, extended anticoagulation is recommended. Similarly, for those with a second unprovoked DVT or PE, indefinite anticoagulation is recommended.

In AT10, the first-line recommended anticoagulant therapy includes dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). The one exception is in patients with cancer-associated thrombosis. In this subset, AT10 recommends LMWH over VKA or DOACs with extended therapy.

Their recommendation is a result of four new randomized trials comparing DOAC versus VKA for acute and long-term treatment of venous thromboembolic event (VTE), which ultimately concluded that DOAC offer similar risk reduction for recurrent VTE, while offering a lower risk of bleeding, particularly intracranial bleeding, when compared with VKA therapy.^[3-6] The biggest hesitation for patient or physician adoption of NOACs has been the lack of effective reversal agents.

This will likely be a temporary problem as the Federal Drug Administration (FDA) is beginning to approve reversal agents. The first was idarucizumab (Praxbind), which the FDA approved for the reversal of dabigatran in patients requiring emergent surgery or who are experiencing serious uncontrolled bleeding. Factor Xa inhibitor antidotes are similarly being studied. And exanet alpha is being evaluated through the ANNEXA-4 study, with promising preliminary results, and while its approval was recently delayed by the FDA, we should see an applicable antidote in the not-so-far future.

For cancer-associated thrombosis, only indirect comparisons are available between LMWH and NOACs, from which the CHEST physicians decided to keep the same recommendation of LMWH as first-line therapy in this population. For patients who develop recurrent DVT or PE while on anticoagulation, AT10 gives a GRADE 2C suggestion to either switch to LMWH or give a higher dose LMWH if already on it.

The rationale, albeit based on low quality evidence and indirect comparisons, is that occult cancer or yet-to-be diagnosed hypercoagulability may attribute to unexplained recurrence and, in these patients, LMWH may be more effective than NOAC or VKA in patients with recurrent VTE.

Role of aspirin in DVT and PE management

For the first time, the CHEST physicians have included a GRADE 2B suggestion that for patients with an unprovoked proximal DVT or PE who have completed their three-month treatment and are stopping anticoagulation that do not have a contraindication, aspirin should be started indefinitely as extended treatment.

Their suggestion is based on two randomized trials comparing aspirin to placebo as extended therapy in patients who have completed three to 18 months of anticoagulation for unprovoked first-time DVTs.^[7],[8] The results demonstrated a 1/3 reduction in the aspirin-treated cohort. AT10 does make a note that aspirin is inferior to anticoagulation in extended therapy for recurrence. As such, aspirin as the extended therapy for patients should be reserved for those patients refusing extended anticoagulation, or for those with increased risk for bleeding.

Isolated distal DVTs

Recommendations for isolated DVTs remains the same. Patients with acute isolated distal DVTs that are symptomatic should be therapeutically anticoagulated, while asymptomatic patients should be monitored with serial imaging in two weeks. If proximal propagation is noted at follow-up imaging, the patient should be anticoagulated. The choice of anticoagulants is the same as for proximal DVT, with NOACs being the first-line treatment over LMWH or VKA.

No more compression stockings for acute DVT?

AT9 recommended routine use of compression stockings following acute DVT as prevention for post-thrombotic syndrome (PTS). Since then, Kahn et al. published a large trial of 806 patients randomized to elastic compression versus placebo compression. Surprisingly, their study found that incidence of PTS was comparable in the two groups (14.2% in compression vs. 12.7% in placebo, p=NS).^[9] As such, AT10 no longer recommends routine compression stockings to prevent PTS. While compression stockings may not prevent PTS, several physicians still advocate their use as they can reduce symptoms of acute or chronic DVT.

Changes in the treatment of PEs

With increased cross-sectional imaging, more subsegmental PEs are being incidentally identified. Many of these patients are asymptomatic and have a lower risk of recurrent VTE than patients who present with larger, clinically significant PEs. AT10 addresses this with a new GRADE 2C suggestion that in patients with a subsegmental PE without DVT, anticoagulation should only be reserved for those who have a high risk for recurrent VTE. All patients should receive bilateral venous duplex examinations to evaluate for DVTs.

In addition, AT10 recommends that for patients with acute PE who are compliant, clinically stable and feel well, and who do not have contraindication to anticoagulation, home or early discharge protocols with outpatient therapy is acceptable. This recommendation must be evaluated against the physician’s judgment. Patients with any presence of right ventricular strain or increased cardiac biomarker levels should not be treated as outpatient and require closer monitoring in the hospital.

Reducing the pulmonary clot burden

The indication for systemic thrombolysis remains the same in patients with acute PE and hypotension (massive PE) who do not have a high bleeding risk—systemic thrombolytic therapy is recommended. In patients with acute PE who do not have associated hypotension (low risk or sub-massive PE), AT10 recommends against systemic thrombolysis (GRADE 1B).

The CHEST physicians do make note that patients who are not clinically hypotensive but are notably deteriorating (persistent tachycardia, increased jugular venous pressure, worsening gas exchange, signs of shock), systemic thrombolytic therapy is indicated (GRADE 2C).

Systemic thrombolysis has been evaluated through multiple trials, which demonstrate that in the setting of massive PEs, systemic thrombolysis leads to significant reduction in overall mortality. The results were less clear in the setting of submassive PEs, with some mortality rates even increasing following lytic therapy.

But while there is theoretical benefits of smaller overall thombolytic doses and decreased risk of systemic bleeding, AT10 does not yet recommend catheter-based thrombus removal over systemic thrombolysis due to lack of definitive evidence. But the real-world experience is continuing to grow. Kuo et al. performed a meta-analysis of catheter-directed therapy (CDT) for the treatment of massive PEs, and reported a pooled clinical success rate of 86.5%, with a major procedural complication rate of 2.4%.^[10]

Additionally, the initial results from the multi-center, prospective Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT) registry evaluating patients treated with CDT were promising, with good clinical success in 97.3% of patients with submassive PEs and 85.7% with massive PEs. Notably, of the 101 patients treated in the registry, there were no intracranial hemorrhage or major bleeds within 30 days.^[11]

AT10 does make the recommendation that in patients who have a high risk of bleeding, have failed systemic thrombolysis, or are too unstable to give systemic thrombolysis a chance to take effect, catheter-assisted thrombus removal is recommended when expertise and resources are available (GRADE 2C).

Finally, AT10 makes a GRADE 2C suggestion that in select patients with chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary thromboendarterectomy should be performed if done by an experienced team.

Conclusion

The CHEST physicians have provided updated guidelines to the treatment of DVTs and PE to include emerging medications. With increasing evidence, DOACs have become first-line therapies for the treatment of VTE. The newly-approved and soon-to-be approved antidotes will allow effective reversal of DOACs in incidences of unwanted bleeding.

While some of the recommendations (or recommendations against) in AT10 are based on low quality evidence, more studies should help elucidate future therapies. In particular, as more physicians become familiar and facile with the utilization of catheter-based therapies for DVT and PE, we may see adjusted guidelines that advocate for CDT versus systemic thrombolysis in the treatment of massive and submassive PEs.

References:

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2. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JR, Wells P, Woller SC, Moores L. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-52.
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8. Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation. 2014;130(13):1062-1071.
9. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebocontrolled trial. Lancet. 2014;383(9920):880-888.
10. Kuo WT1, Gould MK, Louie JD, Rosenberg JK, Sze DY, Hofmann LV. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol. 2009 Nov;20(11):1431-40.
11. Kuo WT, Banerjee A, Kim PS, DeMarco FJ Jr, Levy JR, Facchini FR, Unver K, Bertini MJ, Sista AK, Hall MJ, Rosenberg JK, De Gregorio MA. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry. Chest. 2015 Sep;148(3):667-73.