In early 2016, the latest version of the widely read evidence-based guidelines for the treatment of venous thromboembolism (VTE), sponsored by the American College of Chest Physicians (ACCP) was published in the journal Chest.1 In this Mini Review, I will highlight some of the clinical recommendations that are most relevant to hematologists.
As in previous iterations of these guidelines, the authors grade each recommendation depending on two factors: the lopsidedness of the risk-benefit tradeoff and the strength of the supporting evidence. The strongest possible recommendation is graded “1A,” where the “1” indicates that the risk-benefit tradeoffs are such that most patients and physicians would, in light of the evidence, choose to follow the recommendation, and the “A” indicates that the quality of evidence on which the recommendation is based is high (e.g., more than one randomized controlled trial showing a similar treatment effect). At the opposite extreme, a “2C” recommendation would correspond to an intervention for which different patients or physicians see the risk-benefit tradeoffs differently and for which the quality of the evidence is low (e.g., data from an observational, noncontrolled study).
“For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over Vitamin K Antagonist (VKA) therapy.”
This decision to suggest (albeit not strongly) that a direct oral anticoagulant (DOAC) be used preferentially over warfarin is important because many hematologists had been reluctant to choose this class of medications to treat deep vein thrombosis (DVT) or pulmonary embolism (PE). The authors of this guideline, citing numerous large randomized controlled trials that compared DOACs to warfarin in both atrial fibrillation and VTE, explain that their preference for DOACs is based on the evidence that DOACs are as effective as warfarin but cause less bleeding (especially intracranial hemorrhage). They mention the increased convenience (no anticoagulation monitoring and essentially no dietary interactions) afforded by this class of medications. It is noteworthy that the authors made this recommendation despite the fact that, at the time the guideline was written, no reversal agent for any of the factor Xa inhibitors was approved for use. The authors reinforced the need to incorporate a patient’s preferences into the final decision about treatment, and they may have chosen a strength of “2B” (rather than “1B”) partly to recognize the financial burden that DOACs can present for many patients.
“For VTE and cancer, we suggest LMWH [low molecular-weight heparin] over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C).”
Although prescribing a DOAC to a patient with cancer-associated VTE would not be an “off-label use” in the United States, this recommendation reflects the lack of studies comparing DOACs to long-term LMWH, the current standard of care in this setting. At least one randomized controlled trial of a DOAC (edoxaban) versus LMWH (dalteparin) is underway.2
“In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and a (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B).”
Table. Factors Associated with an Increased Risk of Bleeding on Warfarin*
| Older age |
| Previous bleeding |
| Renal failure |
| Liver failure |
| Thrombocytopenia |
| Previous stroke |
| Diabetes |
| Anemia |
| Antiplatelet therapy |
| Poor anticoagulant control |
| Comorbidity and reduced functional capacity |
| Recent surgery |
| Frequent falls |
| Alcohol abuse |
| Nonsteroidal anti-inflammatory drug |
| Older age |
| Previous bleeding |
| Renal failure |
| Liver failure |
| Thrombocytopenia |
| Previous stroke |
| Diabetes |
| Anemia |
| Antiplatelet therapy |
| Poor anticoagulant control |
| Comorbidity and reduced functional capacity |
| Recent surgery |
| Frequent falls |
| Alcohol abuse |
| Nonsteroidal anti-inflammatory drug |
*Adapted from Kearon et al.1 It is unknown which of these factors will be associated with an increased risk of bleeding among patients treated with other anticoagulants (e.g., low molecular-weight heparin or direct oral anticoagulants).
This recommendation, unchanged from the prior version of these guidelines, highlights the importance of determining whether a clot was provoked or unprovoked when determining duration of anticoagulant therapy. Although the authors are recommending that many VTE patients receive “extended” therapy without a stop date, the absence of the phrase “lifetime anticoagulation” is conspicuous, and the authors emphasize the need to periodically re-assess the risks and benefits of anticoagulation in all such patients. Some of the factors that have been independently associated with an increased risk of major bleeding on warfarin are listed in the Table. The authors suggest that for patients with unprovoked VTE who have none or one of these bleeding risk factors, the risk of ongoing anticoagulation will likely be outweighed by the benefit.
“For DVT, we suggest not using compression stockings routinely to prevent PTS [post-thrombotic syndrome].”
Prior iterations of these guidelines had suggested that compression stockings be used, based on observational studies that were subject to bias. The new recommendation against the use of these stockings reflects the negative result of a randomized trial in which compression stockings were compared to “sham” stockings.3
“In most patients with acute PE not associated with hypotension, we recommend against systemically administered thrombolytic therapy (Grade 1B).”
This affirmation of a recommendation from the prior guidelines is based, for the most part, on the Pulmonary Embolism Thrombolysis trial, which randomly assigned 1,006 patients with PE and right ventricular dysfunction to tenecteplase and heparin, or to heparin therapy alone (with placebo).4 Although thrombolytic therapy reduced the risk of hemodynamic collapse, it also increased the risk of major (including intracranial) bleeding. The authors of the present guideline concluded that this new evidence was consistent with what had been demonstrated in prior studies: for most PE patients without hypotension, thrombolytic therapy does not confer a net benefit over anticoagulation alone. In associated comments, the authors acknowledged that the PE patients without hypotension who have signs of significant cardiopulmonary impairment will be best managed in a setting where any deterioration can be detected rapidly. Indeed they suggest that a patient with low bleeding risk who deteriorates while on anticoagulant treatment should receive systemically administered thrombolytic therapy.
References
Competing Interests
Dr. Garcia has acted as a consultant for and/or received research funding from Boehringer Ingelheim, Janssen, Daiichi Sankyo, Pfizer, and Bristol Meyers Squibb.
