Challenging the Standard of Care: Emerging Concepts in Treatment and Prevention of VTE

Educational Objectives

After completing the activity, the clinician will be better able to detail recent changes in our understanding of and treatments for venous thromboembolism.

Summary

Interviewer: Christopher M. Kramer, MD, FACC

Take-home Messages:

• Venous thromboembolism (VTE), which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), continues to be a major cause of morbidity and mortality among hospitalized patients.
• Newer anticoagulants may mark a landmark change in the treatment of VTE.
• The duration of anticoagulation therapy has changed in recent years, although the appropriate duration of anticoagulant treatment after the first unprovoked VTE remains unclear.

In 2008, Steven K. Galson, MD, MPH, issued the Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism.¹ At the time, DVT/PE was estimated to affect 350,000 to 600,000 people in the United States each year, leading to 100,000 to 180,000 deaths annually. More recent data suggest a possible annual mortality rate of 465,715 for DVT and 295,982 for PE.² Of the PE deaths, only 7% were diagnosed antemortem, 34% were sudden fatal PE, and 59% followed undiagnosed PE.

VTE is a chronic disease with episodic recurrence; in the absence of long-term anticoagulation, ≈30% of patients develop recurrence within the next 10 years. Important to know: that second event usually is clinically more severe than the initial event. Recurrence rate peaks in the first 6 months after a first event, then decreases slowly to stabilize after 3 years, remaining at about 2% per patient-year up to 10 years after the acute event. Pulmonary embolism tends to recur as PE and DVT as DVT.

Rethinking VTE

VTEs are now considered part of a panvascular syndrome that also includes myocardial infarction and stroke. Therefore, Samuel Z. Goldhaber, MD, head of vascular medicine and director of the Thrombosis Research Group at Brigham and Women’s Hospital in Boston, notes it may no longer be viable to think of VTE as a “red-clot” disease and MI and stroke as “white-clot” diseases. Autopsy studies of patients who died from PE show clots that are filled with red cells and polymorphonuclear leukocytes, as well as activated platelets that have a lot of inflammatory mediators ready to burst. Thus, it is mixed red and white clot disease.

It had been thought that VTE shares many risk factors with ischemic heart disease, among them smoking, hypertension, diabetes, and high cholesterol. That may be true, although there has been some contradictory evidence. A report from ARIC (Atherosclerosis Risk in Communities) showed that risk of VTE over 15.5 years (237,375 person-years) was associated with higher body mass index and current smoking, but not with other risk factors for cardiovascular disease.³ Another big contributing factor: a family history of VTE is associated with 2- to 3-fold increased odds of VTE, irrespective of identified known predisposing genetic factors. Inflammatory diseases, such as psoriasis, ulcerative colitis, and rheumatoid arthritis, can also increase the risk of PE and DVT. Even the inflammatory mediators that help preserve red blood cells so they can be transfused from a blood bank can increase the risk of PE and DVT. Stasis and hypercoagulability are still factors; the message now is that they are not alone — many factors contribute to risk for PE and DVT.

New Guidelines, Better Options

Given new treatment options, updated guidelines recently were released by the American College of Chest Physicians, specifically reviewing antithrombotic therapy for venous thromboembolism.⁴ In addition, 2016 saw new comprehensive clinical guidance on treatment of VTE developed by the Anticoagulation Forum.⁵ Those guidelines include 12 manuscripts focused on the epidemiology and management of VTE, with a particular emphasis on management employing drugs — both traditional agents and the more recently approved non-vitamin K oral anticoagulants (NOACs). (Rather than citations for all 12 papers, here is a link to the table of contents: https://link.springer.com/journal/11239/41/1/page/1.)

The availability of NOACs, which can be administered in fixed doses without laboratory monitoring and dose adjustment, is a major landmark in the treatment of VTE. As noted in a recent State-of-the-Art review paper in JACC, evidence suggests rivaroxaban, apixaban, edoxaban (antifactor Xa agents), and dabigatran (an antithrombin agent) are noninferior and probably safer than conventional anticoagulation therapy (low-molecular-weight heparin followed by vitamin K antagonists).⁶ These favorable results have been confirmed in specific patient subgroups, such as the elderly and fragile. However, it should be noted here that some patients, such as those with cancer or with intermediate- to high-risk PE, were underrepresented in the phase III trials.

Anticoagulant treatment is usually withdrawn after 3 months in patients with VTE associated with major temporary risk factors (e.g., surgery, trauma) but are continued indefinitely in the case of VTE recurrence or in patients with cancer-associated thromboembolism. What about the duration of anticoagulant treatment after a first unprovoked VTE (i.e., with no identifiable risk factors)? That is still unclear. In the JACC review, the author noted that in these patients, prolonging anticoagulation beyond the initial 3 months simply delays recurrences without actually reducing the risk for a recurrent event once anticoagulation is withdrawn.

According to Dr. Goldhaber, “Our emerging concept is that VTE is a chronic illness, like coronary disease or diabetes. It really requires lifelong management now. That includes attention to a heart-healthy lifestyle, including good nutrition and exercise, but it may also include consideration of extended-duration anticoagulation.”

Although associated with a reduced rate of bleeding complications, NOACs may still cause bleeding. To reduce these complications, emphasis should be on clinical history and patient education; plus, it is helpful to maintain a follow-up program to provide patients with clinical surveillance and efforts to optimize treatment adherence.

One recent lesson from the EINSTEIN CHOICE (Reduced-dosed Rivaroxaban in the Long-term Prevention of Recurrent Symptomatic Venous Thromboembolism) trial: rivaroxaban, at either a treatment dose (20 mg) or a thromboprophylactic dose (10 mg), was more effective than aspirin for the prevention of recurrent VTE among patients who were in equipoise for continued anticoagulation.⁷ The lower risk of a recurrent event among the patients who received rivaroxaban was significant, while patients on aspirin had an unacceptably high rate of recurrence. Importantly, the beneficial effects of rivaroxaban were equally evident with a standard or half dose, achieved with a rate of bleeding similar to that of aspirin. Bottom line, according to Dr. Goldhaber: aspirin should no longer be considered a good option for long-term protection against VTE.

One concern that may hold back wider use of these agents is a lack of a reversal agent. In October 2015, idarucizumab received expedited approval from the U.S. Food and Drug Administration (FDA) for reversal of the anticoagulant effects of dabigatran for emergency surgery/procedures or in the event of life-threatening or uncontrolled bleeding. As this issue of ACCEL was being completed, the FDA agreed to a second review of Portola Pharmaceuticals Inc.’s andexanet alfa (AndexXa) as a reversal agent for factor Xa inhibitors. The agency rejected Portola’s first submission, citing issues with the drug’s intended label, manufacturing, and postmarket clinical commitments. On August 15, 2017, the company said the FDA had accepted its resubmission and that a decision by the agency is expected by February 2, 2018.

Readings

1. Galson S. The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. Available at: https://www.ncbi.nlm.nih.gov/books/NBK44178/. Accessed August 18, 2017.

2. Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation 2017;135:e146-e603.

3. Wattanakit K, Lutsey PL, Bell EJ, et al. Association between cardiovascular disease risk factors and occurrence of venous thromboembolism: a time-dependent analysis. Thromb Haemost 2012;108:508-15.

4. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-52.

5. Ansell JE. Management of venous thromboembolism: clinical guidance from the Anticoagulation Forum. J Thromb Thrombolysis 2016;41:1-2.

6. Becattini C, Agnelli G. Treatment of Venous Thromboembolism With New Anticoagulant Agents. J Am Coll Cardiol 2016;67:1941-55. www.onlinejacc.org/content/67/16/1941

7. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of Venous Thromboembolism. N Engl J Med 2017;376:1211-2.

Disclosures

Samuel Z. Goldhaber, MD, FACC
Bayer AG (C); Bristol-Myers Squibb Co (C,G); Boeringer Ingelheim GmbH (C); DAIICHI SANKYO CO Ltd (C,G); Janssen Global Services Inc (C); Portola Pharmaceuticals Inc (C); BTG plc (G)

Interviewer: Christopher M. Kramer, MD, FACC
Abbott (C); Regeneron (G)

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

AC491021

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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